Showing papers by "Ashwin N. Ananthakrishnan published in 2020"

Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases

Abstract: Genome-wide association studies (GWAS) are a valuable tool for understanding the biology of complex traits, but the associations found rarely point directly to causal genes. Here, we introduce a new method to identify the causal genes by integrating GWAS summary statistics with gene expression, biological pathway, and predicted protein-protein interaction data. We further propose an approach that effectively leverages both polygenic and locus-specific genetic signals by combining results across multiple gene prioritization methods, increasing confidence in prioritized genes. Using a large set of gold standard genes to evaluate our approach, we prioritize 8,402 unique gene-trait pairs with greater than 75% estimated precision across 113 complex traits and diseases, including known genes such as SORT1 for LDL cholesterol, SMIM1 for red blood cell count, and DRD2 for schizophrenia, as well as novel genes such as TTC39B for cholelithiasis. Our results demonstrate that a polygenic approach is a powerful tool for gene prioritization and, in combination with locus-specific signal, improves upon existing methods.

Complete histologic normalisation is associated with reduced risk of relapse among patients with ulcerative colitis in complete endoscopic remission

Abstract: BACKGROUND Clinical and endoscopic remission are treatment targets in ulcerative colitis (UC). The value of histologic healing in altering clinical outcomes among patients with complete endoscopic healing is not well established. AIM To quantify the association between histologic activity and clinical relapse among patients with UC who were in complete endoscopic remission. METHODS This study included patients with UC from a prospective registry who were in complete endoscopic remission. Histologic activity was quantified by a senior gastrointestinal pathologist. Histologic activity was defined as lack of normalisation (Geboes score > 0) as well as histologically active disease (Geboes score ≥2.1 and ≥3.1). The primary outcome was clinical relapse within 2 years. Multivariable regression adjusting for potential confounders examined the independent predictive value of histologic changes. RESULTS The study included 83 patients (51% women) (median age 44 years; median disease duration 11 years). Forty-one (49%) had complete histologic normalisation. Within two years, 26 (31%) experienced clinical relapse. Patients with complete histologic normalisation were less likely to experience relapse (5/41, 12%) compared to those without normalisation (21/42, 50%, P < 0.001) (multivariable OR 7.22, 95% confidence interval (CI) 2.48-24.70) by the Geboes score. The individual components of the Geboes score predictive of relapse were architectural changes (P = 0.03) and increased chronic inflammatory infiltrate (P < 0.001). CONCLUSIONS Complete histologic healing using the Geboes score was associated with reduced rates of clinical relapse among patients with UC in endoscopic remission.

Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.

Abstract: Background The prevalence of older adults with inflammatory bowel diseases (IBD) is increasing. Frailty is an important predictor of outcomes in many chronic disease states. The implications of frailty have not been well-delineated in IBD. Aims To report the prevalence of a frailty-associated diagnosis and determine the association between frailty and mortality in a cohort of IBD patients. Methods In a cohort of 11 001 IBD patients, we applied a validated definition of frailty using International Classification of Disease codes. We compared frail IBD patients to those without a frailty-related code ("fit"). We constructed multivariable logistic regression models adjusting for clinically pertinent confounders (age, gender, race, IBD type, follow-up, IBD-related surgery, ≥1 comorbidity in the Charlson comorbidity index [CCI], and immunosuppression use) to determine whether frailty predicts mortality. Results A total of 675 (6%) IBD patients had a frailty-related diagnosis. The prevalence of frailty increased with age, rising from 4% in 20-29 year olds to 25% in patients 90 years or older. The most prevalent frailty diagnosis was protein-energy malnutrition. The strongest predictors of frailty were non-IBD comorbidity, all-cause and IBD-related, hospitalisations. Frailty remained independently associated with mortality after adjusting for age, sex, duration of follow-up, comorbidity, need for IBD-related surgery and immunosuppression (OR: 2.90, 95% CI: 2.29-3.68). Conclusions Frailty is prevalent in IBD patients and increases with age. Frailty nearly triples the odds of mortality for IBD patients. Risk stratifying patients by frailty may improve outcomes.

Multi-"-Omics" Profiling in Patients With Quiescent Inflammatory Bowel Disease Identifies Biomarkers Predicting Relapse.

Abstract: Background: Inflammatory bowel diseases (IBD) are characterized by intermittent relapses, and their course is heterogeneous and unpredictable. Our aim was to determine the ability of protein, metabolite, or microbial biomarkers to predict relapse in patients with quiescent disease. Methods: This prospective study enrolled patients with quiescent Crohn disease and ulcerative colitis, defined as the absence of clinical symptoms (Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2) and endoscopic remission within the prior year. The primary outcome was relapse within 2 years, defined as symptomatic worsening accompanied by elevated inflammatory markers resulting in a change in therapy or IBD-related hospitalization or surgery. Biomarkers were tested in a derivation cohort, and their performance was examined in an independent validation cohort. Results: Our prospective cohort study included 164 patients with IBD (108 with Crohn disease, 56 with ulcerative colitis). Upon follow-up for a median of 1 year, 22 patients (13.4%) experienced a relapse. Three protein biomarkers (interleukin-10, glial cell line–derived neurotrophic factor, and T-cell surface glycoprotein CD8 alpha chain) and 4 metabolomic markers (propionyl-L-carnitine, carnitine, sarcosine, and sorbitol) were associated with relapse in multivariable models. Proteomic and metabolomic risk scores independently predicted relapse with a combined area under the curve of 0.83. A high proteomic risk score (odds ratio = 9.11; 95% confidence interval, 1.90-43.61) or metabolomic risk score (odds ratio = 5.79; 95% confidence interval, 1.24-27.11) independently predicted a higher risk of relapse over 2 years. Fecal metagenomics showed an increased abundance of Proteobacteria (P = 0.0019, q = 0.019) and Fusobacteria (P = 0.0040, q = 0.020) and at the species level Lachnospiraceae_ bacterium_2_1_58FAA (P = 0.000008, q = 0.0009) among the relapses. Conclusions: Proteomic, metabolomic, and microbial biomarkers identify a proinflammatory state in quiescent IBD that predisposes to clinical relapse.

Microbiome-Based Biomarkers for IBD.

Abstract: Crohn disease and ulcerative colitis are complex immune-mediated diseases that are characterized by a heterogeneity in presentation and clinical course. Although various clinical covariates predict adverse outcomes in these patients, they are insufficiently informative. The gut microbiome likely plays a central role in the pathogenesis of these diseases. Consequently, microbiome-based biomarkers may play an important role in risk stratification and disease prediction. Initial cross-sectional studies showed a reduced gut microbial diversity in patients with Crohn disease or ulcerative colitis, a depletion of phyla with anti-inflammatory effects such as those belonging to Firmicutes, and an increased abundance of potentially pathogenic bacteria in specific disease phenotypes. Subsequent studies longitudinally tracking microbial changes and clinical outcomes have shown dynamic changes correlating with or predictive of disease activity and resistance to therapy. The development of multicenter cohorts using harmonized protocols is essential to robustly validate these biomarkers and facilitate the integration of their evaluation into clinical practice. .

Incidence and Predictors of Flares in the Postpartum Year Among Women With Inflammatory Bowel Disease.

Abstract: Background The postpartum period is marked by physiological and psychological stresses that may impact activity in inflammatory bowel disease. The predictors and outcomes of disease activity during this period have not been well characterized. Methods We performed a retrospective review of inflammatory bowel disease patients who underwent successful pregnancy and live birth at 2 referral institutions. Data on patient and disease factors including disease activity before and during pregnancy were abstracted from the medical records. We noted whether therapy was dose-reduced or stopped during pregnancy at each trimester and after delivery. Multivariable logistic regression of independent predictors of postpartum flare was performed, adjusting for relevant covariates. Results We identified a total of 206 eligible women (mean age, 33.2 years). Of these, 97 (47%) had a diagnosis of Crohn's disease, whereas the remainder had ulcerative colitis. Nearly half the women delivered vaginally (53%), and the rest delivered by Caesarean section (47%). In the entire cohort, 65 (31.6%) experienced a postpartum flare within the year after delivery. In multivariable analysis, development of a postpartum flare was predicted by disease activity during the third trimester (odds ratio [OR], 6.27; 95% confidence interval [CI], 2.81-17.27), therapy de-escalation during pregnancy (OR, 3.00; 95% CI, 1.03-8.68), and therapy de-escalation after pregnancy (OR, 4.43; 95% CI, 1.55-12.65). Postpartum disease flare was not related to disease type, duration of disease, or mode of childbirth. Conclusions One-third of women with inflammatory bowel disease may experience disease flare during the postpartum year. Continued optimization of therapy before, during, and after pregnancy is essential to prevent this morbidity.

Opportunistic Infections Are More Prevalent in Crohn's Disease and Ulcerative Colitis: A Large Population-Based Study.

Abstract: Background Opportunistic infections (OIs) are more common in patients with inflammatory bowel disease (IBD); however, there have been limited large-scale studies of OIs in IBD. We investigated the epidemiological characteristics of OI in Crohn's disease (CD) and ulcerative colitis (UC) using a large population-based database. Methods Data were collected from a commercial database (Explorys Inc., Cleveland, OH, USA) that provided electronic health records from 26 major integrated US health care systems from 1999 to March 2018. In this data set, we identified all CD and UC patients, based on Systemized Nomenclature of Medicine-Clinical Terms. Within these cohorts, we identified a variety of OIs and compared the prevalence rate of OI in individuals with IBD with that of controls (patients in the database between March 2013 and March 2018 without the diagnosis of IBD). Results Explorys included 153,290 patients with CD and 128,540 patients with UC between March 2013 and March 2018. The prevalence of OIs was 17.8% in CD, 19.2% in UC, and 7% in non-IBD controls. When compared with non-IBD controls, all OIs were more common in CD (prevalence ratio [PR], 2.54; 95% confidence interval [CI], 2.51-2.57) and UC (PR, 2.74; 95% CI, 2.71-2.77). Overall, viral infections were numerically more common, whereas bacterial infections had the highest PRs in CD and UC when compared with controls without IBD. Conclusions We found significantly higher rates of OI in IBD. Our study suggests the need for close follow-up of IBD patients to diagnose and provide vaccinations where applicable for prevention of infections.

Interval Colorectal Cancer in Inflammatory Bowel Disease: The Role of Guideline Adherence

Abstract: Factors associated with interval colorectal cancer (CRC) development in the inflammatory bowel disease (IBD) population remain unclear. Among a cohort of patients with interval CRC, we aimed to evaluate IBD characteristics, colonoscopy quality indicators, and surveillance guideline adherence. We performed a retrospective review of IBD- and non-IBD-associated interval CRCs diagnosed between January 2007 and December 2014 within a large US healthcare system. We evaluated risk factors for CRC among patients with IBD. We assessed adherence to surveillance guidelines according to the American Society for Gastrointestinal Endoscopy (IBD surveillance) and the US Multi-Society Task Force on Colorectal Cancer (polyp surveillance). We compared colonoscopy quality measures between patients with and without IBD. Among 5345 cases of colonic adenocarcinoma, we detected 15 IBD-associated cases of interval CRC and 230 non-IBD-associated cases of interval CRC. Compared to patients without IBD, IBD patients were younger (54.5 vs. 70.4 years; p < 0.0001) and experienced a shorter interval between index colonoscopy and CRC diagnosis (20.7 vs. 35.1 months; p = 0.0009). Fifty three percent (8/15) of interval CRCs in IBD patients were detected within surveillance guidelines. All IBD patients with interval CRC detected after guideline surveillance interval had high-risk features, including active inflammation, previous low-grade or indefinite dysplasia, multiple pseudopolyps on index colonoscopy, or a first-degree relative with CRC. There were no differences in colonoscopy quality measures between patients with and without IBD. This study stresses the importance of strict short-interval surveillance for IBD patients with high-risk features, including active inflammation on index colonoscopy.

Immune-mediated diseases and risk of Crohn's disease or ulcerative colitis: a prospective cohort study.

Abstract: BACKGROUND Although immune-mediated diseases (IMDs) including inflammatory bowel diseases (IBDs) are known to cluster, to what extent this is due to common environmental influences is unknown. AIM To examine the incidence of IBD in individuals with another IMD. METHODS We used data from the prospective Nurses' Health Study II cohort (1995-2017) to examine the effect of diagnoses of several common IMDs on subsequent risk of Crohn's disease (CD) or ulcerative colitis (UC) using Cox proportional hazards models, adjusting for detailed diet and lifestyle confounders. RESULTS We documented 132 cases of CD and 186 cases of UC over 2 016 163 person-years of follow-up (median age at IBD diagnosis 50 years). Compared to participants with no history of IMD, the HRs of CD for those with 1 and ≥ 2 IMDs were 2.57 (95% CI 1.77-3.74) and 2.74 (95% CI 1.36 to 5.49), respectively (Ptrend < 0.0001). This association was only modestly attenuated by adjustment for environmental risk factors (HR 2.35 and 2.46, respectively). The risk of UC was not increased, with multivariable-adjusted HRs of 1.22 (95% CI 0.85-1.76) and 1.33 (95% CI 0.67-2.65) for those with 1 and ≥ 2 IMDs, respectively, compared to those with none (Ptrend 0.16) (Pheterogeneity comparing CD and UC 0.037). Asthma, atopic dermatitis, psoriasis and rosacea were individually associated with higher risk of CD (HR ranging from 2.15 to 3.39) but not UC. CONCLUSIONS Individuals with one or more IMDs are at an increased risk for CD but not UC.

Estimating average treatment effects with a double-index propensity score

Abstract: We consider estimating average treatment effects (ATE) of a binary treatment in observational data when data-driven variable selection is needed to select relevant covariates from a moderately large number of available covariates X . To leverage covariates among X predictive of the outcome for efficiency gain while using regularization to fit a parametric propensity score (PS) model, we consider a dimension reduction of X based on fitting both working PS and outcome models using adaptive LASSO. A novel PS estimator, the Double-index Propensity Score (DiPS), is proposed, in which the treatment status is smoothed over the linear predictors for X from both the initial working models. The ATE is estimated by using the DiPS in a normalized inverse probability weighting estimator, which is found to maintain double robustness and also local semiparametric efficiency with a fixed number of covariates p. Under misspecification of working models, the smoothing step leads to gains in efficiency and robustness over traditional doubly robust estimators. These results are extended to the case where p diverges with sample size and working models are sparse. Simulations show the benefits of the approach in finite samples. We illustrate the method by estimating the ATE of statins on colorectal cancer risk in an electronic medical record study and the effect of smoking on C-reactive protein in the Framingham Offspring Study.

Phenotype and Natural History of Inflammatory Bowel Disease in Patients With Concomitant Eosinophilic Esophagitis.

Abstract: BACKGROUND The co-occurrence of autoimmune diseases is well recognized. Though studies have suggested that eosinophilic esophagitis (EoE) is more common in patients with inflammatory bowel diseases (IBD), whether co-occurrence of EoE modifies natural history of IBD is unknown. METHODS This was a retrospective case-control study at a referral center. Cases consisted of patients with IBD and EoE, with both diseases diagnosed using established criteria. Controls comprised patients with IBD without concomitant EoE. Two controls were selected per case and were matched for duration of IBD. Relevant covariates regarding disease presentation and natural history were extracted from the medical record and compared between the 2 groups. RESULTS A total of 95 IBD-EoE cases and 190 IBD controls were included in our study. The IBD-EoE group was diagnosed with IBD at a younger age than those with IBD alone (22.3 years vs 29.0 years; P < 0.001) and were more likely to be male (80.0% vs 45.8%; P < 0.001). There were no differences in medical or surgical therapy for IBD between the 2 groups. Among those with IBD-EoE, patients for whom IBD was diagnosed first presented more commonly with dysphagia (50.8% vs 26.9%; P = 0.04) and endoscopically had evidence of esophageal rings (50.0% vs 23.1%; P = 0.02) when compared with those where EoE was diagnosed first. CONCLUSION Patients with concurrent IBD-EoE are diagnosed at a younger age and more likely to be males but have similar natural history as those without EoE. There were differences in EoE phenotype based on whether the EoE or IBD was diagnosed first.

Disease and Treatment Patterns Among Patients With Pouch-related Conditions in a Cohort of Large Tertiary Care Inflammatory Bowel Disease Centers in the United States

Abstract: Background Gaps exist in our understanding of the clinical course of pouch-related disorders. Methods We evaluated baseline disease activity and longitudinal treatment patterns among patients with inflammatory conditions of the pouch. Results Among 468 patients with an ileal pouch-anal anastomosis (IPAA), 94 (20%) had acute pouchitis, 96 (21%) had chronic pouchitis, and 192 (41%) had Crohn disease of the pouch. Following an IPAA, 38% of patients were treated with a biologic and 11% underwent inflammatory bowel disease- or bowel-related surgery. Conclusions Treatment patterns after IPAA indicate that pouch-related disorders have a significant impact on individual patients and the healthcare system.

Impact of Diet on Risk of IBD

Abstract: Diet is an important factor influencing the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). Several recent prospective cohorts have suggested various dietary factors may play a role in modifying the risk of these diseases. These include an inverse association between dietary fiber, fruit or vegetable intake and risk of CD and n-3 polyunsaturated fatty acids and UC. In addition to macro-nutrients, dietary additives such as emulsifiers may also play a role.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study

Abstract: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. There was no difference in weight gain among the different biologic therapeutic classes.