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Guilian Birindwa,1,2 Michael Maeng,1,3 Pernille Gro Thrane,1 Christine Gyldenkerne,1,2 Reimar Wernich Thomsen,2 Kevin Kris Warnakula Olesen1 1Department of Cardiology Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Medicine, Department of Cardiology, Aarhus University Hospital, Aarhus University, Aarhus, DenmarkCorrespondence: Kevin Kris Warnakula Olesen, Department of Cardiology, Aarhus University Hospital, Palle-Juul Jensens Boulevard 99, Aarhus N, 8200, Tel +0045 53 80 64 80, Email kevole@clin.au.dkBackground: Diabetes mellitus (DM) patients without coronary artery disease (CAD) have a higher all-cause mortality rate than patients with neither DM nor CAD. We examined cause-specific death of DM patients with and without CAD.Methods: We conducted a cohort study of all patients who underwent CAG in Western Denmark between 2003 and 2016. Using Danish health registries, patients were followed for a maximum of 10 years and stratified according to their DM and CAD status. Outcomes included all-cause-, cancer-, circulatory-, and endocrinologic death. Ten-year cumulative risks were computed as well as adjusted and unadjusted hazard ratios (aHR and HR).Results: A total of 132,432 patients (28,524 deaths, median follow-up of 6.2 years) were included. Compared to patients with neither DM nor CAD, DM patients without CAD had a higher 10-year risk of all-cause death (27.9% versus 19.7%, aHR 1.43 [95% CI 1.35– 1.52]), cancer death (7.2% versus 5.4%, aHR 1.29 [95% CI 1.15– 1.46]), circulatory death (9.1% versus 6.9%, aHR 1.35 [95% CI 1.22– 1.49]), and endocrinologic death (3.9% versus 0.3%, aHR 14.02 [95% CI 10.95– 17.95]). Among endocrinologic deaths, 87% were due to classical complications of DM, such as diabetic nephropathy and ketoacidosis, in DM patients without CAD.Conclusion: Diabetes patients without CAD exhibit a higher risk of all-cause mortality, driven primarily by elevated rates of cancer, circulatory, and endocrinologic deaths, particularly related to diabetic microvascular complications.Keywords: diabetes, coronary artery disease, death

Frederik PB Kristensen,1 Sia K Nicolaisen,1 Jens S Nielsen,2,3 Diana H Christensen,1,4 Kurt Højlund,2,3 Henning Beck-Nielsen,2 Jørgen Rungby,5 Søren G Friborg,6 Ivan Brandslund,7,8 Jens S Christiansen4 ,† Peter Vestergaard,9,10 Niels Jessen,11– 13 Michael H Olsen,14,15 Mette K Andersen,16 Torben Hansen,16 Charlotte Brøns,5 Allan Vaag,5,17 Reimar W Thomsen,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Steno Diabetes Center Copenhagen, Herlev, Denmark; 6Department of Endocrinology, Odense University Hospital, Odense, Denmark; 7Department of Biochemistry, Lillebaelt Hospital, Vejle, Denmark; 8Regional Health Research, University of Southern Denmark, Odense, Denmark; 9Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 10Steno Diabetes Center North Denmark, Aalborg, Denmark; 11Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 12Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark; 13Department of Biomedicine, Aarhus University, Aarhus, Denmark; 14Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 15Department of Internal Medicine and Steno Diabetes Center Zealand, Holbæk Hospital, Holbæk, Denmark; 16Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark; 17Lund University Diabetes Centre, Lund University, Malmö, Sweden†Dr Jens S Christiansen passed away on 16 December 2015Correspondence: Frederik PB Kristensen, Department of Clinical Epidemiology, Aarhus University, Olof Palmes Alle 43-45, Aarhus N, 8200, Denmark, Tel +45 87 16 82 37, Email fpk@clin.au.dkPurpose: This paper provides an overview of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort and biobank, including baseline characteristics of participants enrolled up to 2023, and post-enrollment rates of cardiovascular disease outcomes and mortality.Methods: Since 2010, the DD2 project has enrolled individuals with type 2 diabetes mellitus (T2DM) recently diagnosed by general practitioners and by hospital-based clinicians across Denmark. Data from questionnaires, clinical examinations, and biological samples are collected at enrollment. Additional baseline and longitudinal follow-up data are accessed via linkage to health registries.Results: Between 2010 and 2023, the DD2 project enrolled 11,369 participants (41.3% women, median age 61.4 years). Median T2DM duration at enrollment was 1.3 years, and median BMI was 31.6 kg/m2 for women and 30.5 kg/m2 for men. 18.3% were smokers, 5.7% consumed more than 14/21 units of alcohol weekly (women/men), and 17.9% reported leisure-time physical inactivity. Original midwife records dating back > 80 years revealed that 20.2% of cohort participants had birth weights < 3000 g. Based on complete hospital contact history 10 years before enrollment, 20.7% of cohort participants had macrovascular complications, 17.0% had microvascular complications, and 21.7% had kidney disease based on eGFR or urine albumin-creatinine measurements. At enrollment, statins were used by 68.2%, antihypertensive drugs by 69.9%, and glucose-lowering drugs by 86.5% of individuals. Median HbA1c was 48 mmol/mol and median LDL cholesterol 2.2 mmol/L. Genome-wide genotyping and biomarker data have been analyzed for over 9000 individuals. During the current follow-up time from the enrollment date (median 7.9 years), incident cardiovascular disease rate has been 13.8 per 1000 person-years and the mortality rate has been 17.6 per 1000 person-years.Conclusion: The DD2 cohort, with its detailed information and long-term follow up, can improve our understanding of the progression and prevention of complications among individuals with newly diagnosed T2DM.Keywords: cohort profile, type 2 diabetes mellitus, patient characteristics, Denmark

Aurélie Mailhac,1 Lars Pedersen,1 Anton Pottegård,2 Jens Søndergaard,3 Torben Mogensen,4 Henrik Toft Sørensen,1 Reimar W Thomsen1 1Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Research Unit of General Practice, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Danish Pharmacovigilance Council, Danish Medicines Agency, Copenhagen, DenmarkCorrespondence: Reimar W Thomsen, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark, Email rwt@clin.au.dkPurpose: A surge in the use of semaglutide injection (Ozempic®) approved to treat type 2 diabetes (T2D) has led to a global supply shortage. We investigated contemporary user rates and clinical characteristics of semaglutide (Ozempic®) users in Denmark, and the extent of “off-label” prescribing for weight loss.Patients and Methods: Nationwide population-based cross-sectional study based on linked health registries January 2018 through December 2023. All adults who received a first prescription of semaglutide once weekly (Ozempic®) were included. We examined quarterly rates of new users and total user prevalences, using other glucagon-like peptide-1 receptor agonists and weight loss medications as comparison. We also investigated user characteristics including T2D, glucose control, comedications, and cardiorenal disease.Results: The new user rate of semaglutide (Ozempic®) remained stable at approximately 4 per 1000 adult person-years between 2019 and 2021 and then accelerated, peaking at 10 per 1000 in the first quarter of 2023 after which it declined sharply. User prevalence increased to 91,626 users in Denmark in 2023. The proportion of semaglutide (Ozempic®) new users who had a record of T2D declined from 99% in 2018 to only 67% in 2022, increasing again to 87% in 2023. Among people with T2D who initiated semaglutide (Ozempic®) in 2023, 52% received antidiabetic polytherapy before initiation, 39% monotherapy, and 8% no antidiabetic therapy. Most T2D initiators had suboptimal glucose control, with 83% having an HbA1c ≥ 48 mmol/mol and 68% ≥ 53 mmol/mol despite use of antidiabetic medication, and 29% had established atherosclerotic cardiovascular disease or kidney disease.Conclusion: The use of semaglutide (Ozempic®) in Denmark has increased dramatically. Although not approved for weight loss without T2D, one-third of new users in 2022 did not have T2D. Conversely, most initiators with T2D had a clear medical indication for treatment intensification, and “off-label” use can only explain a minor part of the supply shortage.Keywords: drug utilization, epidemiology, anti-obesity drugs, glucose-lowering drugs, obesity, type 2 diabetes

Sigrid Bjerge Gribsholt,1,2 Dóra Körmendiné Farkas,3 Reimar Wernich Thomsen,3 Bjørn Richelsen,1,2 Henrik Toft Sørensen3 1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Steno Diabetes Center, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, DenmarkCorrespondence: Sigrid Bjerge Gribsholt, Tel +4561651148, Email sigrid.bjerge.gribsholt@clin.au.dkPurpose: Data on long-term mortality among patients with hospital-diagnosed overweight/obesity are limited. Thus, we aim to examine 40-year mortality among patients with hospital-diagnosed overweight/obesity, including cause-specific deaths, secular time trends, and potential effect modification by age, comorbidity, and socioeconomic factors.Patients and Methods: From national registries, we identified all Danes with a first hospital-based overweight/obesity diagnosis (N=331,185), 1979– 2018, and constructed an age- and gender-matched general population comparison cohort (N=1,655,925). We computed mortality rates (MRs) per 1000 person-years and adjusted mortality rate ratios (aMRRs) with 95% confidence intervals (CIs), using Cox regression with adjustment for comorbidities and educational level. We performed stratified analyses on age, comorbidities, and socioeconomic factors.Results: The overall aMRR was 1.70 (95% CI: 1.68– 1.72) for patients with overweight/obesity, mainly due to diabetes and other endocrine diseases (aMRR=2.68 [95% CI: 2.57– 2.81]), cardiovascular (aMRR=1.95 [95% CI: 1.91– 1.98]), and respiratory diseases (aMRR=1.83 [95% CI: 1.77– 1.89]). The 1– 10-year aMRR decreased from 2.06 (95% CI: 2.01– 2.11) in 1979– 1989 to 1.29 (95% CI: 1.26– 1.32) in 2000– 2009. We found effect modification by age: age 18 to < 30 years: aMRR=2.44 (95% CI: 2.24– 2.66) vs age ≥ 70 years: 1.35 (95% CI: 1.33– 1.37); comorbidities: baseline comorbidities: aMRR=1.13 (95% CI: 1.10– 1.15) vs no comorbidities: aMRR=1.83 (95% CI: 1.80– 1.85); and educational level: high educational level: aMRR=1.81 (95% CI: 1.74– 1.88) vs low educational level: aMRR=1.70 (95% CI: 1.67– 1.72).Conclusion: Patients with overweight/obesity had a substantially increased long-term mortality, mainly due to diabetes, cardiovascular, and respiratory diseases. The excess mortality decreased during recent decades. Age, comorbidities, and socioeconomic factors modified the association.Keywords: cohort study, epidemiology, mortality, multi-morbidity, obesity, overweight, socio-economy

Søren Viborg Vestergaard,1 Uffe Heide-Jørgensen,1 Heleen van Haalen,2 Glen James,3 Katarina Hedman,4 Henrik Birn,5,6 Reimar Wernich Thomsen,1 Christian Fynbo Christiansen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Health Economics & Payer Evidence, AstraZeneca, Gothenburg, Sweden; 3Epidemiology, AstraZeneca, Cambridge, UK; 4Biometrics, AstraZeneca, Gothenburg, Sweden; 5Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark; 6Department of Biomedicine, Aarhus University, Aarhus, DenmarkCorrespondence: Søren Viborg VestergaardDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N 8200, DenmarkTel +45 87168514Email sovi@clin.au.dkPurpose: Anemia is prevalent in patients with chronic kidney disease (CKD), but the longitudinal risk of anemia in patients with newly identified CKD is unknown. We therefore examined the risks of experiencing anemia in persons with newly identified CKD.Patients and Methods: This cohort study included adult patients with newly identified CKD stages 3– 5 defined by an estimated glomerular filtration rate (eGFR) level < 60 mL/min/1.73m2 (at least two measurements ≥ 90 days apart) ascertained from a population-based registry with complete laboratory test results in Northern Denmark (population ∼ 2.2 million) during 2009– 2016. We calculated 1) cumulative incidence (risk) of anemia [hemoglobin < 12/< 13 g/dl in women/men] by CKD stage, and 2) adjusted hazard ratios (HRs) of anemia using Cox regression analyses.Results: We identified 55,940 distinct individuals with newly identified CKD stages 3– 5 and no prevalent anemia [n=41,958 patients in stage 3a, n=17,875 in stage 3b, n=5182 in stage 4, and n=931 in stage 5]. After one year, 42.3% (95%-confidence interval [CI]: 41.9– 42.7) of patients with CKD stages 3– 5 had newly measured anemia, increasing to 67.7% (95%-CI: 67.2– 68.2) after five years. The absolute and relative anemia risk increased markedly with higher CKD stages. The adjusted HR of any anemia was 5.42 (95%-CI: 5.09– 5.77) in patients with CKD stage 5 compared to patients with CKD stage 3a.Conclusion: Patients with newly identified CKD stages 3– 5 have a substantial risk of anemia, increasing with higher CKD stages. This study underlines that clinical awareness of anemia risk is important in patients with newly identified or progressed CKD.Keywords: anemia, chronic kidney disease, CKD, epidemiology, cohort study

Anton Pottegård,1 Kasper Bruun Kristensen,1 Mette Reilev,1 Lars Christian Lund,1 Martin Thomsen Ernst,1 Jesper Hallas,1,2 Reimar Wernich Thomsen,3 Christian Fynbo Christiansen,3 Henrik Toft Sørensen,3,4 Nanna Borup Johansen,5 Henrik Støvring,1,6 Steffen Christensen,7 Marianne Kragh Thomsen,8 Anders Husby,9 Marianne Voldstedlund,10 Jesper Kjær,11 Nikolai C Brun5 1Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Clinical Biochemistry and Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; 5Department of Medical Evaluation and Biostatistics, Danish Medicines Agency, Copenhagen, Denmark; 6Department of Public Health – Biostatistics, Aarhus University, Aarhus, Denmark; 7Department of Anesthesia and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark; 8Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark; 9Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 10Infection Preparedness, Statens Serum Institut, Copenhagen, Denmark; 11Data Analytics Center, Danish Medicines Agency, Copenhagen, DenmarkCorrespondence: Anton PottegårdClinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, JB Winsløws Vej 19, 2, Odense DK-5000, DenmarkTel +45 28913340Email apottegaard@health.sdu.dkBackground: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established.Data Structure: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies.Conclusion: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.Keywords: Covid-19, SARS-CoV-2, epidemiology, follow-up, database, prognosis, prospective cohort

Irene Petersen,1,2 Sia Kromann Nicolaisen,2 Federico Ricciardi,3 Manuj Sharma,1 Reimar W Thomsen,2 Gianluca Baio,3 Lars Pedersen2 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 3Department of Statistical Science, University College London, London, UKCorrespondence: Irene PetersenDepartment of Primary Care and Population Health, University College London, London NW3 2PF, UKTel +44 20 801 68032Email i.petersen@ucl.ac.ukBackground: Individuals with type 2 diabetes (T2D) have a twofold increased risk for cardiovascular events (CVE), and CVE is responsible for nearly 80% of the mortality. Current treatment guidelines state that individuals should immediately initiate antidiabetic treatment and cardiovascular risk-factor management from T2D diagnosis. However, the evidence base is sparse, and randomized trials are unlikely to be conducted. We examined the impact of being eligible for T2D treatment, as determined by the threshold of HbA1c ≥ 6.5% (≥ 48 mmol/mol), on all-cause mortality and CVE. We hypothesised that individuals who were just above this threshold had a lower risk of CVE and all-cause mortality than individuals just below.Methods and Findings: We used the regression discontinuity design (RDD), a quasi-experimental design, comparing rates of all-cause mortality and CVE in people just below and just above the eligibility for treatment threshold. We included Danish healthcare records from 43,070 individuals aged 40– 80 years with no previous T2D record and the first record of HbA1c in the range of 6.0– 7.0% (42– 53 mmol/mol) between 2006 and 2014. In total, 36,360 individuals had the first record of HbA1c between 6.0% and 6.4% (42– 47 mmol/mol), and 6710 individuals had a first record between 6.5% and 7.0% (48– 53 mmol/mol). Individuals with a measurement just above 6.5% (48 mmol/mol) had a 21% lower rate of death or CVE, compared to those just below (hazard ratio: 0.79 (95% CI 0.69– 0.90)). Few individuals received early metformin treatment. However, the chance of metformin treatment initiation within 3 months was substantially higher for individuals with an HbA1c measurement above (14%) than below (1%) the threshold.Conclusion: Individuals with first record of HbA1c measure just above treatment threshold experienced a 21% lower rate of death or CVE than those just below. Lifestyle modifications and cardiovascular risk-factor management may contribute to this reduced rate.Keywords: type 2 diabetes, glycated hemoglobin A1c, regression discontinuity design, cardiovascular event, mortality

Sigrid Bjerge Gribsholt,1,2 Lars Pedersen,1 Bjørn Richelsen,3 Reimar Wernich Thomsen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 3The Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Sigrid Bjerge GribsholtDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N 8200, DenmarkTel +45 6 165 1148Email sigrgrib@rm.dkPurpose: Health care databases may be a valuable source for epidemiological research in obesity, if diagnoses are valid. We examined the validity and completeness of International Classification of Diseases, 10th revision [ICD-10] diagnosis coding for overweight/obesity in Danish hospitals.Patients and methods: We linked data from the Danish National Patient Registry on patients with a hospital diagnosis code of overweight/obesity (ICD-10 code E66) with computerized height and weight measurements made during hospital contacts in the Central Denmark Region Clinical Information System. We computed the positive predictive value (PPV) of the IDC-10 diagnosis of overweight/obesity, using a documented body mass index (BMI) ≥25 kg/m2 as gold standard. We also examined the completeness of obesity/overweight diagnosis coding among all patients recorded with BMI ≥25 kg/m2.Results: Of all 19,672 patients registered with a first diagnosis code of overweight/obesity in the National Patient Registry, 17,351 patients (88.2%) had any BMI measurement recorded in the Central Denmark Region Clinical Information System, and 17,240 patients (87.6%) had a BMI ≥25 kg/m2, yielding a PPV of 87.6% (95% CI: 87.2–88.1). The PPV was slightly higher for primary diagnosis codes of overweight/obesity: 94.1% (95% CI: 93.3–94.8) than for secondary diagnosis codes: 86.1% (95% CI: 85.6–86.6). The PPV increased with higher patient age: from 75.3% (95% CI: 73.8–76.9) in those aged 18–29 years to 94.7% (95% CI: 92.6–96.9) in patients aged 80 years and above. Completeness of obesity/overweight diagnosis coding among patients recorded with BMI ≥25 kg/m2 was only 10.9% (95% CI: 10.8–11.0).Conclusion: Our findings indicate a high validity of the ICD-10 code E66 for overweight/obesity when recorded; however, completeness of coding was low. Nonetheless, ICD-10 discharge codes may be a suitable source of data on overweight/obesity for epidemiological research.Keywords: obesity, validation, diagnosis code

Diana Hedevang Christensen,1,2 Søren Tang Knudsen,3 Sia Kromann Nicolaisen,1 Henning Andersen,2,4 Brian Christopher Callaghan,2,5 Nanna Brix Finnerup,2,4,6 Troels Staehelin Jensen,2,4,6 Reimar Wernich Thomsen11Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2International Diabetic Neuropathy Consortium, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; 3Steno Diabetes Center Aarhus (SDCA), Aarhus University Hospital, Aarhus, Denmark; 4Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Neurology, University of Michigan, Ann Arbor, MI, USA; 6Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, DenmarkPurpose: We examined whether diabetic polyneuropathy (DPN) and diabetic foot ulcers in type 2 diabetes can be accurately identified using International Classification of Diseases, 10th revision discharge diagnosis codes, surgery codes, and drug prescription codes.Methods: We identified all type 2 diabetes patients in the Central Denmark region, 2009–2016, who had ≥1 primary/secondary diagnosis code of “diabetes with neurological complication” (E10.4-E14.4), “diabetic polyneuropathy” (G63.2), or “polyneuropathy, unspecified” (G62.9). Patients with potential painful DPN and non-painful DPN were identified based on prescription history for serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, or gabapentinoids. Likewise, type 2 diabetes patients with potential foot ulcers were identified based on diagnosis or surgery codes. We used medical record review as the reference standard and calculated positive predictive values (PPVs).Results: Of 53 randomly selected patients with potential painful DPN, 38 were classified as having DPN when validated against medical records; of these, 18 also had neuropathic pain, yielding a PPV of 72% (95% CI: 58–83%) for DPN and 34% (95% CI: 22–48%) for painful DPN. Likewise, among 54 randomly selected patients with potential non-painful DPN, 30 had DPN based on medical record data; of these, 27 had non-painful DPN, yielding PPVs of 56% (95% CI: 41–69%) and 50% (95% CI: 36–64%), respectively. Secondary E-chapter codes often denoted stroke or mononeuropathies, rather than DPN. Excluding secondary E-chapter codes from the algorithm increased the PPV for DPN to 78% (95% CI: 63–89%) for the painful DPN cohort and to 74% (95% CI: 56–87%) for the non-painful DPN cohort. Of 53 randomly selected patients with potential diabetic foot ulcer, only 18 diagnoses were confirmed; PPV=34% (95% CI: 22–48%).Conclusion: G-chapter and primary E-chapter diagnosis codes can detect type 2 diabetes patients with hospital-diagnosed DPN, and may be useful in epidemiological research. In contrast, our diabetic foot ulcer algorithm did not perform well.Keywords: positive predictive value, epidemiology, registries, diabetic polyneuropathy, diabetic foot ulcer, type 2 diabetes

Lotte Sahin Levison,1 Reimar Wernich Thomsen,2 Diana Hedevang Christensen,2 Thomas Mellemkjær,1 Søren Hein Sindrup,3 Henning Andersen11Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Neurology, Odense University Hospital, Odense, DenmarkPurpose: To validate the diagnostic codes for Guillain-Barré syndrome (GBS) in the Danish National Patient Registry (DNPR). Secondly, to examine 30-year trends in the incidence of GBS in Denmark.Patients and methods: We used the DNPR to identify all patients aged 16 and above diagnosed with a primary GBS diagnosis at any Danish department of neurology between 1987 and 2016. Medical files were reviewed according to the clinical criteria of the National Institute of Neurological Disorders and Stroke Committee and classified according to the Brighton criteria. The incidence rate (IR) was calculated based on data from 1987 to 2016 and stratified by season, gender, and age.Results: Over 30 years, we identified 2,319 patients aged 16 and above in the DNPR. From a validation cohort of 573 patients, we were able to retrieve 425 (74.2%) medical files; 356 GBS diagnoses were confirmed. The overall positive predictive value was 83.8% (95% confidence interval (CI): 80.0–87.0). In 99% of the confirmed patients, the Brighton criteria level 1–3 for GBS were met. The IR was fairly stable over 30 years at 1.77 per 100,000 person years (95% CI: 1.70–1.84). The incidence was higher in the winter season (IR ratio compared with summer: 1.18 (95% CI: 1.09–1.29)), and was strongly associated with male gender (IR ratio vs females: 1.44 (95% CI: 1.33–1.57)). IRs rose with age at diagnosis, particularly after the age of 50 in both men and women and a minor peak was observed for total IR in young adults.Conclusion: Primary diagnostic codes for GBS at Danish departments of neurology have high validity. The DNPR is a well-suited data source for epidemiological research on GBS. The Danish nationwide 30-year GBS IR is stable over time and similar to GBS IRs reported in other European and North American populations.Keywords: registries, positive predictive value, international classification of disease codes, epidemiology

Clément Brault,1,2 Anders H Riis,1 Anil Mor,1 Pierre Duhaut,2 Reimar W Thomsen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Internal Medicine and RECIF, Amiens-Picardie University Hospital, Amiens, France Objective: It has been suggested that a hyper-effective immune system (“hyper-immunity”) is central to the pathogenesis of giant cell arteritis and polymyalgia rheumatica (GCA/PMR). We examined if a low risk of infections, as a marker of hyper-immunity, can predict increased subsequent risk of GCA/PMR.Patients and methods: We conducted a population-based case–control study including all patients aged ≥50 years with incident GCA/PMR diagnosed between 1997 and 2012 in Northern Denmark. For each case, we selected 10 population controls matched on gender, age, place of residence, and time spent in the region. Complete history of hospital-treated infections and community-based anti-infective prescriptions was assessed in population-based registries. We used conditional logistic regression to compute OR of GCA/PMR associated with infections while adjusting for comorbidities, immunosuppressive treatment, and other potential confounders.Results: We included 7,225 GCA/PMR cases and 72,250 controls. When excluding all infections occurring within the last year before GCA/PMR diagnosis, there was no decreased risk for GCA/PMR in people with a history of hospital-treated infection (adjusted OR=1.04, 95% CI: 0.98–1.10) or community anti-infective treatment (adjusted OR=1.07, 95% CI: 0.99–1.16). Within the last year preceding the GCA/PMR index date, patients with hospital-treated infections (adjusted OR=1.59, 95% CI: 1.44–1.75) or community anti-infective treatment (adjusted OR=1.63, 95% CI: 1.48–1.79) had a greatly increased risk of a GCA/PMR diagnosis.Conclusion: These results do not support the hypothesis of “hyper-immunity” leading to GCA/PMR. Instead, incident GCA/PMR is preceded by a slightly increased risk of infection, which may be related to protopathic bias or support theories that infections may be directly involved in the pathogenesis of GCA/PMR. Keywords: giant cell arteritis, polymyalgia rheumatica, infection, immune system

Diana H Christensen,1 Katalin Veres,1 Anne G Ording,1 Jens Otto L Jørgensen,2 Suzanne C Cannegieter,3 Reimar W Thomsen,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands Objective: Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. Design: Nationwide population-based cohort study based on Danish medical registry data. Methods: We identified all patients diagnosed with VTE during 1978–2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. Results: During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42–2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07–3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97–1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08–1.46]). Conclusion: VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism. Keywords: hyperthyroidism, hypothyroidism, venous thromboembolism, cancer, cohort study

Andreas Ebbehoj,1,2 Sarah Forslund Jacobsen,3 Christian Trolle,1 Maciej Grzegorz Robaczyk,4 Åse Krogh Rasmussen,3 Ulla Feldt-Rasmussen,3 Reimar Wernich Thomsen,5 Per Løgstrup Poulsen,1 Kirstine Stochholm,1 Esben Søndergaard1 1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 4Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Pheochromocytoma and catecholamine-secreting paraganglioma (PPGL) are rare but potentially life-threatening tumors. We aimed to validate diagnosis codes for PPGL in the Danish National Patient Registry, the Danish National Pathology Registry, and the Danish Registry of Causes of Death and to create a national cohort of incident PPGL patients by linking these three registries. Patients and methods: We obtained data from the three abovementioned registries for all individuals registered with pheochromocytoma or catecholamine hypersecretion in Denmark during 1977–2016 (average population 5.30 million). We then reviewed health records for all individuals living in the North Denmark Region and Central Denmark Region (average population 1.75 million) to validate the diagnosis of PPGL. We tested a number of algorithms for accurately identifying true cases of PPGL to maximize positive predictive values (PPVs) and completeness. The best algorithm was subsequently validated in an external sample. Results: We identified 2626 individuals with a PPGL diagnosis code in Denmark, including 787 (30.0%) in the North Denmark Region and Central Denmark Region. In this subsample, we retrieved the health records of 771/787 (98.0%) individuals and confirmed 198 incident PPGL patients (25.3%). The PPV of PPGL diagnosis codes was 21.7% in the Danish National Patient Registry, 50.0% in the Danish Registry of Causes of Death, and 79.5% in the Danish National Pathology Registry. By combining patterns of registrations in the three registries, we could increase the PPV to 93.1% (95% confidence interval [CI]: 88.5–96.3) and completeness to 88.9% (95% CI: 83.7–92.9), thus creating a national PPGL cohort of 588 patients. PPV for the optimal algorithm was 95.3% (95% CI: 88.5–98.7) in the external validation sample. Conclusion: Diagnosis codes for pheochromocytoma had low PPV in several individual health registries. However, with a combination of registries we were able to identify a near-complete national cohort of PPGL patients in Denmark, as a valuable source for epidemiological research. Keywords: registry-based research, International Classification of Diseases, ICD, Systematized Nomenclature of Medicine, SNOMED, hospital register diagnoses, pathology register, cause of death register

Sandra Søgaard Tøttenborg,1 Alice Jessie Clark,1 Reimar Wernich Thomsen,2 Søren Paaske Johnsen,2 Peter Lange1,3 1Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Respiratory Section, Hvidovre Hospital, Hvidovre, Denmark Background: Bupropion and varenicline can substantially improve the chances of smoking cessation in patients with COPD, but are unsubsidized and relatively costly. We examined overall use and socioeconomic patterns of use among patients with COPD. Patients and methods: We identified 4,741 COPD patients reporting to be smokers at their first contact for COPD during 2008–2012 in the Danish register of COPD, which covers all pulmonary outpatient clinics in Denmark. Patients were followed for 6 months in the National Prescription Registry. Logistic regression analyses were used to calculate the ORs with corresponding 95% CI of redeeming a prescription for any of the smoking cessation medications in strata of baseline characteristics. Results: During 6 months from first consultation, only 5% redeemed a prescription for bupropion or varenicline. Younger age, female sex, higher education, and higher income were associated with an increased likelihood, while non-Danish ethnicity, living alone, and very severe COPD were associated with a lower likelihood of redeeming bupropion or varenicline. Conclusion: Despite their proven effectiveness, bupropion and varenicline are sparingly used among COPD patients followed in the hospital outpatient setting with the lowest use among the socioeconomically disadvantaged. This highlights a missed opportunity for intervention. Keywords: bupropion, varenicline, smoking intervention, lung disease

Peter Lange,1,2 Sandra Søgaard Tøttenborg,1 Anne Dichmann Sorknæs,3 Jørgen Steen Andersen,4 Mette Søgaard,5 Henrik Nielsen,5 Reimar Wernich Thomsen,5 Katrine Abildtrup Nielsen6 1Section of Social Medicine, Department of Public Health, University of Copenhagen, 2Lung Diseases Department, Respiratory Medicine Section, Lung Diseases Department, Hvidovre Hospital, University of Copenhagen, Copenhagen, 3Medical Department, Odense Universitetshospital–Svendborg Hospital, Svendborg, 4Danish College of General Practitioners, Copenhagen, 5Department of Clinical Epidemiology, Aarhus University Hospital, 6Registry Support Centre of Clinical Quality and Health Informatics (West), Århus, Denmark Aim of database: The Danish Register of Chronic Obstructive Pulmonary Disease (DrCOPD) is a nationwide database aiming to describe the quality of treatment of all patients with chronic obstructive pulmonary disease (COPD) in Denmark. Study population: DrCOPD comprises data on all patients with a diagnosis of COPD. In the hospital setting, both in- and outpatients are included. In the setting of the general practice (GP), DrCOPD aims to include all patients with a COPD diagnosis who attend an annual control visit for COPD. Main variables: DrCOPD includes information on forced expiratory volume in 1 second, smoking status, body mass index, dyspnea, treatment modalities such as rehabilitation, smoking cessation, medical treatment, and the use of noninvasive ventilation during hospitalization due to exacerbations. The outcome variables include frequency of readmission and death 30 days after discharge from hospital. Descriptive data: Since 2008, the registration in the Danish hospitals has gradually become more comprehensive. In 2014, ~90% of 16,106 eligible patients had complete data sets that showed an improvement in the processes describing quality of care, including increased offering of smoking cessation, rehabilitation, and correct treatment with inhaled medication. Data from GPs have been included since 2011, but are still incomplete and comprise only ~20% of all COPD patients seen. The collection of data from GP settings has recently been hampered due to legislative controversies. Conclusion: In relatively few years, DrCOPD has become increasingly comprehensive and has documented an improvement in the management of COPD in Danish hospitals. Keywords: chronic obstructive pulmonary disease, quality of care, exacerbations, register

Diana Hedevang Christensen,1 Jørgen Rungby,2,3 Reimar Wernich Thomsen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Denmark; 2Department of Pharmacology, University of Aarhus, Aarhus, Denmark; 3Department of Endocrinology, Gentofte University Hospital, Copenhagen, Denmark Purpose: The objective of this study was to examine nationwide population-based time trends in the utilization of all glucose-lowering drugs in Denmark from 1999 to 2014. Methods: Based on nationwide data from the Register of Medicinal Products Statistics, we retrieved sales statistics on glucose-lowering drugs and reported the total number of users and the prevalence of users per 1,000 inhabitants in 1-year intervals for all glucose-lowering drug classes. Results: The annual prevalence of glucose-lowering drug users increased more than twofold from 19 per 1,000 inhabitants in 1999 (n=98,362) to 41 per 1,000 in 2014 (n=233,230). Metformin use increased more than sevenfold during the period and was used by 30 of 1,000 inhabitants in 2014, while the prevalence of insulin use increased 1.8-fold to 13 per 1,000 in 2014. After peaking in 2007, use of sulfonylurea halved to 6 per 1,000 in 2014. Newer drug classes including the glucagon-like peptide 1 receptor agonists, the dipeptidylpeptidase-4 inhibitors, and the sodium–glucose cotransporter 2 inhibitors had reached a considerable position by 2014, with 4 per 1,000, 6 per 1,000, and 0.8 per 1,000 inhabitants, respectively; however, the use of glucagon-like peptide 1 receptor agonists and sodium–glucose cotransporter 2 inhibitors in elderly people remained low. Thiazolidinediones decreased to virtually no use (0.03 per 1,000) in 2014. Conclusion: The use of glucose-lowering drugs has doubled during 1999–2014. The pattern of glucose-lowering drug use has changed substantially reflecting the recommendations of metformin as first-line treatment. The newer glucose-lowering drug classes have been well received. Keywords: drug utilization, registries, diabetes mellitus, antidiabetic drugs

Mathias Ried-Larsen,1–3 Reimar W Thomsen,2,4 Klara Berencsi,4 Cecilie F Brinkløv,1,5 Charlotte Brøns,1,5 Laura S Valentiner,1,6 Kristian Karstoft,1,3 Henning Langberg,1,6 Allan A Vaag,1,2,5 Bente K Pedersen,1,3 Jens S Nielsen7 1Department of Infectious Diseases, Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, 2The Danish Diabetes Academy, Odense University Hospital, Odense, 3Department of Infectious Diseases, Centre of Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus Nord, 5Department of Endocrinology (Diabetes and Metabolism), Rigshospitalet, University of Copenhagen, 6CopenRehab, Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, 7Department of Endocrinology, Odense University Hospital, Odense, Denmark Abstract: Promoting physical activity is a first-line choice of treatment for patients with type 2 diabetes (T2D). However, there is a need for more effective tools and technologies to facilitate structured lifestyle interventions and to ensure a better compliance, sustainability, and health benefits of exercise training in patients with T2D. The InterWalk initiative and its innovative application (app) for smartphones described in this study were developed by the Danish Centre for Strategic Research in T2D aiming at implementing, testing, and validating interval walking in patients with T2D in Denmark. The interval walking training approach consists of repetitive 3-minute cycles of slow and fast walking with simultaneous intensity guiding, based on the exercise capacity of the user. The individual intensity during slow and fast walking is determined by a short initial self-conducted and audio-guided fitness test, which combined with automated audio instructions strives to motivate the individual to adjust the intensity to the predetermined individualized walking intensities. The InterWalk app data are collected prospectively from all users and will be linked to the unique Danish nationwide databases and administrative registries, allowing extensive epidemiological studies of exercise in patients with T2D, such as the level of adherence to InterWalk training and long-term effectiveness surveys of important health outcomes, including cardiovascular morbidity and mortality. Currently, the InterWalk app has been downloaded by >30,000 persons, and the achieved epidemiological data quality is encouraging. Of the 9,466 persons providing personal information, 80% of the men and 62% women were overweight or obese (body mass index ≥25). The InterWalk project represents a contemporary technology-driven public health approach to monitor real-life exercise adherence and to propagate improved health through exercise intervention in T2D and in the general population. Keywords: exercise, telemedicine, cell phones

Mette Søgaard,1 Morten Madsen,1 Anders Løkke,2 Ole Hilberg,2 Henrik Toft Sørensen,1 Reimar W Thomsen1 1Department of Clinical Epidemiology, 2Department of Respiratory Medicine, Aarhus University Hospital, Aarhus C, Denmark Background: Pneumonia may be a major contributor to hospitalizations for chronic obstructive pulmonary disease (COPD) exacerbation and influence their outcomes.Methods: We examined hospitalization rates, health resource utilization, 30-day mortality, and risk of subsequent hospitalizations for COPD exacerbations with and without pneumonia in Denmark during 2006–2012.Results: We identified 179,759 hospitalizations for COPD exacerbations, including 52,520 first-time hospitalizations (29.2%). Pneumonia was frequent in first-time exacerbations (36.1%), but declined in successive exacerbations to 25.6% by the seventh or greater exacerbation. Pneumonic COPD exacerbations increased 20% from 0.92 per 1,000 population in 2006 to 1.10 per 1,000 population in 2012. Nonpneumonic exacerbations decreased by 6% from 1.74 per 1,000 population to 1.63 per 1,000 population during the same period. A number of markers of health resource utilization were more prevalent in pneumonic exacerbations than in nonpneumonic exacerbations: length of stay (median 7 vs 4 days), intensive care unit admission (7.7% vs 12.5%), and several acute procedures. Thirty-day mortality was 12.1% in first-time pneumonic COPD exacerbations versus 8.3% in first-time nonpneumonic cases (adjusted HR [aHR] 1.20, 95% confidence interval [CI] 1.17–1.24). Pneumonia also predicted increased mortality associated with a second exacerbation (aHR 1.14, 95% CI 1.11–1.18), and up to a seventh or greater exacerbation (aHR 1.10, 95% CI 1.07–1.13). In contrast, the aHR of a subsequent exacerbation was 8%–13% lower for patients with pneumonic exacerbations.Conclusions: Pneumonia is frequent among patients hospitalized for COPD exacerbations and is associated with increased health care utilization and higher mortality. Nonpneumonic COPD exacerbations predict increased risk of subsequent exacerbations. Keywords: COPD, exacerbation, pneumonia, incidence, mortality

Diana Hedevang Christensen,1,2 Erzsébet Horváth-Puhó,1 Morten Schmidt,1 Christian Fynbo Christiansen,1 Lars Pedersen,1 Bente Lomholt Langdahl,2 Reimar Wernich Thomsen1 1Department of Clinical Epidemiology, 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark Purpose: Bisphosphonate use has been associated with increased risk of fatal stroke. We examined the association between preadmission use of oral bisphosphonates and 30-day mortality following hospitalization for stroke. Patients and methods: We conducted a nationwide population-based cohort study using medical databases and identified all patients in Denmark with a first-time hospitalization for stroke between 1 July 2004 and 31 December 2012 (N=100,043). Cox regression was used to compute adjusted hazard ratios as a measure of 30-day mortality rate ratios (MRRs) associated with bisphosphonate current use (prescription filled within 90 days prior to the stroke) or recent use (prescription filled in the 90–180 days prior to the stroke). Current use was further classified as new or long-term use. Results: We found 51,982 patients with acute ischemic stroke (AIS), 11,779 with intracerebral hemorrhage (ICH), 4,528 with subarachnoid hemorrhage (SAH), and 31,754 with unspecified stroke. Absolute 30-day mortality risks were increased among current vs nonusers of bisphosphonates for AIS (11.9% vs 8.5%), ICH (43.2% vs 34.5%), SAH (40.3% vs 23.2%), and unspecified strokes (18.8% vs 14.0%). However, in adjusted analyses, current bisphosphonate use did not increase 30-day mortality from AIS (MRR, 0.87; 95% confidence interval [CI]: 0.75, 1.01); ICH (MRR, 1.05; 95% CI: 0.90, 1.23); SAH (MRR, 1.15; 95% CI: 0.83, 1.61); or unspecified stroke (MRR, 0.94; 95% CI: 0.81, 1.09). Likewise, no association with mortality was found for recent use. Adjusted analyses by type of bisphosphonate showed increased mortality following stroke among new users of etidronate (MRR, 1.40; 95% CI: 1.01, 1.93) and reduced mortality after AIS among current users of alendronate (MRR, 0.87; 95% CI: 0.74, 1.02). Conclusion: We found no overall evidence that preadmission bisphosphonate use increases 30-day mortality following stroke. Keywords: prognosis, oral bisphosphonates, stroke, mortality, cardiovascular disease, osteoporosis treatment

Elisabeth Svensson,1 Rikke Beck Nielsen,1 Pål Hasvold,2 Pernilla Aarskog,2 Reimar W Thomsen1 1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2AstraZeneca Nordic Baltic, Södertälje, Sweden Purpose: To examine the annual rate and cumulative prevalence of statin use in Denmark 2004–10, including adherence of use and attainment of cholesterol targets. Methods: We included all individuals aged 18–86 years with a first statin prescription in Northern Denmark in 2004–10. We calculated the annual rate and cumulative prevalence of statin use. We examined cholesterol values before and after start of statins and the proportion reaching targets according to European guidelines and cardiovascular risk group. Results: The study population consisted of 161,646 new statin users (51% men; median age 62 years). The peak rate of new statin initiators occurred in 2008, and a cumulative prevalence of 94 users per 1,000 population was reached in 2010. In total, 98% of new users started with simvastatin. Eighty-eight percent (142,897) did not switch statin type during follow-up. Overall persistence was 84%. The reduction in median total cholesterol in new statin users was 28% (from 6.3 mmol/L to 4.5 mmol/L), while it was 43% (from 4.0 mmol/L to 2.3 mmol/L) for low-density lipoprotein cholesterol. Among patients with very high cardiovascular risk, 66% attained the recommended total cholesterol target; corresponding figures were 74% among high-risk patients and 80% among low- to moderate-risk patients. Corresponding figures for low-density lipoprotein cholesterol were 54%, 82%, and 88%, respectively. Conclusions: Statin use has become very prevalent in Danish adults, with high adherence. Cholesterol reduction after statin initiation is similar to that found in clinical trials, yet a substantial proportion of patients does not reach target cholesterol levels. Keywords: statin, cholesterol attainment, Denmark, persistence

Kirstine Kobberøe Søgaard,1 Reimar Wernich Thomsen,1 Henrik Carl Schønheyder,2,3 Mette Søgaard1 1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Microbiology, Aalborg University Hospital, 3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Background: Health care databases are a valuable resource for infectious disease epidemiology if diagnoses are accurately coded. We examined the ability of diagnostic coding to accurately identify Gram-negative bacteremia. Methods: We randomly selected 100 patients among 1,703 patients recorded in the Danish National Patient Register with a diagnosis of either “septicemia/sepsis due to other Gram-negative organisms” (International Classification of Diseases, 10th revision [ICD-10] code A41.5) or “urosepsis” (ICD-10 code A41.9B) who had been admitted at Aalborg University Hospital, Denmark between 1994 and 2012. We estimated the positive predictive value (PPV) of these diagnoses for presence of Gram-negative bacteremia, using microbiological results from blood cultures as standard reference. Complementary clinical information was obtained from the medical records. Results: Of the 100 patients registered with Gram-negative septicemia/sepsis or urosepsis, 72 had blood culture confirmed Gram-negative bacteremia, four patients had monomicrobial Gram-positive bacteremia, 21 patients had a negative blood culture, and three had no blood culture taken. The overall PPV of a blood culture confirmed Gram-negative bacteremia diagnosis was 72% (95% confidence interval [CI]: 62%–81%); for ICD-10 code A41.5 it was 86% (95% CI: 74%–94%) and for ICD-10 code A41.9B it was 55% (95% CI: 39%–70%). The highest PPV was achieved for diagnoses registered in the most recent calendar period (2009–2012) and for secondary discharge diagnoses. Conclusion: Our findings indicated good agreement between ICD-10 code A41.5 “septicemia/sepsis due to other Gram-negative organisms” and Gram-negative bacteremia, whereas ICD-10 code A41.9B “urosepsis” was not suited for identification of Gram-negative bacteremia. Keywords: validation studies, Danish National Patient Register

Torsten Roed,1 Ulrik Sloth Kristoffersen,2 Andreas Knudsen,1,2 Niels Wiinberg,3 Anne-Mette Lebech,1 Thomas Almdal,4 Reimar W Thomsen,5 Andreas Kjær,2 Nina Weis1,61Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; 2Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Physiology, Frederiksberg Hospital, Copenhagen, Denmark; 4Steno Diabetes Center, Copenhagen, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 6Faculty of Health Sciences, University of Copenhagen, Copenhagen, DenmarkObjective: Chronic hepatitis C is a global health problem and has been associated with coronary artery disease. Our aim was to examine the prevalence of coronary artery disease risk markers including endothelial biomarkers in patients with chronic hepatitis C and matched comparisons without manifest cardiovascular disease or diabetes in a cross-sectional design.Methods: Sixty patients with chronic hepatitis C (mean age 51 years) were recruited from the Department of Infectious Diseases at Copenhagen University Hospital, and compared with 60 age-matched non-hepatitis C virus-infected individuals from a general population survey. We examined traditional coronary artery disease risk factors, metabolic syndrome, carotid intima media thickness, and a range of endothelial biomarkers.Results: Patients with chronic hepatitis C had more hypertension (40% versus 25%, prevalence ratio [PR] 1.6; 95% confidence interval [CI] 0.9–2.7) and smoked more (53% versus 38%, PR 1.4; 95% CI 0.9–2.1). The two groups had similar body mass index (mean 25.0 versus 25.7 kg/m2), whereas those with chronic hepatitis C had less dyslipidemia (including significantly lower low-density lipoprotein and cholesterol/high-density lipoprotein ratio), higher glycosylated hemoglobin level (mean 6.2 versus 5.7, difference of means 0.5; 95% CI 0.3–0.8), and a higher prevalence of metabolic syndrome (28% versus 18%, PR 1.6; 95% CI 0.8–3.0). Increased carotid intima media thickness above the standard 75th percentile was seen more frequently in chronic hepatitis C (9% versus 3%, PR 1.7; 95% CI 0.4–6.7), though difference of means was only 0.04 mm (95% CI 0.00–0.10). Patients with chronic hepatitis C had increased hsCRP (high-sensitivity C-reactive protein), sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), and soluble E-selectin, but lower levels of tPAI-1 (tissue-type plasminogen activator inhibitor-1), MMP9 (matrix metallopeptidase 9), and MPO (myeloperoxidase) than their comparisons.Conclusion: Our findings indicate that patients with chronic hepatitis C have increased prevalence of several coronary artery disease risk markers. These results may be important when evaluating the appropriateness of screening for coronary artery disease and its risk factors in chronic hepatitis C.Keywords: risk factors, atherosclerosis, endothelial dysfunction, biomarkers, metabolic syndrome, intima media thickness

Cathrine Wildenschild,1 Frank Mehnert,1 Reimar Wernich Thomsen,1 Helle Klingenberg Iversen,2 Karsten Vestergaard,3 Annette Ingeman,1 Søren Paaske Johnsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 2Department of Neurology, Glostrup Hospital, Glostrup, 3Department of Neurology, Aalborg Hospital, Aarhus University Hospital, Aalborg, DenmarkBackground: The validity of the registration of patients in stroke-specific registries has seldom been investigated, nor compared with administrative hospital discharge registries. The objective of this study was to examine the validity of the registration of patients in a stroke-specific registry (The Danish Stroke Registry [DSR]) and a hospital discharge registry (The Danish National Patient Registry [DNRP]).Methods: Assuming that all patients with stroke were registered in either the DSR, DNRP or both, we first identified a sample of 75 patients registered with stroke in 2009; 25 patients in the DSR, 25 patients in the DNRP, and 25 patients registered in both data sources. Using the medical record as a gold standard, we then estimated the sensitivity and positive predictive value of a stroke diagnosis in the DSR and the DNRP. Secondly, we reviewed 160 medical records for all potential stroke patients discharged from four major neurologic wards within a 7-day period in 2010, and estimated the sensitivity, specificity, positive predictive value, and negative predictive value of the DSR and the DNRP.Results: Using the first approach, we found a sensitivity of 97% (worst/best case scenario 92%-99%) in the DSR and 79% (worst/best case scenario 73%-84%) in the DNRP. The positive predictive value was 90% (worst/best case scenario 72%-98%) in the DSR and 79% (worst/best case scenario 62%-88%) in the DNRP. Using the second approach, we found a sensitivity of 91% (95% confidence interval [CI] 81%–96%) and 58% (95% CI 46%–69%) in the DSR and DNRP, respectively. The negative predictive value was 91% (95% CI 83%–96%) in the DSR and 72% (95% CI 62%–80%) in the DNRP. The specificity and positive predictive value did not differ among the registries.Conclusion: Our data suggest a higher sensitivity in the DSR than the DNRP for acute stroke diagnoses, whereas the positive predictive value was comparable in the two data sources.Keywords: diagnosis, sensitivity, specificity, registries

Frederik Hvid-Jensen,1 Rikke B Nielsen,2 Lars Pedersen,2 Peter Funch-Jensen,3 Asbjørn Mohr Drewes,4 Finn B Larsen,5 Reimar W Thomsen2 1Department of Surgical Gastroenterology L, Aarhus University Hospital, Aarhus, 2Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, 3Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, 4Mech-Sense Centre, Department of Gastroenterology, Aarhus University Hospital, Aalborg, 5Public Health and Quality Improvement, Central Denmark Region, Denmark Purpose: Lifestyle factors may influence observed associations between proton pump inhibitor (PPI) usage and health outcomes. The aim of the study reported here was to examine characteristics and differences in lifestyle among PPI users and nonusers. Methods: This cross-sectional study utilized data from a 2006 population-based health survey of 21,637 persons in the Central Danish Region. All persons using prescribed PPIs were identified through linkage to a population-based prescription database. Biometric measures and prevalence of smoking, excessive alcohol consumption, diet, and physical exercise were analyzed, comparing PPI users with nonusers. Results: Among 10,129 (46.8%) male and 11,508 (53.2%) female survey respondents, 1,356 (13.4%) males and 1,691 (14.7%) females reported ever use of PPIs. PPI users were more obese (16.7%) than nonusers (13.1%), with an age- and sex-standardized prevalence ratio (PR) of 1.3 (95% confidence interval [CI]: 1.2–1.4). The prevalence of smokers was also higher in the PPI group (26.2% vs 22.3% [PR =1.2, 95% CI: 1.1–1.3]), as was the prevalence of ex-smokers (41.0% vs 32.0% [PR =1.2, 95% CI: 1.1–1.2]). Unhealthy diet was slightly more common among PPI users than among nonusers (15.4% vs 13.0%), with a PR of 1.2 (95% CI: 1.1–1.3). Physical exercise level and alcohol consumption were similar in the two groups. Hospital-diagnosed comorbidity was observed in 35% of PPI users (a Charlson Comorbidity Index score of 1 or more) compared with only 15% among nonusers. Conclusion: PPI users are more obese, smoke more, and have significantly more comorbidities than PPI nonusers. These data are important when evaluating unmeasured confounding in observational studies of PPI effects. Keywords: PPI, obesity, smoking, reflux, population-based, gastroesophageal reflux

Eva Bjerre Ostenfeld,1,2 Mette Nørgaard,1 Reimar Wernich Thomsen,1 Lene Hjerrild Iversen,3 Jacob Bonde Jacobsen,1 Mette Søgaard1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Surgery A, Aalborg University Hospital, Aalborg, Denmark; 3Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark Objective: To evaluate recent trends in the prevalence and impact of comorbidity on colorectal cancer (CRC) survival in the Central Region of Denmark. Material and methods: Using the Danish National Registry of Patients, we identified 5,777 and 2,964 patients with a primary colon or rectal cancer, respectively, from 2000 through 2011. We estimated survival according to Charlson Comorbidity Index scores and computed mortality rate ratios (MRRs) using Cox proportional hazard regression analysis, adjusting for age and sex. Results: More than one-third of CRC patients had comorbidity at diagnosis. During the study period, 1-year survival increased substantially in colon cancer patients with Charlson score 0 (72% to 80%) and modestly for Charlson score 3+ patients (43% to 46%). Using colon cancer patients with Charlson score 0 as reference, adjusted 1-year MRRs in patients with Charlson score 3+ were 2.19 (95% confidence interval [CI]: 1.57–3.05) in 2000–2002 and 2.56 (95% CI: 1.96–3.35) in 2009–2011. One-year survival after rectal cancer improved from 81% to 87% in patients with Charlson score 0 and from 56% to 60% in Charlson score 3+. Corresponding MRRs in patients with Charlson 3+ were 2.21 (95% CI: 1.33–3.68) in 2000–2002 and 3.09 (95% CI: 1.91–5.00) in 2009–2011 using Charlson score 0 as reference. Five-year MRRs did not differ substantially from 1-year MRRs. Conclusion: Comorbidity was common among CRC patients and was associated with poorer prognosis. We observed improved survival from 2000 to 2011 for all comorbidity levels, with least improvement for colon cancer patients with comorbid conditions. Keywords: colon, rectal, neoplasms, comorbidity, survival, epidemiology, Denmark

Anne Fia Grann,1 Reimar Wernich Thomsen,1 Jacob Bonde Jacobsen,1 Mette Nørgaard,1 Jan Blaakær,2 Mette Søgaard1 1Department of Clinical Epidemiology, 2Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark Objective: To examine the prevalence of comorbidity among patients diagnosed with epithelial ovarian cancer in the Central Denmark Region and to study the impact of comorbidity on cancer survival over time. Methods: We included women recorded with a first-time diagnosis of epithelial ovarian cancer in the Danish National Registry of Patients in the Central Denmark region between 2000 and 2011. We followed their survival through the Danish Civil Registration System. We estimated 1- and 5-year survival overall and stratified by Charlson Comorbidity Index score. We used Cox proportional hazard regression analyses to compute adjusted mortality rate ratios (MRRs) within different calendar time periods overall and by comorbidity level. Results: We identified 1,540 patients. In 2000–2002, 25% of the newly diagnosed ovarian cancer patients had a comorbidity diagnosis compared with 35% in 2009–2011. Median age increased from 61 to 66 years. One-year overall survival changed from 73% (95% confidence interval [CI]: 69–78) in 2000–2002 to 69% (95% CI: 63–73) in 2009–2011, corresponding to an age- and comorbidity-adjusted MRR of 1.03 (95% CI: 0.79–1.36). Five-year survival changed only slightly during the study period, from 37% (95% CI: 32–42) in 2000–2002 to 39% (95% CI: 34–44) in 2009–2011. In patients with Charlson score ≥3, 1-year survival changed from 63% (95% CI: 35–81) in 2000–2002 to 41% (95% CI: 24–57) in 2003–2005 and thereafter stabilized. One-year survival changed from 56% (95% CI: 44–66) to 64% (95% CI: 53–74) in patients with Charlson score 1–2. Compared with Charlson score 0, adjusted 1-year MRRs for Charlson score ≥3 were 1.44 (95% CI: 0.62–3.36) in 2000–2002 and 2.11 (95% CI: 1.27-3.51) in 2009–2011, whereas adjusted 1-year MRRs for Charlson score 1–2 changed from 2.04 (95% CI: 1.33–3.14) in 2000–2002 to 1.09 (95% CI: 0.69–1.71) in 2009–2011. Conclusion: Comorbidity increased among ovarian cancer patients over time and was associated with poor survival. One- and 5-year overall survivals changed only little and an expected decrease in survival, following increased prevalence of comorbidity and increasing age of patients, may have been counteracted by more aggressive surgery. Keywords: ovarian neoplasm, comorbidity, mortality, survival, epidemiology

Mette Søgaard,1 Reimar Wernich Thomsen,1 Kristine Skovgaard Bossen,2 Henrik Toft Sørensen,1 Mette Nørgaard1 1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Danish Cancer Society, Copenhagen, Denmark Background: A number of studies have shown poorer survival among cancer patients with comorbidity. Several mechanisms may underlie this finding. In this review we summarize the current literature on the association between patient comorbidity and cancer prognosis. Prognostic factors examined include tumor biology, diagnosis, treatment, clinical quality, and adherence. Methods: All English-language articles published during 2002–2012 on the association between comorbidity and survival among patients with colon cancer, breast cancer, and lung cancer were identified from PubMed, MEDLINE and Embase. Titles and abstracts were reviewed to identify eligible studies and their main results were then extracted. Results: Our search yielded more than 2,500 articles related to comorbidity and cancer, but few investigated the prognostic impact of comorbidity as a primary aim. Most studies found that cancer patients with comorbidity had poorer survival than those without comorbidity, with 5-year mortality hazard ratios ranging from 1.1 to 5.8. Few studies examined the influence of specific chronic conditions. In general, comorbidity does not appear to be associated with more aggressive types of cancer or other differences in tumor biology. Presence of specific severe comorbidities or psychiatric disorders were found to be associated with delayed cancer diagnosis in some studies, while chronic diseases requiring regular medical visits were associated with earlier cancer detection in others. Another finding was that patients with comorbidity do not receive standard cancer treatments such as surgery, chemotherapy, and radiation therapy as often as patients without comorbidity, and their chance of completing a course of cancer treatment is lower. Postoperative complications and mortality are higher in patients with comorbidity. It is unclear from the literature whether the apparent undertreatment reflects appropriate consideration of greater toxicity risk, poorer clinical quality, patient preferences, or poor adherence among patients with comorbidity. Conclusion: Despite increasing recognition of the importance of comorbid illnesses among cancer patients, major challenges remain. Both treatment effectiveness and compliance appear compromised among cancer patients with comorbidity. Data on clinical quality is limited. Keywords: comorbidity, cancer, diagnosis, treatment, survival

Thomas Deleuran,1,2 Reimar Wernich Thomsen,1 Mette Nørgaard,1 Jacob Bonde Jacobsen,1 Torben Riis Rasmussen,3 Mette Søgaard1 1Department of Clinical Epidemiology, 2Department of Medicine V, Hepatology and Gastroenterology, 3Department of Respiratory Medicine, Aarhus University Hospital, Aarhus, Denmark Objective: To examine lung cancer survival and the impact of comorbidity in the Central Denmark Region from 2000 to 2011. Methods: We performed a population-based cohort study of lung cancer patients diagnosed during four 3-year calendar periods (2000–2002, 2003–2005, 2006–2008, and 2009–2011) in the Central Denmark Region. The Danish National Registry of Patients was used to identify 9,369 incident lung cancer patients, and to obtain data on their Charlson comorbidity index score, categorized as no (score = 0), medium (score = 1–2), or high (score ≥3) level comorbidity. We calculated 1- and 5-year survival in different calendar time periods overall, and by age, sex, and level of comorbidity, and used Cox regression to compute mortality rate ratios (MRR) for each level of comorbidity versus no comorbidity in different calendar time periods. Results: Overall 1-year survival increased from 31% in 2000–2002 to 37% in 2009–2011, while the 5-year survival increased from 10% in 2000–2002 to predicted 13% in 2009–2011 with the largest improvement observed for women and patients less than 80 years. The adjusted 1-year MRR in patients with high comorbidity compared with those without comorbidity was 1.23 (95% confidence interval [CI]: 1.05–1.46) in 2000–2002 and 1.35 (95% CI: 1.17–1.56) in 2009–2011. The corresponding adjusted 5-year MRRs were 1.21 (95% CI: 1.04–1.40) in 2000–2002 and 1.26 (95% CI: 1.11–1.42) in 2009–2011. Conclusion: Lung cancer patients' survival increased from 2000 to 2011 in the Central Denmark Region, most prominently for women under 80 years and patients with no, or medium level of comorbidity. Their prognosis remained nonetheless dismal with overall 5-year survival of 13%, and comorbidity remained a negative prognostic factor. Keywords: mortality, lung cancer, comorbidity, time-trends

Anne Gulbech Ording,1 Deirdre P Cronin-Fenton,1 Jacob Bonde Jacobsen,1 Mette Nørgaard,1 Reimar Wernich Thomsen,1 Peer Christiansen,2 Mette Søgaard1 1Department of Clinical Epidemiology, 2Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark Objective: Previous studies have suggested that breast cancer survival in Denmark has improved, primarily in cancer patients without comorbidity. We therefore conducted a population-based cohort study to examine recent temporal changes in survival and mortality among breast cancer patients with different extents of comorbidity. Methods: We used population-based medical and administrative registries to identify breast cancer patients diagnosed between 2000 and 2011 in the Central Denmark Region. We defined comorbid diseases according to the Charlson Comorbidity Index (CCI), including a history of hospitalization for comorbid disease up to 10 years before breast cancer diagnosis. We studied the impact of comorbidities on overall 1- and 5-year survival in different calendar time periods, using a hybrid analysis for survival prediction in the most recent calendar periods. Results: We included 9,329 breast cancer patients. The proportion of patients within different comorbidity categories remained stable from 2000 to 2011. One-year survival improved from 91% in 2000–2002 to 95% in 2009–2011, while 5-year survival improved from 72% to a predicted 78%. During the entire study period, comorbidity was a strong predictor of the survival of breast cancer patients. However, we observed improvements over time in 1- and 5-year survival for all comorbidity groups. During the 12-year study period, the estimated 5-year survival for patients with a high comorbidity disease burden (CCI score ≥3) increased from 25% to a predicted 50%, and their 5-year age-adjusted mortality hazard ratio (HR) fell from 4.0 (95% confidence interval [CI]: 3.0, 5.4) to 2.7 (95% CI: 2.0, 3.6), respectively, compared with patients with no comorbid disease. Conclusion: Survival of breast cancer patients diagnosed in the Central Denmark Region improved from 2000 to 2011, regardless of the extent of comorbid disease. Keywords: breast neoplasm, survival, mortality, comorbidity, prognosis

Mary Nguyen-Nielsen,1 Mette Nørgaard,1 Jacob Bonde Jacobsen,1 Michael Borre,2 Reimar Wernich Thomsen,1 Mette Søgaard1 1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Urology, Aarhus University Hospital, Aarhus, Denmark Objective: We investigated temporal changes in overall survival among prostate cancer (PC) patients and the impact of comorbidity on all-cause mortality. Methods: We conducted a population-based cohort study in the Central Denmark Region (1.2 million inhabitants). Using medical registries, we identified 7,654 PC patients with first-time PC diagnosis within the period 2000–2011 and their corresponding comorbidities within 10 years prior to the PC diagnosis. We estimated 1- and 5-year survival in four consecutive calendar periods using a hybrid analysis and plotted Kaplan–Meier survival curves. We used Cox proportional hazards regression to compute 1- and 5-year age-adjusted mortality rate ratios (MRRs) for different comorbidity levels. All estimates are reported with their corresponding 95% confidence intervals (CI). Results: The annual number of PC cases doubled over the 12-year study period. Men aged

Anil Mor, Sinna P Ulrichsen, Elisabeth Svensson, Klara Berencsi, Reimar W Thomsen Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark Background: To reduce the increasing burden of pneumonia hospitalizations, we need to understand their determinants. Being married may decrease the risk of severe infections, due to better social support and healthier lifestyle. Patients and methods: In this population-based case-control study, we identified all adult patients with a first-time pneumonia-related hospitalization between 1994 and 2008 in Northern Denmark. For each case, ten sex- and age-matched population controls were selected from Denmark's Civil Registration System. We performed conditional logistic regression analysis to estimate the odds ratios (ORs) for pneumonia hospitalization among persons who were divorced, widowed, or never married, as compared with married persons, adjusting for age, sex, 19 different comorbidities, alcoholism-related conditions, immunosuppressant use, urbanization, and living with small children. Results: The study included 67,162 patients with a pneumonia-related hospitalization and 671,620 matched population controls. Compared with controls, the pneumonia patients were more likely to be divorced (10% versus 7%) or never married (13% versus 11%). Divorced and never-married patients were much more likely to have previous diagnoses of alcoholism-related conditions (18% and 11%, respectively) compared with married (3%) and widowed (6%) patients. The adjusted OR for pneumonia-related hospitalization was increased, at 1.29 (95% confidence interval [CI]: 1.25-1.33) among divorced; 1.15 (95% CI: 1.12-1.17) among widowed; and 1.33 (95% CI: 1.29-1.37) among never-married individuals as compared with those who were married. Conclusion: Married individuals have a decreased risk of being hospitalized with pneumonia compared with never-married, divorced, and widowed patients. Keywords: marital status, risk, mortality, immune function

Charlotte Steffensen,1 Reimar W Thomsen,2 Allan Vaag,3 Henning Beck-Nielsen,4 Jens Sandahl Christiansen,1 Torben Hansen,5,6 Oluf Borbye Pedersen,5,6 Jørgen Rungby11Aarhus University Hospital, Department of Medicine, Aarhus, 2Aarhus University Hospital, Institute of Clinical Medicine, Department of Clinical Epidemiology, Aarhus, 3Copenhagen University Hospital "Rigshospitalet", Department of Endocrinology, Copenhagen, 4Odense University Hospital, Department of Endocrinology, Odense, 5The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, 6Faculty of Health Sciences, University of Aarhus, Aarhus, DenmarkAbstract: Here we provide an overview of the rationale and methods of a series of planned population based studies within the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project. The project aims to support and evaluate ongoing political and administrative efforts to implement nationwide guidelines for maintaining metabolic control in newly diagnosed type 2 diabetes (T2D) patients to prevent diabetic complications and improve quality of life. The DD2 is designed as a prospective cohort study (collection of epidemiological data) supplemented by randomized clinical intervention trials (on physical exercise and individualized pharmacological treatment) and the establishment of a biobank comprised of material from a large number of newly diagnosed T2D patients. Inclusion of the majority of newly diagnosed T2D patients as they are diagnosed at their general practitioner or diabetes hospital outpatient clinics and entered into the DD2 cohort will establish a nationwide database comprising a large number of future incident cases of T2D in Denmark. These cases will form the project cohort of the DD2. Within the first 6 months of diagnosis, all patients will be invited to contribute to a biobank of DNA, plasma, urine, and tissue sampling. The DNA biobank will enable future studies of the effect of pharmacological treatment and outcome in subsets of patients with specific genetic risk profiles covering disease etiology and specific drug kinetics and metabolism. We will also perform two clinical intervention trials examining: the effectiveness of physical exercise on diabetes-related outcomes and the impact of trial outcomes on individualized pharmacological treatment. Moreover, the DD2 will serve as a platform for testing and developing new antidiabetic drugs. All together, we expect this study to contribute to substantially improved diabetes care in T2D patients locally and abroad.Keywords: type 2 diabetes, prognosis, intervention, physical exercise

Reimar Wernich Thomsen,1 Jens Steen Nielsen,2 Sinna Pilgaard Ulrichsen,1 Lars Pedersen,1 Anne-Marie Sigsgaard Hansen,3 Tove Nilsson11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 2Odense University Hospital, Odense, 3Danish Clinical Registers (DCR), Aarhus, DenmarkAbstract: This paper provides an overview of the baseline data collected in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. The paper presents descriptive data from the first 580 patients enrolled in the DD2. The DD2 database will contain detailed interview data, clinical examination data, and urine and blood samples from up to 10,000 patients newly diagnosed with type 2 diabetes each year, collected from general practitioners and hospital outpatient clinics in all of Denmark. Of the first DD2 patients enrolled, blood and urine samples have been obtained from 97%. The median age of the first 580 patients was 59 years and 322 (56%) were men. Median weight gain from age 20 to maximum lifetime weight was 29 kg for men and 31 kg for women, and 364 patients (63%) did not currently participate in regular sports activities. Two hundred and ninety two patients (50%) had a known family history of diabetes. Two hundred fifty (43%) of the 580 DD2 patients have also been enrolled in the Danish Diabetes Database for Adults from which additional clinical data can be obtained. Among these 250 patients (154 of whom were men, 96 women), 75 (49%) men were currently obese, and 63 (41%) were overweight, whereas 62 (65%) women were obese, and another 21 (22%) were overweight. Twenty-nine patients (12%) received insulin, 164 patients (66%) received oral antidiabetics only, and 57 (23%) received no antidiabetic treatment. Glycemic regulation was modest (the glycosylated hemoglobin A of 46% was ≥7.5%). Two thirds of the patients received antihypertensive and hypolipidemic treatment. Self-reported daily tobacco smoking (23%) and alcohol overuse (6%) seemed comparable to occurrence in the general Danish population. One quarter of the patients with newly diagnosed diabetes had a history of hospital-diagnosed comorbidity at baseline as included in the Charlson comorbidity index, in particular prior myocardial infarction (5%), cerebrovascular disease (5%), peripheral vascular disease (4%), chronic pulmonary disease (6%), and previous solid cancer (6%). In the future, the DD2 database represents a valuable source for outcome studies in type 2 diabetes.Keywords: type 2 diabetes, epidemiological methods, registries, prognosis

Reimar Wernich Thomsen,1 Søren Friborg,2,3 Jens Steen Nielsen,2 Henrik Schroll,4 Søren Paaske Johnsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Endocrinology, Odense University Hospital, Odense, Denmark; 3Danish Clinical Registers, Aarhus, Denmark; 4Danish Quality Unit of General Practice, Odense, DenmarkAbstract: This paper provides a short overview of the Danish health care system and the organization of care for type 2 diabetes patients in Denmark. It also describes the supplementary data sources that are used for collection of baseline data in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project. The Danish National Health Service provides tax-funded medical care for all 5.6 million Danish residents. The health care system is characterized by extensive individual-level registration of data used for planning, administration, quality improvement, and research. It is estimated that there are currently at least 250,000 individuals with known diabetes in Denmark (approximately 4.5% of the Danish population), of which an estimated 80% are followed and treated by their general practitioners and approximately 20% are followed at hospital specialist outpatient clinics. These health care providers form the basis for recruiting diabetes patients in the DD2 project, and the data sources that these providers use in clinical practice give access to important supplementary patient data. The DD2’s patient-enrollment system is designed to be fast and simple, and thus only collects primary interview data that cannot be extracted from already existing data sources. Thus, in addition to an online DD2 questionnaire filled out by general practitioners and hospital physicians at the time of patient enrollment, supplementary data are obtained from the Danish Diabetes Database for Adults, a nationwide clinical quality improvement registry. Both hospital physicians and a growing number of general practitioners routinely report data to this database. For general practitioners, the Danish General Practice Database acts as an important feeder database for the Danish Diabetes Database for Adults and thereby also for the DD2 project.Keywords: type 2 diabetes, data sources, epidemiology, health care, Danish Diabetes Database for Adults (DDDA), Danish General Practice Database (Dansk AlmenMedicinsk Database [DAMD])

Jens Steen Nielsen,1 Reimar W Thomsen,2 Charlotte Steffensen,2 Jens S Christiansen31Department of Endocrinology M, Odense University Hospital, Odense, 2Department of Clinical Epidemiology, 3Department of Endocrinology, Aarhus University Hospital, Aarhus, DenmarkAbstract: This paper aims to describe the patient enrollment system and implementation strategy for the new nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. The paper will also describe the design, current content, and pilot testing of the DD2 registration form. The challenge of the DD2 project was to construct a registration system functioning in the entire Danish health care system, where new type 2 diabetes patients are initially met, and with the capacity to enroll 200 newly diagnosed diabetes patients per week nationwide. This requires a fast and simple registration that is part of everyday clinical practice in hospital outpatient clinics and general practitioner (GP) clinics. The enrollment system is thus built on a tested, rational design where patients need only one visit and only specific limited data about physical activity, anthropometric measures, and family history of diabetes are collected during a brief patient interview. Later, supplemental data will be extracted by computerized linkage with existing databases. The feasibility of this strategy was verified in a pilot study. For maximum flexibility, three different ways to fill in the DD2 registration form were provided and an interactive webpage was constructed. The DD2 project also involves collection of blood and urine samples from each diabetes patient, to be stored in a biobank. Clinicians may obtain the samples themselves or refer patients to the nearest clinical biochemical department. GPs have the additional option of referring patients to the nearest hospital outpatient diabetes clinic to obtain interview data, clinical data, and samples. At present, the enrollment system is in use at 17 hospital outpatient diabetes clinics and 45 GP clinics nationwide, together enrolling 40 new type 2 diabetes patients per week in the DD2 project. A total of 990 patients have now been enrolled and the DD2 is ready to expand nationwide.Keywords: DD2, type 2 diabetes, logistics, implementation, data registration, health information technology

Jeppe Lange1,2, Anders Troelsen3, Reimar W Thomsen4, Kjeld Søballe1,51Lundbeck Foundation Centre for Fast-Track Hip and Knee Surgery, Aarhus C, 2Center for Planned Surgery, Silkeborg Regional Hospital, Silkeborg, 3Department of Orthopaedics, Hvidovre Hospital, Hvidovre, 4Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg, 5Department of Orthopaedics, Aarhus University Hospital, Aarhus C, DenmarkBackground: Two-stage revision is regarded by many as the best treatment of chronic infection in hip arthroplasties. Some international reports, however, have advocated one-stage revision. No systematic review or meta-analysis has ever compared the risk of reinfection following one-stage and two-stage revisions for chronic infection in hip arthroplasties.Methods: The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Relevant studies were identified using PubMed and Embase. We assessed studies that included patients with a chronic infection of a hip arthroplasty treated with either one-stage or two-stage revision and with available data on occurrence of reinfections. We performed a meta-analysis estimating absolute risk of reinfection using a random-effects model.Results: We identified 36 studies eligible for inclusion. None were randomized controlled trials or comparative studies. The patients in these studies had received either one-stage revision (n = 375) or two-stage revision (n = 929). Reinfection occurred with an estimated absolute risk of 13.1% (95% confidence interval: 10.0%–17.1%) in the one-stage cohort and 10.4% (95% confidence interval: 8.5%–12.7%) in the two-stage cohort. The methodological quality of most included studies was considered low, with insufficient data to evaluate confounding factors.Conclusions: Our results may indicate three additional reinfections per 100 reimplanted patients when performing a one-stage versus two-stage revision. However, the risk estimates were statistically imprecise and the quality of underlying data low, demonstrating the lack of clear evidence that two-stage revision is superior to one-stage revision among patients with chronically infected hip arthroplasties. This systematic review underscores the need for improvement in reporting and collection of high-quality data and for large comparative prospective studies on this issue.Keywords: infection, arthroplasty, hip replacement, one-stage, two-stage, reoperation

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

Reimar W Thomsen, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital, DenmarkValidation studies of health care registries are considered boring by some. An epidemiologist recently conducted a validation study based on the Danish National Registry of Patients and received the following unflattering comment from a reviewer: “A good example of a paper of limited scope that probably would only be published electronically where space is unlimited”. We do not subscribe to this point of view. See Original Research article

Objective: To examine the association between diabetes, glycemic control, and risk of tuberculosis (TB).Research Design and Methods: We conducted a population-based case-control study in Northern Denmark. Cases of active TB were all individuals with a first-time principal hospital diagnosis of TB between 1980 and 2008. Each case subject was matched with up to five population control subjects with similar age, sex, place and length of residence in Denmark, and country of emigration. We computed odds ratios (ORs) for a first-time TB diagnosis among people with and without diabetes using regression to control for other comorbidities, alcoholism, immunosuppressive medications, and socioeconomic markers.Results: We identified 2,950 patients, including 156 diabetic individuals (5.3%), with active TB, and 14,274 population control subjects, of which 539 had diabetes (3.8%). The adjusted OR for active TB among subjects with diabetes was 1.18 (95% CI 0.96-1.45) compared with nondiabetic individuals. We found a similar risk increase from diabetes in the 843 (29%) TB case subjects who were immigrants; adjusted OR = 1.23 (95% CI 0.78-1.93). In a subset with laboratory data, diabetic individuals with an HbA(1c) <7.0, 7-7.9, and ≥8.0% had ORs of 0.91 (0.51-1.63), 1.05 (0.41-2.66), and 1.19 (CI 0.61-2.30), respectively, compared with individuals without diabetes.Conclusions: In the low TB-burden country of Denmark, the TB risk increase associated with diabetes is substantially lower than previously suggested. We found no evidence for any association between TB and dysglycemia. [ABSTRACT FROM AUTHOR]