Gastroenterology Fellowship and Postdoctoral Training in Omics and Statistics-Part I: Why Is It Needed?

A multitude of federally and industry-funded efforts are underway to generate and collect human, animal, microbial, and other sources of data on an unprecedented scale; the results are commonly referred to as "big data." Often vaguely defined, big data refers to large and complex datasets consisting of myriad datatypes that can be integrated to address complex questions. Big data offers a wealth of information that can be accessed only by those who pose the right questions and have sufficient technical knowhow and analytical skills. The intersection comprised of the gut-brain axis, the intestinal microbiome and multi-ome, and several other interconnected organ systems poses particular challenges and opportunities for those engaged in gastrointestinal and liver research. Unfortunately, there is currently a shortage of clinicians, scientists, and physician-scientists with the training needed to use and analyze big data at the scale necessary for widespread implementation of precision medicine. Here, we review the importance of training in the use of big data, the perils of insufficient training, and potential solutions that exist or can be developed to address the dearth of individuals in GI and hepatology research with the necessary level of big data expertise.

Gastroenterology Fellowship and Postdoctoral Training in Omics and Statistics-Part II: How Can It Be Achieved?

Data are being generated, collected, and aggregated in massive quantities at exponentially increasing rates. This "big data," discussed in depth in the first section of this two-part series, is increasingly important to understand the nuances of the gastrointestinal tract and its complex interactions and networks involving a host of other organ systems and microbes. Creating and using these datasets correctly requires comprehensive training; however, current instruction in the integration, analysis, and interpretation of big data appears to lag far behind data acquisition. While opportunities exist for those interested in acquiring the requisite training, these appear to be underutilized, in part due to widespread ignorance of their existence. Here, to address these gaps in knowledge, we highlight existing big data learning opportunities and propose innovative approaches to attain such training. We offer suggestions at both the undergraduate and graduate medical education levels for prospective clinical and basic investigators. Lastly, we categorize training opportunities that can be selected to fit specific needs and timeframes.

Inflammatory Bowel Disease-Associated Arthritis Is Associated with Concomitant Autoimmune and Inflammatory Disorders.

BACKGROUND: Extraintestinal Manifestations (EIMs) are a common and potentially debilitating complication of Inflammatory Bowel Diseases (IBD), sometimes requiring additional treatment beyond those used to control intestinal disease. IBD-associated arthritis (IAA), a form of spondyloarthritis, is associated with several factors including disease location, sex, and IBD type. However, much remains unknown about other clinical factors predicting development of EIMs. Our goal was to identify additional factors associated with IAA. METHODS: Participants in the LOCATION-IBD cohort were included in this analysis. We performed univariate and multivariate analysis of demographics, clinical data, and patient-reported outcomes data. RESULTS: The LOCATION-IBD cohort included 182 participants with (n = 53) and without (n = 110) joint EIMs and with joint pain of unclear etiology (n = 19). In a multivariate analysis comparing those with and without joint EIMs, female sex (OR = 2.5, p = 0.014), the presence of concomitant autoimmune and inflammatory disorders (OR = 2.5, p = 0.038), and Crohn's disease (OR = 2.9, p = 0.026) were associated with the presence of joint EIMs. CONCLUSION: This analysis reveals patients with IAA are more likely to have concomitant autoimmune disorders. Further studies are needed to confirm this association, understand the mechanisms underlying the common pathogenesis of these concurrent disorders, and evaluate their impact on the treatment of IAA.

Big Data in Gastroenterology Research.

Studying individual data types in isolation provides only limited and incomplete answers to complex biological questions and particularly falls short in revealing sufficient mechanistic and kinetic details. In contrast, multi-omics approaches to studying health and disease permit the generation and integration of multiple data types on a much larger scale, offering a comprehensive picture of biological and disease processes. Gastroenterology and hepatobiliary research are particularly well-suited to such analyses, given the unique position of the luminal gastrointestinal (GI) tract at the nexus between the gut (mucosa and luminal contents), brain, immune and endocrine systems, and GI microbiome. The generation of 'big data' from multi-omic, multi-site studies can enhance investigations into the connections between these organ systems and organisms and more broadly and accurately appraise the effects of dietary, pharmacological, and other therapeutic interventions. In this review, we describe a variety of useful omics approaches and how they can be integrated to provide a holistic depiction of the human and microbial genetic and proteomic changes underlying physiological and pathophysiological phenomena. We highlight the potential pitfalls and alternatives to help avoid the common errors in study design, execution, and analysis. We focus on the application, integration, and analysis of big data in gastroenterology and hepatobiliary research.

Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans.

BACKGROUND: The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRM S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization. RESULTS: We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses. CONCLUSIONS: Aging influences tissue resident TM S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging. TRIAL REGISTRATION: This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).

Effect of the live oral attenuated typhoid vaccine, Ty21a, on systemic and terminal ileum mucosal CD4+ T memory responses in humans.

Our current understanding of CD4+ T-cell-mediated immunity (CMI) elicited by the oral live attenuated typhoid vaccine Ty21a is primarily derived from studies using peripheral blood. Very limited data are available in humans regarding mucosal immunity (especially CD4+ T) at the site of infection (e.g. terminal ileum; TI). Here using multiparametric flow cytometry, we examined the effect of Ty21a immunization on TI-lamina propria mononuclear cells (LPMC) and peripheral blood CD4+ T memory (TM) subsets in volunteers undergoing routine colonoscopy. Interestingly, we observed significant increases in the frequencies of LPMC CD4+ T cells following Ty21a immunization, restricted to the T effector/memory (TEM)-CD45RA+ (TEMRA) subset. Importantly, Ty21a immunization elicited Salmonella Typhi-responsive LPMC CD4+ T cells in all major TM subsets [interferon (IFN)γ and interleukin (IL)-17A in TEM; IFNγ and macrophage inflammatory protein (MIP)1ß in T central/memory (TCM); and IL-2 in TEMRA]. Subsequently, we analyzed LPMC S. Typhi-responsive CD4+ T cells in depth for multifunctional (MF) effectors. We found that LPMC CD4+ TEM responses were mostly MF, except for those cells exhibiting the characteristics associated with IL-17A responses. Finally, we compared mucosal to systemic responses and observed that LPMC CD4+S. Typhi-specific responses were unique and distinct from their systemic counterparts. This study provides the first demonstration of S. Typhi-specific CD4+ TM responses in the human TI mucosa and provides valuable information about the generation of mucosal immune responses following oral Ty21a immunization.

Correction to: Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.

This manuscript is a secondary analysis of a large multicenter randomized controlled trial. The primary study is Cross RK et al., A Randomized Controlled Trial of TELEmedicine for patients with Inflammatory Bowel Disease (TELE-IBD). Am J Gastroenterol, 2019 Mar.

Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.

INTRODUCTION: Limitations in inflammatory bowel disease (IBD) care necessitate greater patient activation and self-efficacy, measures associated with positive health outcomes. METHODS: We assessed change in patient activation and general self-efficacy from baseline to 12 months through our TELEmedicine for IBD trial, a multicenter, randomized controlled trial consisting of a web-based monitoring system that interacts with participants via text messaging. A total of 222 adults with IBD who had experienced an IBD flare within 2 years prior to the trial were randomized into either a control arm that received standard care (SC) or an intervention arm that completed self-testing through the TELE-IBD system every other week (EOW) or weekly (W). RESULTS: Changes in self-efficacy scores were not significantly different between control and experimental groups. Patient activation scores were significantly different between standard care and the TELE-IBD EOW group only (p = 0.03). CONCLUSIONS: Use of remote monitoring did not improve self-efficacy or patient activation compared to routine care.

A Randomized Controlled Trial of TELEmedicine for Patients with Inflammatory Bowel Disease (TELE-IBD).

INTRODUCTION: Telemedicine has shown promise in inflammatory bowel disease (IBD). The objective of this study was to compare disease activity and quality of life (QoL) in a 1-year randomized trial of IBD patients receiving telemedicine vs. standard care. METHODS: Patients with worsening symptoms in the prior 2 years were eligible for randomization to telemedicine (monitoring via texts EOW or weekly) or standard care. The primary outcomes were the differences in change in disease activity and QoL between the groups; change in healthcare utilization among groups was a secondary aim. RESULTS: 348 participants were enrolled (117 control group, 115 TELE-IBD EOW, and 116 TELE-IBD weekly). 259 (74.4%) completed the study. Age was 38.9 ± 12.3 years, 56.6% were women, 91.9% were Caucasian, 67.9% had Crohn's disease (CD) and 42.5% had active disease at baseline. In CD, all groups experienced a decrease in disease activity (control -5.2 ± 5.0 to 3.7 ± 3.6, TELE-IBD EOW 4.7 ± 4.1 to 4.2 ± 3.9, and TELE-IBD weekly 4.2 ± 4.2 to 3.2 ± 3.4, p < 0.0001 for each of the groups) In UC, only controls had a significant decrease in disease activity (control 2.9 ± 3.1 to 1.4 ± 1.4, p = 0.01, TELE-IBD EOW 2.7 ± 3.1 to 1.7 ± 1.9, p = 0.35, and TELE-IBD Weekly 2.5 ± 2.5 to 2.0 ± 1.8, p = 0.31). QoL increased in all groups; the increase was significant only in TELE-IBD EOW (control 168.1 ± 34.0 to 179.3 ± 28.2, p = 0.06, TELE-IBD EOW 172.3 ± 33.1 to 181.5 ± 28.2, p = 0.03, and TELE-IBD Weekly 172.3 ± 34.5 to 179.2 ± 32.8, p = 0.10). Unadjusted and adjusted changes in disease activity and QoL were not significantly different among groups. Healthcare utilization increased in all groups. TELE-IBD weekly were less likely to have IBD-related hospitalizations and more likely to have non-invasive diagnostic tests and electronic encounters compared to controls; both TELE-IBD groups had decreased non-IBD related hospitalizations and increased telephone calls compared to controls. DISCUSSION: Disease activity and QoL, although improved in all participants, were not improved further through use of the TELE-IBD system. TELE-IBD participants experienced a decrease in hospitalizations with an associated increase in non-invasive diagnostic tests, telephone calls and electronic encounters. Research is needed to determine if TELE-IBD can be improved through patient engagement and whether it can decrease healthcare utilization by replacing standard care.

Reduced Imaging Radiation Exposure and Costs Associated with Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

BACKGROUND: Radiation exposure from diagnostic imaging may increase cancer risk of Crohn's disease (CD) patients, who are already at increased risk of certain cancers. AIM: To compare imaging radiation exposure and associated costs in CD patients during the year pre- and post-initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: Adults were identified from a large US claims database between 1/1/2005 and 12/31/2009 with ≥ 1 abdominal imaging scan and 12 months of enrollment before and after initiating therapy with anti-TNF or corticosteroids. Imaging utilization, radiation exposure, and healthcare costs pre- and post-initiation were examined. RESULTS: Anti-TNF-treated patients had significantly fewer imaging examinations the year prior to initiation than corticosteroid-treated patients. Cumulative radiation doses before initiation were significantly higher for corticosteroid patients compared to anti-TNF patients (22.3 vs. 17.7 millisieverts, P = 0.0083). After therapy initiation, anti-TNF-treated patients had significantly fewer imaging examinations (2.9 vs. 5.2, P < 0.0001) and less radiation exposure (7.4 vs. 15.4 millisieverts, P <0.0001) than corticosteroid-treated patients in the follow-up period. Reductions in imaging costs adjusted for 1000 patient-years after initiation of therapy were - $275,090 and - $121,960 (P = 0.0359) for anti-TNF versus corticosteroid patients, respectively. CONCLUSIONS: This analysis demonstrated that patients treated with anti-TNF agents have fewer imaging examinations, less radiation exposure, and lower healthcare costs associated with imaging than patients treated with corticosteroids. These benefits do not account for additional long-term benefits that may be gained from reduced radiation exposure.

Racial differences in disease activity and quality of life in patients with Crohn's disease.

BACKGROUND: The existing literature on racial differences in Crohn's disease (CD) activity and quality of life (QOL) is limited and extrapolated from surrogate measures. AIM: The aim of our study was to compare objective markers of disease activity and QOL over time by race. STUDY: A clinical data repository of inflammatory bowel disease (IBD) patients at University of Maryland, Baltimore IBD Program, was used. CD patients from 2004 to 2009 were included if they had greater than or equal to two clinic visits with disease activity and QOL scores during the study period. Differences in disease activity and QOL were compared by race over time. RESULTS: A total of 296 patients with CD met inclusion criteria; of these, 19% (56/296) were African Americans (AA) and 81% (240/296) were Caucasian. Baseline disease activity and QOL scores did not differ by race (p > 0.05). Caucasians had a steady decline in disease activity and increase in QOL. AA experienced a similar pattern of change in disease activity and QOL scores over time; however, the declines were not statistically significant between groups. At each time point post-baseline, disease activity and QOL scores were similar between races. CONCLUSION: We found that Caucasian and AA patients with CD had similar disease activity and QOL scores at initial presentation and over time. Thus, AA do not represent a more severe subgroup of CD patients to treat. These findings have important implications for clinicians that care for patients with CD.

ExpLOring the role of the intestinal MiCrobiome in InflammATory bowel disease-AssocIated SpONdylarthritis (LOCATION-IBD).

Background: Inflammatory Bowel Disease (IBD)-associated arthritis is a frequent and potentially debilitating complication of IBD, that can affect those with or without active intestinal disease, and is often difficult to treat. The microbiome is known to play a role in IBD development and has been shown to be associated with inflammatory arthritis without concomitant IBD, but its role in IBD-associated arthritis is still unexplored. Further, disease localization is associated with development of IBD-associated arthritis, and stool compositional profiles are predictive of disease localization, yet mucosal location-specific microbiomes have not been well characterized. To address this gap in understanding, we designed a study (LOCATION-IBD) to characterize the mucosa-associated intestinal microbiome and metabolome in IBD-associated arthritis. Methods: Adults with an established diagnosis of IBD undergoing clinical colonoscopy between May of 2021 and February of 2023 were invited to participate in this study; those interested in participation who met inclusion criteria were enrolled. Prior to enrollment, participants were stratified into those with or without IBD-associated arthritis. All participants were interviewed and had clinical and demographic data collected, and 97.8% completed clinical colonoscopy with biopsy collection. Results and conclusion: A total of 182 participants, 53 with confirmed IBD-associated arthritis, were enrolled in this study, resulting in 1151 biopsies obtained for microbiome and metabolome analysis (median 6, mean 6.3 per participant). Clinical and demographic data obtained from the study population will be analyzed with microbiome and metabolome data obtained from biopsies, with the goal of better understanding the mechanisms underpinning the host-microbiome relationship associated the development of IBD-associated arthritis.

Update in the management of extraintestinal manifestations of inflammatory bowel disease.

Inflammatory bowel disease, comprised of Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Up to 40 % of patients with inflammatory bowel disease can develop inflammation in other organ systems of the body. These extraintestinal manifestations (EIM) can affect the musculoskeletal, ocular, mucocutaneous, and hepatobiliary systems. Symptoms related to EIM can result in impaired quality of life, and complications of EIM can lead to disfigurement, functional deficits, and even life-threatening organ dysfunction. Some EIM parallel the activity of IBD, and respond to treatment of the underlying disease. Others, however, follow an independent course and require targeted treatment.

Comparative effectiveness of anti-TNF agents for Crohn's disease in a tertiary referral IBD practice.

BACKGROUND: The three Food and Drug Administration (FDA)-approved anti-tumor necrosis factor drugs (anti-TNFs) for Crohn's disease (CD) have not been directly compared. AIM: To compare the efficacy of the three anti-TNFs for CD in clinical practice. METHODS: Retrospective review of patients initiated on anti-TNF between 2004 and 2008. Disease activity, quality of life, and remission rates were compared between groups over 1 year. RESULTS: Sixty patients with CD were initiated on anti-TNF from 2004 to 2008: 31 on infliximab (IFX) and 29 on adalimumab (ADA) or certolizumab pegol (CTZ). More patients in the ADA/CTZ scores group had prior exposure to anti-TNF (76 versus 10%, p < 0.01). Mean Harvey-Bradshaw Index (HBI) scores in the IFX group were lower than in the ADA/CTZ group at 12 months (2.72 ± 3.34 versus 5.63 ± 5.33, p = 0.03). At 12 months, more IFX patients were in remission compared with those on ADA/CTZ (88 versus 53%, p ≤ 0.01). Mean short inflammatory bowel disease questionnaire (SIBDQ) scores were not different between the IFX and ADA/CTZ groups at 12 months. Stratified analyses and logistic regression based on prior anti-TNF use did not show differences in remission rates at any time point post-baseline between groups. CONCLUSIONS: After adjustment for prior anti-TNF there was no difference in remission rates between the IFX and ADA/CTZ groups at any time point post-baseline. This suggests that differences between groups were accounted for by a higher rate of prior anti-TNF in the ADA/CTZ group. Our results should be reviewed with caution given the small sample size.

Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.

TELEmedicine for Patients With Inflammatory Bowel Disease (TELE-IBD) Does Not Improve Depressive Symptoms or General Quality of Life Compared With Standard Care at Tertiary Referral Centers.

BACKGROUND: Depression is common in patients with inflammatory bowel disease (IBD) and contributes to poor quality of life (QoL). The use of information technology for the remote management of patients with IBD is growing, but little is known about its impact on depressive symptoms (DS) and QoL. We aimed to evaluate the impact of telemedicine on DS and generic QoL in IBD patients. METHODS: We analyzed data from the Telemedicine for Patients with IBD (TELE-IBD) study. During this 12-month clinical trial, patients were randomized to receive text message-based telemedicine weekly (TELE-IBD W), every other week (TELE-IBD EOW), or to standard care. Depressive symptoms and QoL were assessed over time with the Mental Health Inventory 5 (MHI-5) and the Short Form 12 (SF-12), respectively. We compared the change in MHI-5 and SF-12 (with separate physical (PCS) and mental component summary (MCS) scores) between the study arms. RESULTS: A total of 217 participants were included in this analysis. After 1 year, there was no significant difference in the change in MHI-5 (TELE-IBD W +3.0 vs TELE-IBD EOW +0.7 vs standard care +3.4; P = 0.70), MCS (TELE-IBD W +1.4 vs TELE-IBD EOW +1.0 vs standard care +2.5; P = 0.89), and PCS scores (TELE-IBD W +0.4 vs TELE-IBD EOW +0.6 vs standard care +3.7; P = 0.06) between the groups. CONCLUSIONS: Text message-based telemedicine does not improve DS or QoL when compared with standard care in IBD patients treated at tertiary referral centers. Further studies are needed to determine whether telemedicine improves DS or QoL in settings with few resources.