E-cigarette Use and Disease Outcomes in Inflammatory Bowel Diseases: A Case-Control Study.

INTRODUCTION: Traditional cigarette use adversely impacts disease outcomes in Crohn's disease (CD). There has been a worldwide increase in the use of e-cigarettes over the past decade. The impact of use of nicotine containing e-cigarettes on disease outcomes in CD or ulcerative colitis (UC) has not been well defined. METHODS: This was a retrospective case-control study of patients with CD or UC who were current users of nicotine containing e-cigarettes (cases). Each case was matched to two non-vaping controls. Our primary study outcome was a composite of new biologic initiation, switch of existing biologic therapy, or IBD-related hospitalization or surgery over 2 years. Multivariable models adjusting for relevant covariates were construction. RESULTS: The study consisted of 127 patients with IBD who were current e-cigarette users compared to 251 controls. Current e-cigarette users were younger than non-users and were more likely to have had an IBD-related surgery previously. On multivariable analysis among those with CD, current e-cigarette use was not associated with higher risk of study outcome (OR 0.82, 95% CI 0.36-1.87). No difference was observed separately among those who were current or former smokers. Similarly, in those with UC, current e-cigarette use was not associated with the primary outcome (OR 1.05, 95% CI 0.33-3.39). CONCLUSION: Current e-cigarette use was not associated with worse outcomes among patients with IBD. However, larger studies particularly of patients de novo initiating vaping are needed to draw robust conclusions. Patients should be discouraged from initiating vaping recognizing overall adverse health effects.

Pretreatment Frailty Is Independently Associated With Increased Risk of Infections After Immunosuppression in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Infections are an important adverse effect of immunosuppression for treatment of inflammatory bowel diseases (IBDs). However, risk of infection cannot be sufficiently determined based on patients' ages or comorbidities. Frailty has been associated with outcomes of patients with other inflammatory diseases. We aimed to determine the association between frailty and risk of infections after immunosuppression for IBD. METHODS: We performed a cohort study of 11,001 patients with IBD, using a validated frailty definition based on International Classification of Disease codes to identify patients who were frail vs fit in the 2 years before initiation of an anti-tumor necrosis factor (TNF) or immunomodulator therapy, from 1996 through 2010. Our primary outcome was an infection in the first year after treatment. We constructed multivariable logistic regression models, adjusting for clinically pertinent confounders (age, comorbidities, steroid use, and combination therapy) to determine the association between frailty and posttreatment infections. RESULTS: There were 1299 patients treated with an anti-TNF agent and 2676 patients treated with an immunomodulator. In this cohort, 5% of patients who received anti-TNF therapy and 7% of patients who received an immunomodulator were frail in the 2 years before immunosuppression. Frail patients were older and had more comorbidities. Higher proportions of frail patients developed infections after treatment (19% after TNF and 17% after immunomodulators) compared with fit patients (9% after TNF and 7% after immunomodulators; P < .01 for frail vs fit in both groups). Frail patients had an increased risk of infection after we adjusted for age, comorbidities, and concomitant medications (anti-TNF adjusted odds ratio, 2.05 [95% confidence interval, 1.07-3.93] and immunomodulator adjusted odds ratio, 1.81 [95% confidence interval, 1.22-2.70]). CONCLUSIONS: Frailty was associated with infections after immunosuppression in patients with IBD after we adjust for age and comorbidities. Systematic assessment and strategies to improve frailty might reduce infection risk in patients with IBD.

A Phenome-Wide Analysis of Healthcare Costs Associated with Inflammatory Bowel Diseases.

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are associated with considerable direct healthcare costs. There have been few comprehensive analyses of all IBD- and non-IBD comorbidities that determine direct costs in this population. METHODS: We used data from a validated cohort of patients with inflammatory bowel disease (IBD). Total healthcare costs were estimated as a sum of costs associated with IBD-related hospitalizations and surgery, imaging (CT or MR scans), outpatient visits, endoscopic evaluation, and emergency room (ER) care. All ICD-9 codes were extracted for each patient and clustered into 1804 distinct phecode clusters representing individual phenotypes. A phenome-wide association analysis (PheWAS) was performed using logistic regression to identify predictors of being in the top decile of costs. RESULTS: Our cohort is comprised of 10,721 patients with IBD among whom 50% had CD. The median age was 46 years. The median total cost per patient is $11,203 (IQR $2396-30,563). The strongest association with total healthcare costs was intestinal obstruction without mention of hernia (p = 5.93 × 10-156) and other intestinal obstruction (p = 9.24 × 10-131). In addition, strong associations were observed for symptoms consistent with severity of IBD including the presence of fluid-electrolyte imbalance (p = 1.90 × 10-130), hypovolemia (p = 1.65 × 10-114), abdominal pain (p = 7.29 × 10-60), and anemia (p = 1.90-10-83). Cardiopulmonary diseases and psychological comorbidity also demonstrated significant associations with total costs with the latter being more strongly associated with ER visit-related costs. CONCLUSIONS: Surrogate markers suggesting possible irreversible bowel damage and active disease demonstrate the greatest influence on IBD-related healthcare costs.

Use of Narrative Concepts in Electronic Health Records to Validate Associations Between Genetic Factors and Response to Treatment of Inflammatory Bowel Diseases.

Crohn's disease (CD) and ulcerative colitis (UC) are heterogeneous. With availability of therapeutic classes with distinct immunologic mechanisms of action, it has become imperative to identify markers that predict likelihood of response to each drug class. However, robust development of such tools has been challenging because of need for large prospective cohorts with systematic and careful assessment of treatment response using validated indices. Most hospitals in the United States use electronic health records (EHRs) that warehouse a large amount of narrative (free-text) and codified (administrative) data generated during routine clinical care. These data have been used to construct virtual disease cohorts for epidemiologic research as well as for defining genetic basis of disease states or discrete laboratory values.1-3 Whether EHR-based data can be used to validate genetic associations for more nuanced outcomes such as treatment response has not been examined previously.

Impact of ICD10 and secular changes on electronic medical record rheumatoid arthritis algorithms.

OBJECTIVE: The objective of this study was to compare the performance of an RA algorithm developed and trained in 2010 utilizing natural language processing and machine learning, using updated data containing ICD10, new RA treatments, and a new electronic medical records (EMR) system. METHODS: We extracted data from subjects with ≥1 RA International Classification of Diseases (ICD) codes from the EMR of two large academic centres to create a data mart. Gold standard RA cases were identified from reviewing a random 200 subjects from the data mart, and a random 100 subjects who only have RA ICD10 codes. We compared the performance of the following algorithms using the original 2010 data with updated data: (i) a published 2010 RA algorithm; (ii) updated algorithm, incorporating ICD10 RA codes and new DMARDs; and (iii) published algorithm using ICD codes only, ICD RA code ≥3. RESULTS: The gold standard RA cases had mean age 65.5 years, 78.7% female, 74.1% RF or antibodies to cyclic citrullinated peptide (anti-CCP) positive. The positive predictive value (PPV) for ≥3 RA ICD was 54%, compared with 56% in 2010. At a specificity of 95%, the PPV of the 2010 algorithm and the updated version were both 91%, compared with 94% (95% CI: 91, 96%) in 2010. In subjects with ICD10 data only, the PPV for the updated 2010 RA algorithm was 93%. CONCLUSION: The 2010 RA algorithm validated with the updated data with similar performance characteristics as the 2010 data. While the 2010 algorithm continued to perform better than the rule-based approach, the PPV of the latter also remained stable over time.

Statin Use Is Associated With Reduced Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Chemopreventive strategies have produced weak or inconsistent results. Statins have been associated inversely with sporadic CRC. We examined their role as chemopreventive agents in patients with IBD. METHODS: We collected data from 11,001 patients with IBD receiving care at hospitals in the Greater Boston metropolitan area from 1998 through 2010. Diagnoses of CRC were determined using validated International Classification of Diseases, 9th revision, Clinical Modification codes. Statin use before diagnosis was assessed through analysis of electronic prescriptions. We performed multivariate logistic regression analyses, adjusting for potential confounders including primary sclerosing cholangitis, smoking, increased levels of inflammation markers, and CRC screening practices to identify an independent association between statin use and CRC. We performed sensitivity analyses using propensity score adjustment and variation in the definition of statin use. RESULTS: In our cohort, 1376 of the patients (12.5%) received 1 or more prescriptions for a statin. Patients using statins were more likely to be older, male, white, smokers, and have greater comorbidity than nonusers. Over a follow-up period of 9 years, 2% of statin users developed CRC compared with 3% of nonusers (age-adjusted odds ratio, 0.35; 95% confidence interval, 0.24-0.53). On multivariate analysis, statin use remained independently and inversely associated with CRC (odds ratio, 0.42; 95% confidence interval, 0.28-0.62). Our findings were robust on a variety of sensitivity and subgroup analyses. CONCLUSIONS: Statin use was associated inversely with the risk of CRC in a large IBD cohort. Prospective studies on the role of statins as chemopreventive agents are warranted.

Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases.

BACKGROUND & AIMS: Crohn's disease and ulcerative colitis are associated with an increased risk of colorectal cancer (CRC). Surveillance colonoscopy is recommended at 2- to 3-year intervals beginning 8 years after diagnosis of inflammatory bowel disease (IBD). However, there have been no reports of whether colonoscopy examination reduces the risk for CRC in patients with IBD. METHODS: In a retrospective study, we analyzed data from 6823 patients with IBD (2764 with a recent colonoscopy, 4059 without a recent colonoscopy) seen and followed up for at least 3 years at 2 tertiary referral hospitals in Boston, Massachusetts. The primary outcome was diagnosis of CRC. We examined the proportion of patients undergoing a colonoscopy within 36 months before a diagnosis of CRC or at the end of the follow-up period, excluding colonoscopies performed within 6 months before a diagnosis of CRC, to avoid inclusion of prevalent cancers. Multivariate logistic regression was performed, adjusting for plausible confounders. RESULTS: A total of 154 patients developed CRC. The incidence of CRC among patients without a recent colonoscopy (2.7%) was significantly higher than among patients with a recent colonoscopy (1.6%) (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39-0.80). This difference persisted in multivariate analysis (OR, 0.65; 95% CI, 0.45-0.93) and was robust when adjusted for a range of assumptions in sensitivity analyses. Among patients with CRC, a colonoscopy within 6 to 36 months before diagnosis was associated with a reduced mortality rate (OR, 0.34; 95% CI, 0.12-0.95). CONCLUSIONS: Recent colonoscopy (within 36 months) is associated with a reduced incidence of CRC in patients with IBD, and lower mortality rates in those diagnosed with CRC.

Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases.

INTRODUCTION: Inflammatory bowel diseases [IBD; Crohn's disease (CD), ulcerative colitis] often affect women in their reproductive years. Few studies have analyzed the impact of mode of childbirth on long-term IBD outcomes. METHODS: We used a multi-institutional IBD cohort to identify all women in the reproductive age-group with a diagnosis of IBD prior to pregnancy. We identified the occurrence of a new diagnosis code for perianal complications, IBD-related hospitalization and surgery, and initiation of medical therapy after either a vaginal delivery or caesarean section (CS). Cox proportional hazards models adjusting for potential confounders were used to estimate independent effect of mode of childbirth on IBD outcomes. RESULTS: Our cohort included 360 women with IBD (161 CS). Women in the CS group were likely to be older and more likely to have complicated disease behavior prior to pregnancy. During follow-up, there was no difference in the likelihood of IBD-related surgery (multivariate hazard ratio 1.75, 95 % confidence interval (CI) 0.40-7.75), IBD-related hospitalization (HR 1.39), initiation of immunomodulator therapy (HR 1.45), or anti-TNF therapy (HR 1.11). Among the 133 CD pregnancies with no prior perianal disease, we found no excess risk of subsequent new diagnosis perianal fistulae with vaginal delivery compared to CS (HR 0.19, 95 % CI 0.04-1.05). CONCLUSIONS: Mode of delivery did not influence natural history of IBD. In our cohort, vaginal delivery was not associated with increased risk of subsequent perianal disease in women with CD.

Thromboprophylaxis is associated with reduced post-hospitalization venous thromboembolic events in patients with inflammatory bowel diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) have increased risk for venous thromboembolism (VTE); those who require hospitalization have particularly high risk. Few hospitalized patients with IBD receive thromboprophylaxis. We analyzed the frequency of VTE after IBD-related hospitalization, risk factors for post-hospitalization VTE, and the efficacy of prophylaxis in preventing post-hospitalization VTE. METHODS: In a retrospective study, we analyzed data from a multi-institutional cohort of patients with Crohn's disease or ulcerative colitis and at least 1 IBD-related hospitalization. Our primary outcome was a VTE event. All patients contributed person-time from the date of the index hospitalization to development of VTE, subsequent hospitalization, or end of follow-up. Our main predictor variable was pharmacologic thromboprophylaxis. Cox proportional hazard models adjusting for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: From a cohort of 2788 patients with at least 1 IBD-related hospitalization, 62 patients developed VTE after discharge (2%). Incidences of VTE at 30, 60, 90, and 180 days after the index hospitalization were 3.7/1000, 4.1/1000, 5.4/1000, and 9.4/1000 person-days, respectively. Pharmacologic thromboprophylaxis during the index hospital stay was associated with a significantly lower risk of post-hospitalization VTE (HR, 0.46; 95% CI, 0.22-0.97). Increased numbers of comorbidities (HR, 1.30; 95% CI, 1.16-1.47) and need for corticosteroids before hospitalization (HR, 1.71; 95% CI, 1.02-2.87) were also independently associated with risk of VTE. Length of hospitalization or surgery during index hospitalization was not associated with post-hospitalization VTE. CONCLUSIONS: Pharmacologic thromboprophylaxis during IBD-related hospitalization is associated with reduced risk of post-hospitalization VTE.

Serum inflammatory markers and risk of colorectal cancer in patients with inflammatory bowel diseases.

BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) (Crohn's disease, ulcerative colitis) are at increased risk of colorectal cancer (CRC). Persistent inflammation is hypothesized to increase risk of CRC in patients with IBD; however, the few studies in this area have been restricted to cross-sectional assessments of histologic severity. No prior studies have examined association between C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) elevation and risk of CRC in an IBD cohort. METHODS: From a multi-institutional validated IBD cohort, we identified all patients with at least one measured CRP or ESR value. Patients were stratified into quartiles of severity of inflammation on the basis of their median CRP or ESR value, and subsequent diagnosis of CRC was ascertained. Logistic regression adjusting for potential confounders was used to identify the independent association between CRP or ESR elevation and risk of CRC. RESULTS: Our study included 3145 patients with at least 1 CRP value (CRP cohort) and 4008 with at least 1 ESR value (ESR cohort). Thirty-three patients in the CRP cohort and 102 patients in the ESR cohort developed CRC during a median follow-up of 5 years at a median age of 55 years. On multivariate analysis, there was a significant increase in risk of CRC across quartiles of CRP elevation (P(trend) = .017; odds ratio for quartile 4 vs quartile 1, 2.72; 95% confidence interval, 0.95-7.76). Similarly higher median ESR was also independently associated with risk of CRC across the quartiles (odds ratio, 2.06; 95% confidence interval, 1.14-3.74) (P(trend) = .007). CONCLUSIONS: An elevated CRP or ESR is associated with increased risk of CRC in patients with IBD.

Association between reduced plasma 25-hydroxy vitamin D and increased risk of cancer in patients with inflammatory bowel diseases.

BACKGROUND & AIMS: Vitamin D deficiency is common among patients with inflammatory bowel diseases (IBD) (Crohn's disease or ulcerative colitis). The effects of low plasma 25-hydroxy vitamin D (25[OH]D) on outcomes other than bone health are understudied in patients with IBD. We examined the association between plasma level of 25(OH)D and risk of cancers in patients with IBD. METHODS: From a multi-institutional cohort of patients with IBD, we identified those with at least 1 measurement of plasma 25(OH)D. The primary outcome was development of any cancer. We examined the association between plasma 25(OH)D and risk of specific subtypes of cancer, adjusting for potential confounders in a multivariate regression model. RESULTS: We analyzed data from 2809 patients with IBD and a median plasma level of 25(OH)D of 26 ng/mL. Nearly one-third had deficient levels of vitamin D (<20 ng/mL). During a median follow-up period of 11 years, 196 patients (7%) developed cancer, excluding nonmelanoma skin cancer (41 cases of colorectal cancer). Patients with vitamin D deficiency had an increased risk of cancer (adjusted odds ratio, 1.82; 95% confidence interval, 1.25-2.65) compared with those with sufficient levels. Each 1-ng/mL increase in plasma 25(OH)D was associated with an 8% reduction in risk of colorectal cancer (odds ratio, 0.92; 95% confidence interval, 0.88-0.96). A weaker inverse association was also identified for lung cancer. CONCLUSIONS: In a large multi-institutional IBD cohort, a low plasma level of 25(OH)D was associated with an increased risk of cancer, especially colorectal cancer.

Association Between Inflammation, Incident Heart Failure, and Heart Failure Subtypes in Patients With Rheumatoid Arthritis.

OBJECTIVE: In rheumatoid arthritis (RA), there are limited data on risk factors for the clinical heart failure (HF) subtypes of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This study examined the association between inflammation and incident HF subtypes in RA. Because inflammation changes over time with disease activity, we hypothesized that the effect of inflammation may be stronger at the 5-year follow-up than at the standard 10-year follow-up from general population studies of cardiovascular risk. METHODS: We studied an electronic health record (EHR)-based RA cohort with data pre- and post-RA incidence. We applied a validated approach to identify HF and extract ejection fraction to classify HFrEF and HFpEF. Follow-up started from the RA incidence date (index date) to the earliest occurrence of incident HF, death, last EHR encounter, or 10 years. Baseline inflammation was assessed using erythrocyte sedimentation rate or C-reactive protein values. Covariates included demographic characteristics, established HF risk factors, and RA-related factors. We tested the association between baseline inflammation with incident HF and its subtypes using Cox proportional hazards models. RESULTS: We studied 9,087 patients with RA; 8.2% developed HF during 10 years of follow-up. Elevated inflammation was associated with increased risk for HF at both 5- and 10-year follow-ups (hazard ratio [HR] 1.66, 95% confidence interval [95% CI] 1.12-2.46 and HR 1.46, 95% CI 1.13-1.90, respectively), which is also seen for HFpEF at 5 years (HR 1.72, 95% CI 1.09-2.70) and 10 years (HR 1.45, 95% CI 1.07-1.94). HFrEF was not associated with inflammation for either follow-up time. CONCLUSION: Elevated inflammation early in RA diagnosis was associated with HF; this association was driven by HFpEF and not HFrEF, suggesting a window of opportunity for prevention of HFpEF in RA.

Multi-ancestry genome- and phenome-wide association studies of diverticular disease in electronic health records with natural language processing enriched phenotyping algorithm.

OBJECTIVE: Diverticular disease (DD) is one of the most prevalent conditions encountered by gastroenterologists, affecting ~50% of Americans before the age of 60. Our aim was to identify genetic risk variants and clinical phenotypes associated with DD, leveraging multiple electronic health record (EHR) data sources of 91,166 multi-ancestry participants with a Natural Language Processing (NLP) technique. MATERIALS AND METHODS: We developed a NLP-enriched phenotyping algorithm that incorporated colonoscopy or abdominal imaging reports to identify patients with diverticulosis and diverticulitis from multicenter EHRs. We performed genome-wide association studies (GWAS) of DD in European, African and multi-ancestry participants, followed by phenome-wide association studies (PheWAS) of the risk variants to identify their potential comorbid/pleiotropic effects in clinical phenotypes. RESULTS: Our developed algorithm showed a significant improvement in patient classification performance for DD analysis (algorithm PPVs ≥ 0.94), with up to a 3.5 fold increase in terms of the number of identified patients than the traditional method. Ancestry-stratified analyses of diverticulosis and diverticulitis of the identified subjects replicated the well-established associations between ARHGAP15 loci with DD, showing overall intensified GWAS signals in diverticulitis patients compared to diverticulosis patients. Our PheWAS analyses identified significant associations between the DD GWAS variants and circulatory system, genitourinary, and neoplastic EHR phenotypes. DISCUSSION: As the first multi-ancestry GWAS-PheWAS study, we showcased that heterogenous EHR data can be mapped through an integrative analytical pipeline and reveal significant genotype-phenotype associations with clinical interpretation. CONCLUSION: A systematic framework to process unstructured EHR data with NLP could advance a deep and scalable phenotyping for better patient identification and facilitate etiological investigation of a disease with multilayered data.

The Mass General Brigham Biobank Portal: an i2b2-based data repository linking disparate and high-dimensional patient data to support multimodal analytics.

OBJECTIVE: Integrating and harmonizing disparate patient data sources into one consolidated data portal enables researchers to conduct analysis efficiently and effectively. MATERIALS AND METHODS: We describe an implementation of Informatics for Integrating Biology and the Bedside (i2b2) to create the Mass General Brigham (MGB) Biobank Portal data repository. The repository integrates data from primary and curated data sources and is updated weekly. The data are made readily available to investigators in a data portal where they can easily construct and export customized datasets for analysis. RESULTS: As of July 2021, there are 125 645 consented patients enrolled in the MGB Biobank. 88 527 (70.5%) have a biospecimen, 55 121 (43.9%) have completed the health information survey, 43 552 (34.7%) have genomic data and 124 760 (99.3%) have EHR data. Twenty machine learning computed phenotypes are calculated on a weekly basis. There are currently 1220 active investigators who have run 58 793 patient queries and exported 10 257 analysis files. DISCUSSION: The Biobank Portal allows noninformatics researchers to conduct study feasibility by querying across many data sources and then extract data that are most useful to them for clinical studies. While institutions require substantial informatics resources to establish and maintain integrated data repositories, they yield significant research value to a wide range of investigators. CONCLUSION: The Biobank Portal and other patient data portals that integrate complex and simple datasets enable diverse research use cases. i2b2 tools to implement these registries and make the data interoperable are open source and freely available.

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

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.

Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease.

BACKGROUND: Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear. OBJECTIVES: This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention. METHODS: A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy. RESULTS: Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor. CONCLUSIONS: Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.

Association Between Anti-Citrullinated Fibrinogen Antibodies and Coronary Artery Disease in Rheumatoid Arthritis.

OBJECTIVE: Antibodies against citrullinated fibrinogen (anti-Cit-fibrinogen) have been implicated in rheumatoid arthritis (RA) and associated with cardiovascular risk in RA. The objective of this study was to examine the association between anti-Cit-fibrinogens and coronary artery disease (CAD) outcomes. METHODS: We performed the study in an RA cohort based in a large academic institution linked with electronic medical record data containing information on CAD outcomes from medical record review. Using a published bead-based assay method, we measured 10 types of anti-Cit-fibrinogens. We applied a score test to determine the association between the anti-Cit-fibrinogens as a group with CAD outcomes. Principal components analysis (PCA) was performed to assess whether the anti-Cit-fibrinogens clustered into groups. Each group was then additionally tested for association with CAD. Sensitivity analyses were also performed using a published International Classification of Disease, Ninth Revision code group for ischemic heart disease (IHD) as the outcome. RESULTS: We studied 1,006 RA subjects (mean ± SD age 61.0 ± 13.0 years; 72.2% anti-cyclic citrullinated peptide positive). As a group, anti-Cit-fibrinogen was associated with CAD (P = 1.1 × 10-4 ). From the PCA analysis, we observed 3 main groups, of which only 1 group, containing 7 of the 10 anti-Cit-fibrinogens, was significantly associated with CAD outcomes (P = 0.015). In the sensitivity analysis, all anti-Cit-fibrinogens as a group remained significantly associated with IHD (P = 2.9 × 10-4 ). CONCLUSION: Anti-Cit-fibrinogen antibodies as a group were associated with CAD outcomes in our RA cohort, with the strongest signal for association arising from a subset of the autoantibodies.

The Association Between Arthralgia and Vedolizumab Using Natural Language Processing.

Background: The gut-selective nature of vedolizumab has raised questions regarding increased joint pain or arthralgia with its use in inflammatory bowel disease (IBD) patients. As arthralgias are seldom coded and thus difficult to study, few studies have examined the comparative risk of arthralgia between vedolizumab and tumor necrosis factor inhibitor (TNFi). Our objectives were to evaluate the application of natural language processing (NLP) to identify arthralgia in the clinical notes and to compare the risk of arthralgia between vedolizumab and TNFi in IBD. Methods: We performed a retrospective study using a validated electronic medical record (EMR)-based IBD cohort from 2 large tertiary care centers. The index date was the first date of vedolizumab or TNFi prescription. Baseline covariates were assessed 1 year before the index date; patients were followed 1 year after the index date. The primary outcome was arthralgia, defined using NLP. Using inverse probability of treatment weight to balance the cohorts, we then constructed Cox regression models to calculate the hazard ratio (HR) for arthralgia in the vedolizumab and TNFi groups. Results: We studied 367 IBD patients on vedolizumab and 1218 IBD patients on TNFi. Patients on vedolizumab were older (mean age, 41.2 vs 34.9 years) and had more prevalent use of immunomodulators (52.3% vs 31.9%) than TNFi users. Our data did not observe a significantly increased risk of arthralgia in the vedolizumab group compared with TNFi (HR, 1.20; 95% confidence interval, 0.97-1.49). Conclusions: In this large observational study, we did not find a significantly increased risk of arthralgia associated with vedolizumab use compared with TNFi.

Validation of a risk stratification tool for fall-related injury in a state-wide cohort.

OBJECTIVE: A major preventable contributor to healthcare costs among older individuals is fall-related injury. We sought to validate a tool to stratify such risk based on readily available clinical data, including projected medication adverse effects, using state-wide medical claims data. DESIGN: Sociodemographic and clinical features were drawn from health claims paid in the state of Massachusetts for individuals aged 35-65 with a hospital admission for a period spanning January-December 2012. Previously developed logistic regression models of hospital readmission for fall-related injury were refit in a testing set including a randomly selected 70% of individuals, and examined in a training set comprised of the remaining 30%. Medications at admission were summarised based on reported adverse effect frequencies in published medication labelling. SETTING: The Massachusetts health system. PARTICIPANTS: A total of 68 764 hospitalised individuals aged 35-65 years. PRIMARY MEASURES: Hospital readmission for fall-related injury defined by claims code. RESULTS: A total of 2052 individuals (3.0%) were hospitalised for fall-related injury within 90 days of discharge, and 3391 (4.9%) within 180 days. After recalibrating the model in a training data set comprised of 48 136 individuals (70%), model discrimination in the remaining 30% test set yielded an area under the receiver operating characteristic curve (AUC) of 0.74 (95% CI 0.72 to 0.76). AUCs were similar across age decades (0.71 to 0.78) and sex (0.72 male, 0.76 female), and across most common diagnostic categories other than psychiatry. For individuals in the highest risk quartile, 11.4% experienced fall within 180 days versus 1.2% in the lowest risk quartile; 57.6% of falls occurred in the highest risk quartile. CONCLUSIONS: This analysis of state-wide claims data demonstrates the feasibility of predicting fall-related injury requiring hospitalisation using readily available sociodemographic and clinical details. This translatable approach to stratification allows for identification of high-risk individuals in whom interventions are likely to be cost-effective.

Phenome-Wide Association Study of Autoantibodies to Citrullinated and Noncitrullinated Epitopes in Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) develop autoantibodies against a spectrum of antigens, but the clinical significance of these autoantibodies is unclear. Using a phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA. METHODS: This study was conducted in a cohort of RA patients identified from the electronic medical records (EMRs) of 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all International Classification of Diseases, Ninth Revision (ICD-9) codes for each subject and grouped them into disease categories (PheWAS codes), using a published method. We tested for the association of each autoantibody (grouped by the targeted protein) with PheWAS codes. To determine significant associations (at a false discovery rate [FDR] of ≤0.1), we reviewed the medical records of 50 patients with each PheWAS code to determine positive predictive values (PPVs). RESULTS: We studied 1,006 RA patients; the mean ± SD age of the patients was 61.0 ± 12.9 years, and 79.0% were female. A total of 3,568 unique ICD-9 codes were grouped into 625 PheWAS codes; the 206 PheWAS codes with a prevalence of ≥3% were studied. Using the PheWAS method, we identified 24 significant associations of autoantibodies to epitopes at an FDR of ≤0.1. The associations that were strongest and had the highest PPV for the PheWAS code were autoantibodies against fibronectin and obesity (P = 6.1 × 10-4 , PPV 100%), and that between fibrinogen and pneumonopathy (P = 2.7 × 10-4 , PPV 96%). Pneumonopathy codes included diagnoses for cryptogenic organizing pneumonia and obliterative bronchiolitis. CONCLUSION: We demonstrated application of a bioinformatics method, the PheWAS, to screen for the clinical significance of RA-related autoantibodies. Using the PheWAS approach, we identified potentially significant links between variations in the levels of autoantibodies and comorbidities of interest in RA.