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Jesper Nors,1,2,* Trine Block Mattesen,1,* Deirdre Cronin-Fenton,3 Aurélie Mailhac,3 Jesper Bertram Bramsen,1,2 Kåre Andersson Gotschalck,2,4 Rune Erichsen,2,3,5 Claus Lindbjerg Andersen1,2 1Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Surgery, Horsens Regional Hospital, Horsens, Denmark; 5Department of Surgery, Randers Regional Hospital, Horsens, Denmark*These authors contributed equally to this workCorrespondence: Claus Lindbjerg Andersen, Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark, Tel +45 78455319, Email cla@clin.au.dkPurpose: Colorectal cancer (CRC) recurrence is not routinely recorded in Danish health data registries. Here, we aimed to revalidate a registry-based algorithm to identify recurrences in a contemporary cohort and to investigate the accuracy of estimating the time to recurrence (TTR).Patients and Methods: We ascertained data on 1129 patients operated for UICC TNM stage I–III CRC during 2012– 2017 registered in the CRC biobank at the Department of Molecular Medicine, Aarhus University Hospital, Denmark. Individual-level data were linked with data from the Danish Colorectal Cancer Group database, Danish Cancer Registry, Danish National Registry of Patients, and Danish Pathology Registry. The algorithm identified recurrence based on diagnosis codes of local recurrence or metastases, the receipt of chemotherapy, or a pathological tissue assessment code of recurrence more than 180 days after CRC surgery. A subgroup was selected for validation of the algorithm using medical record reviews as a reference standard.Results: We found a 3-year cumulative recurrence rate of 20% (95% CI: 17– 22%). Manual medical record review identified 80 recurrences in the validation cohort of 522 patients. The algorithm detected recurrence with 94% sensitivity (75/80; 95% CI: 86– 98%) and 98% specificity (431/442; 95% CI: 96– 99%). The positive and negative predictive values of the algorithm were 87% (95% CI: 78– 93%) and 99% (95% CI: 97– 100%), respectively. The median difference in TTR (TTRMedical_chart-TTRalgorithm) was − 8 days (IQR: − 21 to +3 days). Restricting the algorithm to chemotherapy codes from oncology departments increased the positive predictive value from 87% to 94% without changing the negative predictive value (99%).Conclusion: The algorithm detected recurrence and TTR with high precision in this contemporary cohort. Restriction to chemotherapy codes from oncology departments using department classifications improves the algorithm. The algorithm is suitable for use in future observational studies.Keywords: time to recurrence, surveillance, chemotherapy, oncology

Louise Thomsen,* Frederikke Schønfeldt Troelsen,* David Nagy, Nils Skajaa, Dóra Körmendiné Farkas, Rune Erichsen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, 8200, Denmark*These authors contributed equally to this workCorrespondence: Louise ThomsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N, 8200, DenmarkTel +45 20477642Email louisethomsen3@gmail.comPurpose: Venous thromboembolism may be a harbinger of cancer. Patients with diverticular disease are suggested to have an increased risk of developing venous thromboembolism compared with the general population, but it remains unclear whether venous thromboembolism is also a marker of occult cancer in these patients. We investigated the risk of cancer after venous thromboembolism among patients with diverticular disease.Patients and Methods: We used Danish health registries to conduct a nationwide, population-based cohort study during 1996– 2017. We identified all venous thromboembolism patients with a diagnosis of diverticular disease and calculated absolute risks of cancer and standardized incidence ratios (SIRs) by comparing observed and expected cancer incidence based on national cancer incidence in the Danish population.Results: We followed 3406 patients with venous thromboembolism and diverticular disease for a median of 3.0 years (interquartile range: 1.0– 6.0). During the first year of follow-up, we observed 212 cancer cases. The corresponding one-year risk of cancer was 6.2% (95% confidence interval [CI]: 5.5– 7.1) with a SIR of 2.9 (95% CI: 2.5– 3.3). The SIRs were particularly elevated for cancers of the stomach, pancreas, ovary, and kidney. During the second and subsequent years of follow-up, 337 cancers were diagnosed with a SIR of 1.1 (95% CI: 1.0– 1.3).Conclusion: Venous thromboembolism is a harbinger of occult cancer in patients with diverticular disease.Keywords: epidemiology, pulmonary embolism, deep venous thrombosis, diverticulitis, perforated diverticulitis, cancer

Lindsay J Collin,1,2 Anders H Riis,2 Richard F MacLehose,3 Thomas P Ahern,4 Rune Erichsen,2,5 Ole Thorlacius-Ussing,6 Timothy L Lash1 1Department of Epidemiology, Emory University, Atlanta, GA, USA; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA; 4Department of Surgery, The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, VT, USA; 5Department of Surgery, Randers Regional Hospital, Randers, Denmark; 6Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, DenmarkCorrespondence: Lindsay J CollinDepartment of Epidemiology, Emory University, 1518 Clifton RoadNE, Atlanta, GA 30322, USATel +1 530-386-3341Email lindsay.jane.collin@emory.eduBackground: Among men and women diagnosed with colorectal cancer (CRC), 20– 50% will develop a cancer recurrence. Cancer recurrences are not routinely captured by most population-based registries; however, linkage across Danish registries allows for the development of predictive models to detect recurrence. Successful application of such models in population-based settings requires validation against a gold standard to ensure the accuracy of recurrence identification.Objective: We apply a recently developed validation study design for prospectively collected validation data to validate predicted CRC recurrences against gold standard diagnoses from medical records in an actively followed cohort of CRC patients in Denmark.Methods: We use a Bayesian monitoring framework, traditionally used in clinical trials, to iteratively update classification parameters (positive and negative predictive values, and sensitivity and specificity) in an adaptive validation substudy design. This design allows determination of the sample size necessary to estimate the corresponding parameters and to identify when validation efforts can cease based on predefined criteria for parameter values and levels of precision.Results: Among 355 men and women diagnosed with CRC in Denmark and actively followed semi-annually, there were 63 recurrences diagnosed by active follow-up and 70 recurrences identified by a predictive algorithm. The adaptive validation design met stopping criteria for the classification parameters after 120 patients had their recurrence information validated. This stopping point yielded parameter estimates for the classification parameters similar to those obtained when the entire cohort was validated, with 66% less patients needed for the validation study.Conclusion: In this proof of concept application of the adaptive validation study design for outcome misclassification, we demonstrated the ability of the method to accurately determine when sufficient validation data have been collected. This method serves as a novel validation substudy design for prospectively collected data with simultaneous implementation of a validation study.Keywords: validation study design, colorectal cancer recurrence

Tue Højslev Avlund,1 Rune Erichsen,1,2 Lene Hjerrild Iversen1,2 1Department of Surgery, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Randomized controlled trials have not provided clear evidence for the use of self-expanding metal stents (SEMS) for colonic cancer obstruction. Existing observational research mainly originates from highly specialized single-center settings with limited generalizability. The conduct of population-based nationwide studies is possible by using Danish medical databases. However, the quality of the coding of SEMS procedures in these databases is unclear. Methods: From March 1, 2010 through December 31, 2013, we compared the registration of SEMS procedures among obstructive colorectal cancer patients in the Danish National Patient Register (DNPR) and the Danish Colorectal Cancer Group (DCCG) database to the registration in a prospective SEMS database (the reference standard). Results: Ninety-three patients were included in the reference standard for the evaluation of DNPR data. In the DNPR, only two patients were incorrectly registered (positive predictive value [PPV]=98%, 95% CI: 92%–100%) whereas six patients were not captured by the DNPR (sensitivity =94%, 95% CI: 87%–98%). For the evaluation of the DCCG database, the reference standard included 54 patients. Only two patients in the DCCG database were incorrectly recorded (PPV =95%, 95% CI: 82%–99%), whereas 19 patients were not captured by the DCCG database (sensitivity =65%, 95% CI: 51%–77%). Conclusion: We found high PPV and sensitivity of SEMS coding in the DNPR, supporting the use of these data in future research. The PPV of SEMS data in the DCCG database was high, but the sensitivity was low, suggesting that data on SEMS treatment from this database should be used with caution. Keywords: validation study, colorectal neoplasms, surgery, endoscopy, self-expandable metallic stents

Jonathan Montomoli, Rune Erichsen, Henrik Gammelager, Alma B Pedersen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark Purpose: The aim of this study was to examine the prognostic impact of liver disease on mortality following hip fracture (HF). Patients and methods: This nationwide cohort study, based on prospectively collected data retrieved from Danish registries, included all patients diagnosed with incident HF in Denmark during 1996–2013. Patients were classified based on the coexisting liver disease at the time of HF, ie, no liver disease, noncirrhotic liver disease, and liver cirrhosis. We computed 30-day and 31–365-day mortality risks. To compare patients with and without liver disease, we computed mortality adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox regression controlled for potential confounders. Results: Among 152,180 HF patients, 2,552 (1.7%) patients had noncirrhotic liver disease and 1,866 (1.2%) patients had liver cirrhosis. Thirty-day mortality was 9.4% among patients with noncirrhotic liver disease, 12.6% among patients with liver cirrhosis patients, and 9.7% among patients without liver disease. Compared to patients without liver disease, crude and adjusted HRs within 30 days following HF were, respectively, 0.96 (95% CI: 0.85–1.10) and 1.24 (95% CI: 1.09–1.41) for patients with noncirrhotic liver disease and 1.30 (95% CI: 1.14–1.48) and 2.25 (95% CI: 1.96–2.59) for those with liver cirrhosis. Among patients who survived 30 days post-HF, the 31–365-day mortality was 18.5% among patients with noncirrhotic liver disease, 26.4% among patients with liver cirrhosis, and 19.4% among patients without liver disease. Corresponding crude and adjusted HRs were, respectively, 0.95 (95% CI: 0.86–1.04) and 1.08 (95% CI: 0.99–1.20) for patients with noncirrhotic liver disease and 1.40 (95% CI: 1.27–1.54) and 1.91 (95% CI: 1.72–2.12) for those with liver cirrhosis. Conclusion: Liver disease patients, especially those with liver cirrhosis, had increased 30-day mortality and 31–365-day mortality following HF, compared to patients without liver disease. Keywords: epidemiology, liver cirrhosis, hip fracture, mortality, noncirrhotic liver disease

Michael D Kappelman,1 Aksel Lange,2 Rachel L Randell,3 Patricia V Basta,4 Robert S Sandler,5 Kristina Laugesen,2 Anna Byrjalsen,2 Tina Christensen,2 Trine Frøslev,2 Rune Erichsen2,6 1Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Department of Clinical Epidemiology,Aarhus University Hospital, Aarhus, Denmark; 3Department of Pediatrics, Duke University School of Medicine, Duke University, Durham, NC, USA; 4Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6Surgical Department, Horsens Regional Hospital, Horsens, Denmark Background: Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene–environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn’s disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls.Subjects and methods: Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs).Results: A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls.Conclusion: This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene–environment interactions in complex chronic conditions such as CD. Keywords: Crohn’s disease, children, genetic, DNA, SNP

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

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 Aalborg, respectively. Kappa, sensitivity, and specificity of chemotherapy reporting in the DNRP was high (≥0.88), but the sensitivity of individual chemotherapies varied by hospital. Conclusion: The validity of chemotherapy reporting in the DNRP was high, although some variation by hospital exists. The DNRP represents a population-based nationwide resource that can be used to provide timely and accurate evaluations of chemotherapy use among CRC patients in Denmark. Keywords: chemotherapy, colorectal cancer, administrative data

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 study

Jihen Zalfani, Trine Frøslev, Morten Olsen, Inès Ben Ghezala, Henrik Gammelager, Johan FB Arendt, Rune ErichsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkObjective: Valid data on anemia caused by bleeding are needed for epidemiological research and monitoring health care. The Danish National Registry of Patients (DNRP) is a nationwide medical database with information on all Danish residents' hospital history. We aimed to assess the positive predictive value (PPV) of the diagnostic coding of anemia caused by bleeding in the DNRP.Methods: In the DNRP, we identified all patients with International Classification of Disease, 10th edition codes for anemia caused by bleeding (acute: D50.0; chronic: D62.6) at three Danish hospitals from 2000 through 2009. For these patients we computed the PPV using hemoglobin level data, from Aarhus University laboratory database, as reference standard. Anemia was defined by a hemoglobin level less than 7.0 mmol/L for women and less than 8.0 mmol/L for men.Results: We identified 3391 patients in the DNRP with a diagnosis of anemia caused by bleeding. The overall PPV was 95.4% (95% confidence interval [CI]: 94.6%–96.0%). The PPV was 97.6% (95% CI: 96.6%–98.3%) for men and 94.0% (95% CI: 92.9%–94.9%) for women, and the PPV increased with age at diagnosis. The PPV varied according to type of discharging departments, from 89.2% (95% CI: 83.4%–93.4%) in gynecology to 96.8% (95% CI: 94.9%–98.2%) in surgery, and was lower for outpatients compared with inpatients.Conclusion: We found a high PPV of the coding for anemia caused by bleeding in the DNRP. The registry is a valid source of data on anemia caused by bleeding for various purposes including research and monitoring health care.Keywords: anemia, Danish National Registry of Patients, International Classification of Diseases, predictive value, laboratory database, validation

Jonathan Montomoli,1 Stephen Jacques Hamilton-Dutoit,2 Trine Frøslev,1 Aliki Taylor,3 Rune Erichsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark; 3Centre for Observational Research, Amgen, Uxbridge, UKBackground: The occurrence of KRAS mutations and their association with prognosis in metastatic colorectal cancer patients is not well documented in population-based studies.Objectives: To examine the feasibility of identifying archived colorectal cancer specimens, and through linkage with nationwide Danish population-based databases to investigate the prevalence of KRAS mutations and their association with colorectal cancer survival.Methods: We used the Danish Pathology Database to identify the physical location of primary (or in some cases secondary) tumor specimens from selected metastatic colorectal cancer patients referred to our hospital for palliative chemotherapy between November 1, 2008 and September 30, 2009. Routinely stored paraffin tissue blocks were obtained from the pathology archives of the originating hospital. KRAS mutation tumor status was assessed for each patient using the commercialized TheraScreen KRAS Mutation Kit. Using the unique identifier number, we linked the patients to the Danish National Registry of Patients and the Danish Civil Registration System to obtain data on date of first colorectal cancer diagnosis and follow-up status. We estimated prevalence of KRAS mutations and the 1-, 2-, and 5-year survival after colorectal cancer diagnosis using the Kaplan–Meier technique.Results: We identified 106 metastatic colorectal cancer patients (64% males). All were successfully linked to the registries, and archived tumor-tissue samples were obtained and analyzed in each case. The overall prevalence of KRAS mutations was 55%, and 1-, 2-, and 5-year overall survival after colorectal cancer diagnosis was 91%, 68%, and 25%, respectively.Conclusion: It is feasible to use Danish population-based registries to obtain archived tissue samples from metastatic colorectal cancer patients, and to estimate prevalence of KRAS mutation and subsequently evaluate the association with colorectal cancer survival.Keywords: feasibility study, KRAS, colorectal neoplasms, survival, registries

Malene Schou Nielsson,1 Rune Erichsen,1 Trine Frøslev,1 Aliki Taylor,2 John Acquavella,2 Vera Ehrenstein11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research International, Amgen Ltd Thousand Oaks, CA, USA Background: The purpose of this study was to estimate the positive predictive value (PPV) of the coding for bisphosphonate treatment in selected cancer patients from the Danish National Patient Registry (DNPR).Methods: Through the DNPR, we identified all patients with recorded cancer of the breast, prostate, lung, kidney, and with multiple myeloma. We restricted the study sample to patients with bisphosphonate treatment recorded during an admission to Aalborg Hospital, Denmark, from 2005 through 2009. We retrieved and reviewed medical records of these patients from the initial cancer diagnosis onwards to confirm or rule out bisphosphonate therapy. We calculated the PPV of the treatment coding as the proportion of patients with confirmed bisphosphonate treatment.Results: We retrieved and reviewed the medical records of 60 cancer patients with treatment codes corresponding to bisphosphonate therapy. Recorded code corresponded to treatment administered intravenously for 59 of 60 patients, corresponding to a PPV of 98.3% (95% confidence interval 92.5–99.8). In the remaining patient, bisphosphonate treatment was also confirmed but was an orally administered bisphosphonate; thus, the treatment for any bisphosphonate regardless of administration was confirmed for all 60 patients (PPV of 100%, 95% confidence interval 95.9–100.0).Conclusion: The PPV of bisphosphonate treatment coding among cancer patients in the DNPR is very high and the recorded treatment nearly always corresponds to intravenous administration.Keywords: bisphosphonate, neoplasm metastases, predictive value of tests, validation studies

Ane Birgitte Telén Andersen, Dóra Körmendiné Farkas, Frank Mehnert, Vera Ehrenstein, Rune ErichsenDepartment of Clinical Epidemiology, Aarhus University Hospital, DenmarkPurpose: Use of paracetamol during pregnancy may increase the risk of asthma in offspring. The association between prenatal exposure to maternal use of paracetamol and risk of asthma was investigated.Methods: A cohort study of 197,060 singletons born in northern Denmark in 1996–2008 was conducted, with follow-up until the end of 2009. Maternal paracetamol use during pregnancy was defined as a redeemed prescription. Asthma in offspring was defined as at least two prescriptions of both a β-agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during follow-up. Absolute risk of asthma in offspring was estimated using the Kaplan–Meier method and incidence rate ratios adjusted for known risk factors were estimated using Cox proportional-hazards regression.Results: Overall, 976 (0.5%) children were exposed prenatally to maternal use of prescription paracetamol. During follow-up, 24,506 (12.4%) children developed asthma. Absolute risk of asthma was 7.5% after 2 years and 14.4% after 10 years among the unexposed children. Corresponding risks were 12.7% and 21.6% among the exposed children. The adjusted incidence rate ratio was 1.35 (95% confidence interval: 1.17–1.57) for exposure in any trimester of pregnancy. A similar association was present for paracetamol exposure in each of the trimesters and for maternal use of prescription nonsteroidal anti-inflammatory drugs. Furthermore, maternal prescription use in the year following the relevant delivery also showed similar associations.Conclusion: A robust association was found between prenatal exposure to maternal use of prescription paracetamol and the risk of asthma; however, noncausal explanations could not be ruled out for such association.Keywords: acetaminophen, asthma, children, paracetamol, pregnancy

Jonathan Montomoli1, Rune Erichsen1, Mette Nørgaard1, Morten Høyer2, Jesper Bach Hansen3, Jacob Bonde Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; 3Medical Department of Gastroenterology, Aalborg Hospital, Aalborg, DenmarkObjective: Primary liver cancer (PLC) is a serious disease with high mortality. During the last decade, improvements in the diagnostic procedures and treatment of PLC may have improved survival. However, few updated longitudinal studies examined this issue. In a population-based setting, we studied changes in the prognoses over time.Methods: Between 1998 and 2009, we identified all patients with PLC in the central and northern Denmark regions, with a combined population of 1.8 million. We determined age- and period-stratified survival, and computed mortality rate ratios (MRRs) with 95% confidence intervals (CIs), using Cox proportional hazard regression to assess changes over time, while controlling for age and gender. We conducted the analyses for PLC overall and separately for hepatocellular carcinoma (HCC) and cholangiocarcinoma, respectively.Results: We included 1064 patients with PLC. Their median age was 69 years (range 17–94 years). The number of patients diagnosed with PLC in the period 2007–2009 was approximately 40% higher than the number in 1998–2000. One-year survival increased from 16% in 1998–2000 to 28% in 2007–2009, corresponding to an adjusted 1-year MRR of 0.65 (95% CI: 0.54–0.79). In patients aged ,60 years, we found the most pronounced increase in 1-year survival, from 14% to 49% in women and from 19% to 41% in men. The 3- and 5-year survival in the entire cohort increased from 5% to a predicted 11% and from 2% to a predicted 7% during our study period, respectively. Accordingly, the expected 3- and 5-year adjusted MRRs were 0.68 (95% CI: 0.57–0.82) and 0.68 (95% CI: 0.57–0.81), respectively. One-, 3-, and 5-year survival improved during the study period for both HCC and cholangiocarcinoma.Conclusion: PLC survival remains poor in the Danish population, although we observed an increase over the period 1998–2009, particularly in young people.Keywords: liver neoplasm, prognosis, mortality, epidemiology

Morten Høyer1,2, Rune Erichsen1, Per Gandrup3, Mette Nørgaard1, Jacob Bonde Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Gastrointestinal Surgery, Aarhus University Hospital, Aalborg, DenmarkObjective: In Denmark, the strategy for treatment of cancer with metastases to the liver has changed dramatically during the period 1998 to 2009, when multidisciplinary care and a number of new treatments were introduced. We therefore examined the changes in survival in Danish patients with colorectal carcinoma (CRC) or other solid tumors (non-CRC) who had liver metastases at time of diagnosis.Study design and methods: We included patients diagnosed with liver metastases synchronous with a primary cancer (ie, a solid cancer diagnosed at the same date or within 60 days after liver metastasis diagnosis) during the period 1998 to 2009 identified through the Danish National Registry of Patients. We followed those who survived for more than 60 days in a survival analysis (n = 1021). Survival and mortality rate ratio (MRR) at 1, 3, and 5 years stratified by year of diagnosis were estimated using Cox proportional hazards regression analysis.Results: In the total study population of 1021 patients, 541 patients had a primary CRC and 480 patients non-CRC. Overall, the 5-year survival improved from 3% (95% confidence interval [CI]: 1%–6%) in 1998–2000 to 10% (95% CI: 6%–14%) in 2007 to 2009 (predicted value). The 5-year survival for CRC-patients improved from 1% (95% CI: 0%–5%) to 11% (95% CI: 6%–18%) whereas survival for non-CRC patients only increased from 5% (95% CI: 1%–10%) to 8% (95% CI: 4%–14%).Conclusion: We observed improved survival in patients with liver metastases in a time period characterized by introduction of a structured multidisciplinary care and improved treatment options. The survival gain was most prominent for CRC-patients.Keywords: liver metastases, colorectal cancer, noncolorectal cancer, survival improvement

Michael Borre1,2, Rune Erichsen1, Lars Lund3, Erik Højkjær Larsen4, Mette Nørgaard1, Jacob Bonde Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Department of Urology, Aarhus University Hospital, Skejby, Denmark; 3Department of Urology, Region Hospital Viborg, Denmark; 4Department of Urology, Aarhus University Hospital, Aalborg, DenmarkObjective: Prostate cancer is the most common noncutaneous cancer among Danish men. During the last decade, use of prostate specific antigen (PSA) testing has increased, and in clinically localized prostate cancer, curative intended treatment has gained a footing. Our aim was to examine possible changes in the short- and long-term survival of patients with prostate cancer during 1998–2009.Study design and setting: From two Danish regions (population, 1.8 million) we included all patients (N = 10,547) with an incident diagnosis of prostate cancer retrieved from the Danish National Registry of Patients. We determined survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox proportional hazard regression to assess changes over time, controlling for age.Results: During the study period, the annual number of incident prostate cancer patients more than doubled, and the median age at diagnosis decreased from 74 to 70 years. The survival improved over the study period, particularly in the last half of the period (2004–2009). Thus, 1-year survival increased from 80% (1998–2000) to 90% (2007–2009), corresponding to an age-adjusted MRR of 0.54 (95% confidence interval CI: 0.46–0.63). The expected increase in 3- and 5-year survival was even more pronounced: 47%–73% and 34%–60%, respectively. This corresponded to a 3-year age-adjusted MRR of 0.46 (95% CI: 0.42–0.51) and a 5-year MRR of 0.50 (95% CI: 0.46–0.54). The 1-, 3-, and 5-year overall survival increased in all age groups (

Tau Pelant1,2, Erik Højkjær Larsen1,2, Lars Lund3, Michael Borre4, Rune Erichsen1, Mette Nørgaard1, Jacob Bonde Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Department of Urology, Aarhus University Hospital, Aalborg, Denmark; 3Department of Urology, Viborg Hospital, Denmark; 4Department of Urology, Aarhus University Hospital, Skejby, DenmarkObjective: For decades, kidney cancer patients in Denmark have had lower survival than patients in the other Scandinavian countries. Our aim was to study possible changes in survival of patients with kidney cancer after implementation of two national Danish cancer plans.Study design and setting: From 1998 through 2009 we included all patients (N = 2659) with an incident diagnosis of kidney cancer in two Danish regions (population 1.8 million). Data were retrieved from the Danish National Registry of Patients. We computed survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox regression to assess changes over time, controlling for age and gender. We lacked data on stage distribution. Among patients who had a nephrectomy we also computed 30-day mortality and 30-day MRRs.Results: During the study period, we identified 2659 patients with kidney cancer. The annual number of patients increased from 583 in the period 1998–2000 to 853 in the period 2007–2009. The median age at diagnosis was 69 years throughout the study period. The overall 1-year survival improved from 56% (1998–2000) to 63% (2007–2009), corresponding to an adjusted MRR of 0.78 (95% confidence interval [CI] 0.66–0.93). We predicted the 3-year survival to increase from 40% to 51% and the 5-year survival to increase from 33% to 42%, corresponding to predicted MRRs of 0.76 (95% CI 0.66–0.87) and 0.77 (95% CI 0.68–0.89), respectively. Survival increased in all age groups (15–59 years, 60–74 years, 75+ years) and in both genders, except for men below 60 years, for whom the 1-year survival declined from 76% to 69%. The 30-day mortality after nephrectomy declined from 4% to 2% during the study period.Conclusion: We observed an improvement in the survival and relative mortality in kidney cancer patients, although not in men younger than 60 years.Keywords: kidney neoplasm, outcome research, mortality rate ratio, MRR

Deirdre P Cronin-Fenton1, Rune Erichsen1, Frank V Mortensen2, Sarunas Dikinis3, Mette Nørgaard1, Jacob Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Department of Gastrointestinal Surgery L, Aarhus University Hospital, Denmark; 3Department of Gastrointestinal Surgery A, Aalborg Hospital, Aarhus University Hospital, DenmarkObjectives: Pancreatic cancer has a relatively low incidence but ranks fourth among cancer-related deaths in western countries. In Denmark, cancer survival generally is lower than in other countries with comparable health care systems. As a result, in 2000, a national strategy to improve cancer survival was introduced. Here we examine time trends in survival and relative mortality among pancreatic cancer patients, using Danish population and medical databases.Methods: Using the Danish National Patient Registry (DNPR), we identified all incident pancreatic cancer patients (n = 2968) diagnosed between 1998 and 2009 in the Central and North Denmark Regions. We computed the 1-, 3-, and 5-year survival and relative mortality (MRR) and associated 95% confidence intervals (CI) adjusting for age and gender. Among surgical patients, we also computed 30-day mortality and 30-day MRR.Results: Median age at diagnosis was approximately 71 years. The annual number of patients increased from 189 in 1998–2000 to 302 in 2007–2009. There was a slight improvement in 1-, 3-, and 5-year survival over time from 14.8% to 17.7%; 3.5% to a predicted 5.6%; and from 2.0% to a predicted 3.8%, from 1998–2000 to 2007–2009, respectively. Correspondingly, the adjusted relative mortality decreased from 1998–2000 to 2007–2009. Thirty-day post-operative mortality decreased from 12.2% in 1998–2000 to 5.8% in 2007–2009, corresponding to a 30-day MRR of 0.38, 95% CI = 0.09, 1.6 in 2007–2009.Conclusion: There was a slight, albeit modest, improvement in survival and relative mortality in pancreatic cancer patients between 1998 and 2009. As we lacked staging information, it is not clear if this improvement is attributable to earlier stage at diagnosis. However, these improvements likely reflect the national cancer strategy which aimed to centralize cancer services and involved the introduction of palliative and adjuvant chemotherapy for pancreatic cancer in Denmark. The dismal prognosis of pancreatic cancer means that efforts to improve survival need to be intensified.Keywords: pancreatic cancer, survival, relative mortality, epidemiology

Eva B Ostenfeld1, Rune Erichsen1, Lene H Iversen1,2, Per Gandrup3, Mette Nørgaard1, Jacob Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark; 3Department of Surgery A, Aarhus University Hospital, Aalborg, DenmarkObjective: The prognosis for colon and rectal cancer has improved in Denmark over the past decades but is still poor compared with that in our neighboring countries. We conducted this population-based study to monitor recent trends in colon and rectal cancer survival in the central and northern regions of Denmark.Material and methods: Using the Danish National Registry of Patients, we identified 9412 patients with an incident diagnosis of colon cancer and 5685 patients diagnosed with rectal cancer between 1998 and 2009. We determined survival, and used Cox proportional hazard regression analysis to compare mortality over time, adjusting for age and gender. Among surgically treated patients, we computed 30-day mortality and corresponding mortality rate ratios (MRRs).Results: The annual numbers of colon and rectal cancer increased from 1998 through 2009. For colon cancer, 1-year survival improved from 65% to 70%, and 5-year survival improved from 37% to 43%. For rectal cancer, 1-year survival improved from 73% to 78%, and 5-year survival improved from 39% to 47%. Men aged 80+ showed most pronounced improvements. The 1- and 5-year adjusted MRRs decreased: for colon cancer 0.83 (95% confidence interval CI: 0.76–0.92) and 0.84 (95% CI: 0.78–0.90) respectively; for rectal cancer 0.79 (95% CI: 0.68–0.91) and 0.81 (95% CI: 0.73–0.89) respectively. The 30-day postoperative mortality after resection also declined over the study period. Compared with 1998–2000 the 30-day MRRs in 2007–2009 were 0.68 (95% CI: 0.53–0.87) for colon cancer and 0.59 (95% CI: 0.37–0.96) for rectal cancer.Conclusion: The survival after colon and rectal cancer has improved in central and northern Denmark during the 1998–2009 period, as well as the 30-day postoperative mortality.Keywords: neoplasms, survival, epidemiology, colorectal cancer

Lars Lund1,2, R Erichsen1, M Nørgaard1, E H Larsen3, M Borre4, J Jacobsen11Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Department of Urology, Viborg Hospital, Denmark; 3Department of Urology, Aarhus University Hospital, Aalborg, Denmark; 4Department of Urology, Aarhus University Hospital, Skejby, DenmarkObjective: Invasive bladder cancer (IBC) is a common urological malignancy accounting for 4%–5% of all cancers in Denmark. Our aim was to examine possible changes in short- and long-term survival of patients with IBC during 1998–2009.Study design and setting: Data on all patients (N = 4032) with an incident diagnosis of IBC within a population of 1.8 million were retrieved from the Danish National Registry of Patients from 1998 to 2009. We computed survival after 1, 3, and 5 years, stratified by age and gender, and estimated mortality rate ratios (MRR) using Cox proportional hazard regression to compare mortality over time, controlling for age and gender. Data on tumor stage or histology were not included.Results: During the study period, the annual numbers of incident IBC patients remained stable. The median age was 74 years in each of the four 3-year periods in the study. The survival was relatively stable during the first three periods, whilst data from the last period showed modest improvement. The overall 1-year survival increased from 68% in 1998–2000 to 70% in 2007–2009, corresponding to an age and gender adjusted MRR of 0.89 (95% confidence interval [CI] 0.76–1.03). The 3- and 5-year survival was predicted to increase from 44% to 49% and from 35% to 40% respectively. This corresponded to a 3-year age and gender adjusted MRR of 0.87 (95% CI 0.77–0.98) and a 5-year MRR of 0.88 (95% CI 0.79–0.99). The 1-, 3-, and 5-year survival increased for men in all age groups (

Anne Fia Grann, Rune Erichsen, Anders Gunnar Nielsen, Trine Frøslev, Reimar W ThomsenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkAbstract: This paper provides an introduction to the clinical laboratory information system (LABKA) research database in Northern and Central Denmark. The database contains millions of stored laboratory test results for patients living in the two Danish regions, encompassing 1.8 million residents, or one-third of the country's population. More than 1700 different types of blood test analyses are available. Therefore, the LABKA research database represents an incredible source for studies involving blood test analyses. By record linkage of different Danish registries with the LABKA research database, it is possible to examine a large number of biomarkers as predictors of disease risk and prognosis and as markers of disease severity, and to evaluate medical treatments regarding effectiveness and possible side effects. Large epidemiological studies using routinely stored blood test results for individual patients can be performed because it is possible to link the laboratory data to high-quality individual clinical patient data in Denmark.Keywords: biochemistry, laboratory procedures, diagnosis, therapeutic drug monitoring, epidemiological methods, registries

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Background Patients with Barrett's oesophagus may be at increased risk of mortality overall, and cardiovascular disease has been suggested as the main underlying cause of death. Aim To examine cause-specific mortality and risk of cardiovascular events among patients with Barrett's oesophagus. Methods Utilising existing Danish data sources (1997-2011), we identified all patients with histologically verified Barrett's oesophagus ( n = 13 435) and 123 526 members of the general population matched by age, sex and individual comorbidities. We calculated cause-specific mortality rates and incidence rates of cardiovascular diseases. We then compared rates between patients with Barrett's oesophagus and the general population comparison cohort, using stratified Cox proportional hazard regression. Results Patients with Barrett's oesophagus had a 71% increased risk of overall mortality. The cause-specific mortality rate per 1000 person-years for patients with Barrett's oesophagus was 8.5 for cardiovascular diseases, 14.7 for non-oesophageal cancers, and 5.4 for oesophageal cancer. Compared to the general population cohort, corresponding hazard ratios were 1.26 (95% confidence interval ( CI): 1.15-1.38), 1.77 (95% CI: 1.65-1.90), and 19.4 (95% CI: 16.1-23.4), respectively. The incidence rates of cardiovascular diseases per 1000 person-years for Barrett's oesophagus patients and for persons from the general population cohort, respectively, varied from 0.4 and 0.2 for subarachnoid bleeding (hazard ratio 1.10, 95% CI: 0.87-1.39) to 8.1 and 5.9 for congestive heart failure (hazard ratio 1.33, 95% CI: 1.21-1.46). Conclusion Prophylactic measures targeted at cardiovascular diseases and non-oesophageal cancers potentially could be more important than measures against oesophageal cancer, for improving prognosis among patients with Barrett's oesophagus. [ABSTRACT FROM AUTHOR]

The Blume–Emery–Griffiths model with a random crystal field is studied in a random graph architecture, in which the average connectivity is a controllable parameter. The disordered average over the graph realizations is treated by replica symmetry formalism of order parameter functions. A self consistent equation for the distribution of local fields is derived, and numerically solved by a population dynamics algorithm. The results show that the average connectivity amounts to changes in the topology of the phase diagrams. Phase diagrams for representative values of the model parameters are compared with those obtained for fully connected mean field and renormalization group approaches. [ABSTRACT FROM AUTHOR]

Background:It is unknown whether comorbidity interacts with colorectal cancer (CRC) to increase the rate of mortality beyond that explained by the independent effects of CRC and comorbid conditions.Methods:We conducted a cohort study (1995-2010) of all Danish CRC patients (n=56 963), and five times as many persons from the general population (n=271 670) matched by age, gender, and specific comorbidities. To analyse comorbidity, we used the Charlson Comorbidity Index (CCI) scores. We estimated standardised mortality rates per 1000 person-years, and calculated interaction contrasts as a measure of the excess mortality rate not explained by the independent effects of CRC or comorbidities.Results:Among CRC patients with a CCI score=1, the 0-1 year mortality rate was 415 out of 1000 person-years (95% confidence interval (CI): 401, 430) and the interaction accounted for 9.3% of this rate (interaction contrast=39 out of 1000 person-years, 95% CI: 22, 55). For patients with a CCI score of 4 or more, the interaction accounted for 34% of the mortality (interaction contrast=262 out of 1000 person-years, 95% CI: 215, 310). The interaction between CRC and comorbidities had limited influence on mortality beyond 1 year after diagnosis.Conclusion:Successful treatment of the comorbidity is pivotal and may reduce the mortality attributable to comorbidity itself, and also the mortality attributable to the interaction. [ABSTRACT FROM AUTHOR]

Colorectal cancer has recently been associated with an increased atrial fibrillation risk, but evidence is very sparse. So, we conducted a population-based case-control study in northern Denmark (population 1.7 million) during 1998-2006 to estimate the atrial fibrillation/flutter risk in colorectal cancer patients. We identified 28,333 atrial fibrillation/flutter cases and 283,260 sex-, age-, and county-matched population controls. We searched the databases for a prior colorectal cancer diagnosis, a prior cancer diagnosis other than colorectal cancer, and performance of surgery within 30 days prior to atrial fibrillation/flutter. We used conditional logistic regression to estimate the OR of atrial fibrillation/flutter in patients with colorectal cancer, cancers other than colorectal and in patient with surgery. Among cases, 0.59% (n = 168) had a colorectal cancer diagnosis within 90 days before their atrial fibrillation/flutter diagnosis, compared with 0.05% (n = 155) of controls (adjusted OR = 11.8; 95% CI 9.3-14.9). Beyond the first 90 days after a colorectal cancer diagnosis, atrial fibrillation/flutter risk was no longer increased. There was likewise an increased atrial fibrillation/flutter risk in patients diagnosed with another cancer form in the prior 90 days (OR = 7.0, 95% CI 6.3-7.8). Furthermore, the atrial fibrillation/flutter risk was elevated fivefold in patients who had undergone surgery, whether or not cancer-related. We therefore conclude that colorectal cancer patients are at increased atrial fibrillation/flutter risk exclusively in the first 90 days after cancer diagnosis, but to no greater an extent than are patients with other cancers. The performance of surgery probably plays an important role in this association. [ABSTRACT FROM AUTHOR]