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Ane Birgitte Telén Andersen,1 Rune Erichsen,1 Michael David Kappelman,2 Trine Frøslev,1 Vera Ehrenstein1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Pediatrics, Division of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Objective: The incidences of celiac disease (CD) and asthma are increasing and the two conditions are associated in individuals. Risk of asthma may be passed on to the next generation through shared risk factors. We examined whether parental CD is associated with risk of asthma in offspring. Methods: We conducted a population-based Danish nationwide cohort study, using medical databases, covering the period 1 January 1979 to 31 December 2009. For each child with a parental history of CD, we randomly sampled 100 children without this history from the children born in the same calendar year. We used Cox proportional-hazards regression to estimate incidence rate ratios for asthma, adjusting for measured covariates. Results: We identified 1,107 children with a parental history of CD and 110,700 children without this parental history. During up to 32 years of follow-up, 6,125 children received a hospital diagnosis of asthma. The adjusted incidence rate ratio for asthma associated with a parental history of CD was 1.09 (95% confidence interval: 0.86–1.39) and was similar for maternal and paternal CD. Inclusion of asthma-medication in the definition of asthma did not substantially change the results. Conclusion: There was no convincing evidence of an increased risk of asthma among offspring of parents with CD. Keywords: asthma, celiac disease, children, cohort study, parents

AIMS: Inflammation is considered to play a role in the development of atrial fibrillation (AF). Hence inflammatory bowel disease (IBD) may be associated with AF. We therefore examined the incidence of AF and stroke in patients with IBD.METHODS AND RESULTS: From Danish nationwide registries 1996-2011, we identified 24 499 patients with new-onset IBD and 236 275 age- and sex-matched controls. Poisson regression analyses with continuously updated covariates were used to estimate incidence rate ratios (IRRs) of AF and stroke. Disease activity stages of flare (new disease activity), persistent activity, and remission were defined by corticosteroid prescriptions, IBD hospital admissions, and biological treatment. Inflammatory bowel disease patients had a mean age of 43.9 years, 53.9% were women, and mean follow-up was 6.8 years. Among IBD patients, 685 had AF and 549 had a stroke, corresponding to incidence rates per 1000 person-years of 4.16 vs. 2.70 for AF and 3.33 vs. 2.44 for stroke, compared with matched controls. Overall IBD-associated risk of AF corresponded to IRR 1.26 (1.16-1.36), but was driven by increased AF incidence during IBD flares [IRR 2.63 (2.26-3.06)] and persistent activity [IRR 2.06 (1.67-2.55)], whereas no increased AF risk was observed in remission periods [IRR 0.97 (0.88-1.08)]. Likewise increased stroke risk was exclusively found during active IBD [IRRs: 1.57 (1.27-1.93), 1.71 (1.32-2.21), and 1.04 (0.93-1.15) for flares, persistent activity, and remission, respectively].CONCLUSION: Active IBD is associated with increased risk of AF and stroke. These findings may be relevant to clinical practice.

BACKGROUND: Inflammatory bowel disease (IBD) has been linked to adverse cardiovascular events, but a relation to heart failure (HF) is uncertain. We investigated the IBD-associated risk of HF in a nationwide setting.METHODS AND RESULTS: A total of 5 436 647 Danish citizens, with no history of IBD or HF, were included on January 1, 1997, and followed up until first hospitalization for HF, death, or December 31, 2011. Of these subjects, 23 681 developed IBD for which disease activity was determined continuously throughout the study. The risk of hospitalization for HF was estimated with a Poisson regression model adjusting for comorbidity and cardiovascular pharmacotherapy as time-dependent covariates. During a mean follow-up of 11.8 years in the reference population and 6.4 years in the IBD group, hospitalization for HF occurred in 553 subjects with IBD and 171 405 in the reference population. Patients with IBD had a 37% increased risk of hospitalization for HF (incidence rate ratio, 1.37; 95% confidence interval, 1.26-1.49) compared with the reference population. IBD activity-specific analyses showed markedly increased risk of HF hospitalization during flares (incidence rate ratio, 2.54; 95% confidence interval, 2.13-3.04) and persistent activity (incidence rate ratio, 2.73; 95% confidence interval, 2.25-3.33) but not in IBD remission (incidence rate ratio, 1.04; 95% confidence interval, 0.94-1.16).CONCLUSIONS: In a nationwide cohort, IBD was associated with an increased risk of hospitalization for HF, and this risk was strongly correlated to periods of active disease. The mechanisms underlying this finding warrant further studies.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with increased cardiovascular risk. We examined the effect of active IBD on major adverse cardiovascular outcomes after myocardial infarction (MI).METHODS AND RESULTS: In nationwide registries, we identified 86 790 patients with first-time MI from the period 2002 to 2011. A total of 1030 patients had IBD, and we categorized their disease activity stages into either flare (120 days), persistent (>120 days) activity, or remission. Short-term mortality was estimated in a logistic regression-model, whereas risk of recurrent MI, all-cause mortality, and a composite of recurrent MI, cardiovascular death, and stroke were estimated by Cox regression-models. Odds ratio of death during hospitalization or within 30 days of discharge (n=13 339) corresponded to 3.29 (95% confidence interval [CI], 1.98-5.45) for patients in IBD flares, 1.62 (95% CI, 0.95-2.77) for persistent activity, and 0.97 (95% CI, 0.78-1.19) for remission when compared with the non-IBD group. Among 73 451 patients, including 863 with IBD, alive 30 days after discharge, IBD was associated with hazard ratios of 1.21 (95% CI, 0.99-1.49) for recurrent MI, 1.14 (95% CI, 1.01-1.28) for all-cause mortality, and 1.17 (95% CI, 1.03-1.34) for the composite end point. When compared with the non-IBD group, IBD flares, in particular, were associated with increased risks of recurrent MI (hazard ratio, 3.09; 95% CI, 1.79-5.32), all-cause mortality (hazard ratio, 2.25; 95% CI, 1.61-3.15), and the composite end point (hazard ratio, 2.04; 95% CI, 1.35-3.06), whereas no increased risk was identified in remission.CONCLUSIONS: Active inflammatory bowel disease worsens prognosis after MI, in particular, in relation with flares.

Ane Birgitte Telén Andersen, Vera Ehrenstein, Rune Erichsen, Trine Frøslev, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Purpose: Inflammatory bowel disease (IBD) and autism spectrum disorders (ASD) may share genetic and environmental risk factors. We examined whether parental IBD is associated with an increased risk of ASD in offspring. Methods: We conducted a registry-based nationwide cohort study including children born alive in Denmark from January 1, 1994 to December 31, 2009, with follow-up throughout 2010. IBD in parents and ASD in offspring were identified using inpatient and outpatient hospital diagnoses. We computed risk of ASD and crude and adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CI) using Cox proportional-hazards regression. We evaluated the risk of ASD according to maternal and paternal IBD, and separately for maternal and paternal Crohn's disease (CD) and ulcerative colitis (UC). Children with parents free of IBD were the comparison cohort. Results: We identified 1,005,330 children during the study period. Among them, 11,888 (1.2%) had a parent with IBD and 8,087 (0.8%) had a diagnosis of ASD during up to 17 years of follow-up. The 10-year risks of ASD were 0.7% among children of parents with IBD and 0.9% among children of parents without IBD. The aIRR for ASD among children with parental IBD was 0.8 (95% CI: 0.6–1.0), and results were similar regardless of parent of IBD origin or whether a parent had CD or UC. The estimates were similar for different ASD subtypes. Conclusion: We found no evidence of an increased risk of ASD among children born to parents with IBD. Keywords: autistic disorder, children, cohort study, epidemiology, inflammatory bowel disease, parents

Jennifer L Lund,1 Trine Frøslev,1 Thomas Deleuran,1,2 Rune Erichsen,1 Tove Nilsson,1 Annette Nørkær Pedersen,3 Morten Høyer4 1Department of Clinical Epidemiology, 2Department of Medicine V (Hepatology and Gastroenterology), 3Hospital Pharmacy, 4Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Background: The Danish National Registry of Patients (DNRP) is a potentially valuable resource for monitoring national trends in the use of chemotherapy and evaluating the benefits and harms of alternative treatments among colorectal cancer (CRC) patients in Denmark. However, the validity of chemotherapy reporting in the DNRP is unknown. In this study, we evaluated the validity of the DNRP for identifying the receipt of chemotherapy and specific treatments, and the timing and number of treatments among CRC patients, using medical records and pharmacy data as the reference standard. Methods: We selected a random sample of CRC patients with lymph node involvement who were diagnosed at Aarhus University Hospital (n = 25) or Aalborg University Hospital (n = 25) from 2009 to 2010. Administration dates, specific treatments, and number of treatment courses were abstracted for the 180 days post diagnosis from the DNRP, medical records, and pharmacy production databases. The prevalence of chemotherapy, timing of first administration, and number of courses were described. DNRP data were compared with the reference standard for each hospital, and the kappa, sensitivity, specificity, positive and negative predictive values, and 95% confidence intervals were calculated for the receipt of any chemotherapy and specific treatments. Results: The prevalence of chemotherapy was 72% and 68% among CRC patients treated in Aarhus and Aalborg, respectively, with >90% of patients without distant metastasis receiving treatment within 90 days from diagnosis. Patients received on average 4.6 and 4.7 treatment courses in Aarhus and Aalbor

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

Inès Ben Ghezala, Johan Frederik Berg Arendt, Rune Erichsen, Jihen Zalfani, Henrik Gammelager, Trine Frøslev, Morten OlsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkPurpose: The aim of this validation study was to assess the positive predictive value (PPV) of the International Classification of Diseases, 10th revision (ICD-10) diagnosis of vitamin B12 (cobalamin [Cbl]) deficiency anemia in the Danish National Patient Register (DNPR).Patients and methods: We identified all patients above 18 years of age recorded in the DNPR with a diagnosis of Cbl deficiency anemia (ICD-10 code: D51) admitted to two Danish university hospitals and one Danish regional hospital from 2000 through 2009. We assessed the PPV using biochemical parameters on Cbl deficiency with or without anemia as reference standards. These data were obtained from the Laboratory Information Systems Database. Data on prescriptions with Cbl supplementation drugs were obtained from the Aarhus University Prescription Database.Results: We identified 1089 patients coded with a Cbl deficiency anemia diagnosis in the DNPR. The PPV was 31.5% (95% confidence interval [CI]: 28.8%–34.3%) and 36.8% (95% CI: 34.0%–39.7%) depending on definitions of Cbl deficiency with anemia. When using Cbl deficiency without anemia as a reference standard, the PPV was 51.3% (95% CI: 48.4%–54.3%). The PPV for Cbl supplemented patients was 22.2% (95% CI: 18.0%–26.9%) and for non-Cbl supplemented patients 63.9% (95% CI: 60.5%–67.3%).Conclusion: The PPVs of the ICD-10 diagnosis coding for Cbl deficiency anemia were generally low in the DNPR. Therefore, this register should be used with caution to study patients with Cbl deficiency anemia.Keywords: vitamin B12 deficiency anemia, Danish National Patient Register, Laboratory Information Systems Database, International Classification of Diseases, positive predictive value, validation stu