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Oscar Rosenkrantz,1,2 Jannik Wheler,1 Mats Christian Westphal Thrane,3 Lars Pedersen,1 Henrik Toft Sørensen1 1Department of Clinical Epidemiology and Center for Population Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark; 3Danish Health Data Authority, Copenhagen, DenmarkCorrespondence: Oscar Rosenkrantz, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43, 45, DK, Aarhus N, 8200, Denmark, Tel +45 87 16 72 12, Email oscar.oelrich.rosenkrantz@clin.au.dkBackground: The Danish National Hospital Medication Register (DHMR), one of the first nationwide in-hospital medication registries in the world, contains detailed information on medication administration and dispensing.Objective: To provide an overview of the information recorded in the DHMR and to highlight its strengths and limitations as a pharmacoepidemiological research tool.Methods: We reviewed the registry´s geographic and clinical specialty coverage and medications recorded according to the main groups of the Anatomical Therapeutic Chemical classification system.Results: From May 2018 through December 2023, the DHMR recorded data on more than 1.9 million unique patients from all approximately 50 public hospitals and associated hospital outpatient clinics, totaling 105.3 million recordings of hospital medication use. The registry records detailed data on the indication for medication, medication type, pharmaceutical form, dosage, and administration time, collected through electronic medical record systems. Although the data quality has not yet been evaluated in a scientific context, some potential limitations are known. These include regional differences in the data collection and a lack of data from certain clinical specialties. Due to its recent establishment in 2018, the registered number of patients treated may still be limited for some rarely used medications.Conclusion: The DHMR is an important new resource for research in Denmark. Combined with the Danish National Prescription Registry, which covers all community pharmacies, it offers access to accurate data on medication exposure in the Danish population. Users should be aware of potential issues with lack of information before 2018.Keywords: pharmacoepidemiology, hospital medication system, pharmacotherapy, data source, drug databases, registry data, Denmark

Jakob Kjølby Eika,1,2,* Kasper Bonnesen,1,2,* Lars Pedersen,1,2 Vera Ehrenstein,1,2 Henrik Toft Sørensen,1,2 Morten Schmidt1– 3 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Cardiology, Gødstrup Regional Hospital, Herning, Denmark*These authors contributed equally to this workCorrespondence: Morten Schmidt, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark and Department of Clinical Medicine, Aarhus University, Olof Palmes Allé 43– 45, Aarhus, 8200, Denmark, Tel +45 87 16 72 12, Email morten.schmidt@clin.au.dkPurpose: Ibuprofen is used to treat acute pericarditis, but high-dose ibuprofen has also been associated with increased cardiovascular risks. We examined the cardiovascular safety of using ibuprofen for acute pericarditis.Patients and Methods: A Danish nationwide, population-based cohort study including patients ≥ 18 years with first-time acute pericarditis (n=12,381) during 1996– 2020 was conducted. Ibuprofen use was modelled in two ways: First, we considered patients exposed based on the tablet strength of their first ibuprofen filling (a proxy for an intention-to-treat analysis). Second, we considered patients exposed in a time-varying manner (a proxy for an as-treated analysis). The primary outcome of major adverse cardiovascular events (MACE) was a composite of myocardial infarction, ischemic stroke, congestive heart failure, and cardiovascular death.Results: In the intention-to-treat analysis, the 1-year risk of MACE was 1.37% (95% confidence interval [CI]: 1.03– 1.79) for ibuprofen initiators and 4.32% (95% CI: 3.89– 4.78) for non-initiators. Compared with non-initiators within 1-year follow-up, the adjusted hazard ratio for MACE was 0.75 (95% CI: 0.67– 0.85) for initiators overall, 0.38 (95% CI: 0.28– 0.52) for initiators of > 400 mg tablets, and 0.87 (95% CI: 0.76– 0.99) for initiators of ≤ 400 mg tablets. In the as-treated analysis, compared with no use, the hazard ratio associated with ibuprofen use was 0.69 (95% CI: 0.54– 0.89) for MACE, 0.82 (95% CI: 0.54– 1.26) for myocardial infarction, 0.74 (95% CI: 0.45– 1.22) for ischemic stroke, 0.67 (95% CI: 0.47– 0.96) for congestive heart failure, and 0.60 (95% CI: 0.31– 1.17) for cardiovascular death.Conclusion: Ibuprofen use for acute pericarditis was not associated with increased cardiovascular risks, supporting its safety in current practice.Keywords: Pericarditis, Anti-Inflammatory Agents, non-steroidal, Cohort Study, Epidemiology

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

Niels Obel,1,2 Matthew P Fox,3 Malte M Tetens,2 Lars Pedersen,4 Tyra Grove Krause,5 Henrik Ullum,5 Henrik Toft Sørensen4 1Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Copenhagen, 2300, Denmark; 2Department of Infectious Diseases, Copenhagen University Hospital – Rigshospitalet, Copenhagen, 2100, Denmark; 3Departments of Epidemiology and Global Health, School of Public Health, Boston University, Boston, MA, USA; 4Department of Clinical Epidemiology, Aarhus University, Aarhus N, 8200, Denmark; 5Statens Serum Institut, Copenhagen, 2300, DenmarkCorrespondence: Niels Obel, Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark, Tel +4532683252, Email niob@ssi.dkBackground: Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods.Methods: Nationwide population-based cohort study including two cohorts of Danish residents 60– 90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR).Results: Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09– 1.21) for eye examinations to 3.05 (95% CI: 2.24– 4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19– 0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37– 0.67) after stroke.Conclusion: Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.Plain Language Summary: Why was this study done: After the emergence of new SARS-CoV-2 variants and the rollout of multiple booster SARS-CoV-2 vaccines, the impact of vaccination on risk of SARS-CoV-2 infection and death after the infection has mainly been explored in observational studies. We used negative control methods to investigate whether confounding affects the results of observational SARS-CoV-2 vaccine effectiveness studies.Findings: We used Danish registry data obtained during the SARS-CoV-2 vaccine roll-out to conduct a nationwide, matched population-based cohort study of Danish residents 60– 90 years in which we compared vaccinated individuals with non-vaccinated individuals. Compared with unvaccinated individuals, vaccinated individuals had increased risks of SARS-CoV2 infection but also had increased risks of all negative control outcomes (mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear). The risk of death after SARS-CoV2 infection was lower in the vaccinated cohort, as was the risk of death after acute myocardial infarction, stroke, cancer, low energy fracture, and head-trauma.Meaning: The negative control methods indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be prone to substantial confounding which may impact the observed associations. This bias may both lead to underestimation of vaccine effectiveness (increased risk of SARS-CoV2 infection among vaccinated individuals) and overestimation of the vaccine effectiveness (decreased risk of death after of SARS-CoV2 infection among vaccinated individuals). Our results highlight the need for randomized vaccine efficacy studies after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.Keywords: COVID-19, vaccines, cohort studies, bias, confounding factors, epidemiologic

Jonas F Ludvigsson,1 Johan Askling,1 Sven Cnattingius,1 Per Hall,1 Lars Klareskog,1 Olof Nyren,1 John A Baron,2 Henrik Toft Sørensen3 1Karolinska Institutet, Solna, Sweden; 2University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Aarhus University, Aarhus, DenmarkCorrespondence: Jonas F Ludvigsson, Email jonasludvigsson@yahoo.com

Søren Korsgaard, Frederikke Schønfeldt Troelsen, Katalin Veres, Cecilia Hvitfeldt Fuglsang, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, DenmarkCorrespondence: Søren Korsgaard, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43– 45, Aarhus N, 8200, Denmark, Tel +45 87167212, Email soren.korsgaard@clin.au.dkPurpose: In the Danish National Patient Registry (DNPR), covering all Danish hospitals and widely used in research, diseases have been recorded using International Classification of Diseases (ICD) codes, transitioning from the Eighth to the Tenth revision in 1994. Uncertainty exists regarding whether including ICD-8 codes alongside ICD-10 is needed for complete disease identification. We assessed the extent of left-truncation and left-censoring in the DNPR arising from omitting ICD-8 codes.Patients and Methods: We sampled 500,000 Danes ≥ 40 years of age in 1995, 2010, and 2018. From the DNPR, we identified cardiovascular, endocrine, gastrointestinal, neurological, pulmonary, rheumatic, and urogenital diseases as well as fractures. We obtained the number of people with a disease recorded with ICD-8 codes only (ie, the ICD-8 record would be left-truncated by not using ICD-8 codes), ICD-8 plus ICD-10 codes (ie, the ICD-8 record would be left-censored by not using ICD-8 codes), and ICD-10 codes only. For each ICD group, we calculated the proportion of people with the disease relative to the total sample (ie, 500,000 people) and the total number of people with the disease across all ICD groups.Results: Overall, the left-truncation issue decreased over the years. Relative to all people with a disease, the left-truncated proportion was for example 59% in 1995 and < 2% in 2018 for diabetes mellitus; 93% in 1995, and 54% in 2018 for appendicitis. The left-truncation issue increased with age group for most diseases. The proportion of disease records left-censored by not using ICD-8 codes was generally low but highest for chronic diseases.Conclusion: The left-truncation issue diminished over sample years, particularly for chronic diseases, yet remained rather high for selected surgical diseases. The left-truncation issue increased with age group for most diseases. Left-censoring was overall a minor issue that primarily concerned chronic diseases.Keywords: epidemiology, methodology, bias, left-truncation, left-censoring

Mohab Basem,1 Kasper Bonnesen,1 Lars Pedersen,1 Henrik Toft Sørensen,1 Morten Schmidt1,2 1Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2Department of Cardiology, Gødstrup Regional Hospital, Herning, DenmarkCorrespondence: Mohab Basem, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43– 45, Aarhus N, 8200, Denmark, Tel +45 87167212, Email mohabbasem@gmail.comAim: To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI).Methods: Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010– 2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (< 3.0 vs ≥ 3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death).Results: We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11– 1.32) overall, 1.19 (1.06– 1.33) in the low LDL-C group, and 1.23 (1.07– 1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07– 1.39) in the low LDL-C group and 1.54 (1.30– 1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results.Conclusion: In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death. Keywords: cardiovascular disease, non-steroidal anti-inflammatory drugs, cholesterol, low-density lipoprotein cholesterol, myocardial infarction, effect modification

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

Sara Hatam,1,&ast; Sean Timothy Scully,2,&ast; Sarah Cook,3,&ast; Hywel T Evans,2,&ast; Alastair Hume,4 Constantinos Kallis,3 Ian Farr,2 Chris Orton,2 Aziz Sheikh,1 Jennifer K Quint3 1Usher Institute, The University of Edinburgh, Edinburgh, UK; 2Population Data Science, Swansea University Medical School, Swansea, UK; 3School of Public Health, Imperial College London, London, UK; 4EPCC, The University of Edinburgh, Edinburgh, UK&ast;These authors contributed equally to this workCorrespondence: Jennifer K Quint, Email j.quint@imperial.ac.ukBackground: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations.Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons.Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.Keywords: COPD, asthma, ILD, HER, harmonisation, data curation

Jan P Vandenbroucke,1– 3 Henrik Toft Sørensen,1,4 David H Rehkopf,5 Jaimie L Gradus,6 Johan P Mackenbach,7 M Maria Glymour,8 Sandro Galea,9 Victor W Henderson1,10 1Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 2Leiden University, Leiden, Netherlands; 3London School of Hygiene & Tropical Medicine, London, UK; 4Aarhus University Hospital, Aarhus, Denmark; 5Stanford Center for Population Health Sciences, Stanford University, CA, USA; 6Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA; 7Department of Public Health, Erasmus University Rotterdam, Rotterdam, Holland; 8Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, MA, USA; 9School of Public Health, Boston University, Boston, MA, USA; 10Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USAAbstract: This paper is a summary of key presentations from a workshop in Iceland on May 3– 4, 2023 arranged by Aarhus University and with participation of the below-mentioned scientists.Below you will find the key messages from the presentations made by:Professor Jan Vandenbroucke, Department of Clinical Epidemiology, Aarhus University, Emeritus Professor, Leiden University; Honorary Professor, London School of Hygiene & Tropical Medicine, UKProfessor, Chair Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, DenmarkProfessor David H. Rehkopf, Director, the Stanford Center for Population Health Sciences, Stanford University, CA., USProfessor Jaimie Gradus, Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Johan Mackenbach, Emeritus Professor, Department of Public Health, Erasmus University Rotterdam, HollandProfessor, Chair M Maria Glymour, Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, Massachusetts, USProfessor, Dean Sandro Galea, School of Public Health, Boston University, Boston, Massachusetts, USProfessor Victor W. Henderson, Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, US; Department of Clinical Epidemiology, Aarhus University, Aarhus, DKKeywords: Ageing, Multimorbidity, Social inequality

Henrik Toft Sørensen,1 Tina Christensen,1 Hans Erik Bøtker,2 Christian Fynbo Christiansen,1 Cecilia H Fuglsang,1 Sigrid B Gribsholt,1 Frederik Pagh Bredahl Kristensen,1 Kristina Laugesen,1 Anne Sofie D Laursen,1 Mette Nørgaard,1 Morten Schmidt,1 Nils Skajaa,1 Frederikke S Troelsen,1 Lars Pedersen1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkPurpose: Humans are living longer and may develop multiple chronic diseases in later life. The Better Health in Late Life cohort study aims to improve our understanding of the risks and outcomes of multimorbidity in the Danish population.Methods: A randomly-selected sample of Danish residents who were 50– 65 years of age received a questionnaire and an invitation to participate in this study. Respondents completed an online survey between October 2021 and January 2022 which addressed topics that included self-assessed health, mental health, sleep, specific medical conditions, use of painkillers, diet, alcohol consumption, smoking, physical activity, and body composition. This information was linked to the Danish health and social registries (some established in 1943 and onwards) that maintain data on filled prescriptions, hospital records, socioeconomic status, and health care utilization.Results: Responses were received from 115,431 of the 301,244 residents invited to participate (38%). We excluded respondents who answered none of the questions as well as those who provided no information on sex or indicated an age other than 50– 65 years. Of the 114,283 eligible respondents, 54.8% were female, 30.3% were overweight, and 16.7% were obese. Most participants reported a weekly alcohol consumption of less than seven units and 13.3% were current smokers; 5.2% had a history of hospitalization for solid cancer, and 3.0%, 2.3%, 2.0%, and 0.9% reported chronic pulmonary disease, diabetes, stroke, and myocardial infarction, respectively. The most frequently filled prescriptions were for medications used to treat the nervous system and cardiovascular diseases (38.1% and 37.4%, respectively).Keywords: aging, epidemiology, health registries, life course epidemiology, multimorbidity, prospective cohort

Søren Hauge Okholm,1 Dávid Nagy,1 Dóra Körmendiné Farkas,1 Cecilia Hvitfeldt Fuglsang,1 Frederikke Schønfeldt Troelsen,1 Victor W Henderson,1,2 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USACorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus N, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkIntroduction: Cancer may increase the risk of bleeding. However, whether subdural hematoma is a marker of occult cancer remains unknown. We examined the association between non-traumatic subdural hematoma and cancer risk in a cohort study.Materials and Methods: Using Danish nationwide health registries, we identified 2713 patients with non-traumatic subdural hematoma and no previous cancer diagnosis, who were hospitalized between April 1, 1996 and December 31, 2019. We computed age-, sex-, and calendar year-standardized incidence ratios (SIRs) as the ratio of the observed to expected number of patients with cancer by using national incidence rates as reference as a measure of relative risk.Results: We identified 77 cancer cases within the first year of follow-up and 272 cancer cases thereafter. The one-year risk of cancer was 2.8% (95% confidence interval: 2.2– 3.5), and the one-year SIR was 1.7 (95% confidence interval: 1.3– 2.1). During the subsequent years, the SIR was 1.0 (95% confidence interval: 0.9– 1.1). The relative risk was elevated for some hematological and liver cancers.Conclusion: The risk of a new cancer diagnosis was clearly increased in patients with non-traumatic subdural hematoma compared with the general population during the first year of follow-up. However, the absolute risk was low, thus limiting the clinical relevance of pursuing early cancer detection in these patients.Keywords: cancer, cohort study, epidemiology, non-traumatic subdural hematoma, population-based

Kristina Laugesen,1 Jonas Mengel-From,2,3 Kaare Christensen,2– 4 Jørn Olsen,1 David M Hougaard,5,6 Lasse Boding,7 Anja Olsen,8,9 Christian Erikstrup,10 Merete Lund Hetland,11,12 Estrid Høgdall,12,13 Alisa D Kjaergaard,14 Erik Sørensen,15 Anja Brügmann,16 Eva Rabing Brix Petersen,17 Ivan Brandslund,17,18 Børge G Nordestgaard,19 Gorm B Jensen,20 Nils Skajaa,1 Frederikke Schønfeldt Troelsen,1 Cecilia Hvitfeldt Fuglsang,1 Lise Skovgaard Svingel,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Epidemiology, Biostatistics and Biodemography, the Danish Twin Registry, and the Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; 4Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; 5iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark; 6Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark; 7The Danish National Biobank, Statens Serum Institut, Copenhagen, Denmark; 8Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; 9Department of Public Health, Aarhus University, Aarhus, Denmark; 10Department of Clinical Immunology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 11The DANBIO Registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark; 12Department of Clinical Medicine, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; 13Bio- and GenomeBank Denmark (RBGB), Molecular Unit, Department of Pathology, Herlev Hospital, Herlev, Denmark; 14Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 15Department of Clinical Immunology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark; 16Department of Pathology, Aalborg University Hospital, Aalborg, Denmark; 17Department of Clinical Biochemistry and Immunology, Lillebaelt Hospital, Vejle, Denmark; 18Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; 19The Copenhagen General Population Study, Department of Clinical Biochemistry, Copenhagen University Hospital – Herlev Gentofte, University of Copenhagen, Herlev, Denmark; 20The Copenhagen City Heart Study, Frederiksberg and Bispebjerg Hospital, Frederiksberg, DenmarkCorrespondence: Kristina Laugesen, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 871 68063, Email Kristina.laugesen@clin.au.dkAbstract: Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.Keywords: biobank, research, healthcare system, registries, epidemiology, precision medicine

Simon Kok Jensen,1,2 Uffe Heide-Jørgensen,1,2 Søren Viborg Vestergaard,1,2 Henrik Toft Sørensen,1,2 Christian Fynbo Christiansen1,2 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Simon Kok Jensen, Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 8716 8481, Email skj@clin.au.dkPurpose: Creatinine data are key in identifying acute and chronic kidney disease. In Denmark, routine clinical care creatinine data have been collected regionally in the Clinical Laboratory Information System Research Database (LABKA) since the 1990s and nationwide in the Register of Laboratory Results for Research (RLRR) since 2013. Here we describe the geographical coverage of the databases and characteristics of Danish individuals with creatinine tests. This information is pivotal for the design and interpretation of studies using these data to examine kidney disease epidemiology.Patients and Methods: We included all creatinine tests in LABKA and RLRR from 1990 through 2018. The daily number of creatinine tests by municipality and region of residence were plotted and geographical coverage was ascertained. In addition, we characterized a contemporary cohort of creatinine-tested individuals in 2016– 2018.Results: During 1990– 2018, 61,011,941 creatinine tests were available for 4,647,966 unique Danish residents. The North Denmark Region was the first region to achieve complete reporting in November 2004, and nationwide reporting was complete starting in October 2015. In each year from 2016 to 2018, more than a third of Danish residents had a recorded creatinine measurement, with the highest proportion of tested individuals aged 77– 87 years and the lowest proportion aged 3– 5 years. During 2016– 2018, the creatinine-tested cohort had a median age of 53 years (IQR, 35– 67 years) and included 54.3% women. The most common comorbidity was a hospital-based diagnosis of hypertension (12.0%), and the most common prescription drug was angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (15.8%).Conclusion: In combination, the population-based LABKA and RLRR databases provide regional creatinine data with long follow-up and nationwide data for the Danish population. There was considerable variation in the time of complete geographical coverage by region, which needs to be considered when using these data for studies on kidney disease epidemiology.Keywords: cohort, creatinine, epidemiology, glomerular filtration rate, kidney disease, registries

Blean Girma,1 Dóra Körmendiné Farkas,2 Kristina Laugesen,2 Nils Skajaa,2 Victor W Henderson,2,3 Paolo Boffetta,4,5 Henrik Toft Sørensen2 1Department of Environmental Medicine and Public Health, Icahn School of Medicine, New York, NY, USA; 2Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 3Departments of Epidemiology & Population Health and of Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA; 4Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA; 5Department of Medical and Surgical Sciences, University of Bologna, Bologna, ItalyCorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkIntroduction: It is unclear whether Guillain–Barré syndrome (GBS) can be a marker of a paraneoplastic syndrome. We examined whether GBS is associated with cancer and whether the prognosis of GBS patients with cancer differs from that of other cancer patients.Materials and Methods: We conducted a population-based cohort study of patients diagnosed with GBS between 1978 and 2017 using Danish registry-data. Main outcome measures were cancer incidence and mortality after cancer diagnosis. We calculated absolute risks of a cancer diagnosis, treating death as competing risk, and standardized incidence ratios (SIRs) as measures of relative risk. We matched each GBS cancer patient with up to 10 cancer patients without a GBS diagnosis and examined the six-month survival after cancer diagnosis using Cox regression analysis.Results: We identified 7897 patients (58% male, median age 57 years) with GBS. During a median follow-up of 9.5 years, the one-year risk of cancer was 2.7% (95% confidence interval (CI), 2.4– 3.1). The SIR was increased throughout follow-up, but most noticeably during the first year after diagnosis (SIR: 3.35, 2.92– 3.83). SIRs were particularly elevated for hematologic cancers (SIR: 8.67, 6.49– 11.34), smoking-related cancers (SIR: 3.57, 2.81– 4.47), and cancers of neurological origin (SIR: 8.60, 5.01– 13.77). Lung cancer was the main contributor to the overall excess risk, which persisted after 36 months of follow-up (SIR: 1.17, 1.09– 1.25). The mortality rate ratio comparing patients diagnosed with any cancer within one year of their GBS diagnosis and matched GBS-free cancer cohort members was 1.56 (95% CI, 1.27– 1.90).Conclusion: GBS patients had a three-fold increased risk of cancer diagnosis in the first year of follow-up. The absolute cancer risk was almost 3.0%. A GBS diagnosis was an adverse prognostic marker for survival following cancer diagnosis. Clinicians should consider occult cancer in patients hospitalized with GBS.Keywords: Guillain–Barré syndrome, cancer, paraneoplastic syndrome, survival, risk, cohort

Helle Jørgensen,1– 3 Erzsébet Horváth-Puhó,2 Kristina Laugesen,2 Sigrid K Braekkan,1,3 John-Bjarne Hansen,1,3 Henrik Toft Sørensen2 1Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway; 2Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 3Division of Internal Medicine, University Hospital of North Norway, Tromsø, NorwayCorrespondence: Helle Jørgensen, Email helle.jorgensen@uit.noBackground: Venous thromboembolism (VTE) is associated with increased risk of disability pension. How socioeconomic status (SES) impacts the risk of disability pension after a VTE is unknown. The aim of this nationwide population based cohort study to investigate the interaction between SES and incident VTE on the risk of subsequent disability pension.Methods: Using Danish national medical and administrative databases, we established a nationwide cohort of 41,781 individuals aged 25– 65 years with incident VTE during 1995– 2016 and a comparison cohort (n=208,905) from the general population matched on year of birth, sex, and calendar year of VTE. We computed incidence rates (IRs) as the number of disability pension events per 1000 person-years at risk and measured the interaction between VTE and levels of SES (high, medium, low) on an additive scale by calculating interaction contrasts (difference in IR difference).Results: Among individuals with high SES, the disability pension IR per 1000 person-years was 5.4 (95% CI: 4.8– 6.1) in the VTE cohort and 1.6 (95% CI: 1.5– 1.7) in the comparison cohort (IR difference 3.8). The corresponding disability pension IR in individuals with low SES was 55.1 (95% CI: 52.1– 58.1) in the VTE cohort and 26.1 (95% CI: 25.1– 27.1) in the comparison cohort (IR difference 24.0). An interaction contrast of 25.1 indicated that interaction accounted for 45.6% (25.1/55.1) of the disability pension IR in individuals with VTE and low SES.Conclusion: SES and VTE interact to increase the risk of disability pension after VTE beyond their independent effects.Keywords: education, employment, income, deep-vein thrombosis, pulmonary embolism, burden of illness

Henrik Toft Sørensen1,2 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus N, DK-8200, Denmark; 2Clinical Excellence Research Center, Stanford University, Palo Alto, CA, USACorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University, Olof Palmes Allé 43-45, Aarhus N, DK-8200, Denmark, Email hts@clin.au.dkAbstract: Despite the Covid-19 pandemic, international travel is expected to increase in the future. Before the pandemic, the United Nations World Tourism Organization estimated that by 2030 nearly 2 billion people would travel internationally each year. This raises the risk of unavailable medical record information if a complication or an emergency occurs in another country (particularly problematic for the growing numbers of older travelers with multimorbidity). We propose that an international medical record containing current health information be developed to allay this additional risk of traveling.Keywords: e-health, epidemiology, global health, medical records, travel medicine

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

Eyal Cohen,1– 3 Péter Szentkúti,4 Erzsébet Horváth-Puhó,4 Hilary K Brown,3,5 Sonia M Grandi,2 Henrik Toft Sørensen,4,6 Joel G Ray2,3,7 1Department of Pediatrics and Edwin S.H. Leong Centre for Healthy Children, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 2Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada; 3Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Health & Society, University of Toronto Scarborough; 6Clinical Excellence Research Center, Stanford University, Stanford, CA, USA; 7St.Michael’s Hospital Department of Medicine, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Eyal Cohen, Department of Pediatrics and Edwin S.H. Leong Centre for Healthy Children, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, Tel +1 416-813-7654, Email eyal.cohen@sickkids.caBackground: The mother of an infant with a major congenital anomaly is at a higher risk of premature cardiometabolic disease, possibly from chronic caregiver stress and distraction from self-care, including maintaining a healthy lifestyle and body weight.Objective: To compare the interpregnancy weight gain in women whose first infant had a major congenital anomaly vs those without an affected child.Methods: Multivariable linear regression compared women whose infant had an anomaly vs those whose infant did not, adjusting for interpregnancy time interval, demographics, smoking and health status at the first pregnancy.Results: Of the 199,536 women who had two consecutive singleton births, 4035 (2.0%) had a child with an anomaly at the first birth. The mean (SD) maternal BMI at the start of the first pregnancy was 24.1 (4.7) and 23.7 (4.4) kg/m2 in women with, and without, an anomaly-affected newborn. By the start of the second pregnancy, 3 years later, they had gained a mean (SD) of 2.2 (5.5) and 1.8 (5.2) kg, respectively – an adjusted absolute higher gain of 0.26 kg (95% CI 0.10 to 0.42) in women with an anomaly-affected first-born infant compared to those with an unaffected pregnancy. The adjusted interpregnancy weight gain difference was greatest in women whose first-born infant had a multi-organ anomaly at 0.59 kg (95% CI 0.02 to 1.16). The adjusted odds ratio of moving from a normal BMI category of 18.5– 24.9 kg/m2 in the first pregnancy, to an overweight or obese BMI category of 25+ kg/m2 in the second, was 1.18 (95% CI 1.06 to 1.32) comparing mothers with vs without an anomaly-affected child in the first pregnancy.Conclusion: Mothers of an infant with a major congenital anomaly have a modestly higher interpregnancy weight gain and tend to climb to a higher BMI category. The long-term implications of this greater weight trajectory require further study.Keywords: weight gain, congenital anomaly, inter-pregnancy, body mass index

Henrik Toft Sørensen,1 Nils Skajaa,1 Frederikus Albertus Klok,2 Kristina Laugesen,1 Dóra Körmendiné Farkas1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus N, DK-8200, Denmark; 2Department of Medicine - Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the NetherlandsCorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University, Olof Palmes Allé 43-45, Aarhus N, DK-8200, Denmark, Email hts@clin.au.dkBackground: Strong evidence indicates that venous thromboembolism is a presenting symptom of cancer. Cancer is a known cause of pulmonary hypertension; however, it remains unknown whether pulmonary hypertension is a marker of occult cancer. We examined the association between a pulmonary hypertension diagnosis and cancer risk in a cohort study using population-based data from the Danish health system.Patients and Methods: Using Danish nationwide registries, we identified 6335 patients with a pulmonary hypertension diagnosis and without a previous cancer diagnosis between 1995 and 2017. We computed the age-, sex-, and calendar year-standardized incidence ratio (SIR) as the ratio of observed to expected number of cancers using national incidence rates as the reference. We performed a subgroup analysis among patients with chronic thromboembolic pulmonary hypertension in the period in which a specific ICD-10 code was available (2006– 2017).Results: We identified 212 cancers within the first year of follow-up and 796 cancers thereafter. The one-year risk of cancer was 3.3% and the one-year SIR was 1.96 (95% confidence interval [CI]: 1.70– 2.23). In the second and subsequent years, the SIR remained elevated (SIR: 1.15 [95% CI: 1.08– 1.24]). In patients with chronic thromboembolic pulmonary hypertension, the one-year SIR was 1.41 (95% CI: 0.82– 2.25).Conclusion: Cancer risk was clearly higher in patients with pulmonary hypertension compared with the general population. The association was particularly strong in the first year of follow-up, but remained elevated thereafter. However, absolute risks were low, limiting the clinical relevance of pursuing early cancer detection in these patients.Keywords: pulmonary hypertension, chronic thromboembolic pulmonary hypertension, venous thrombosis, pulmonary embolism, cancer, cohort

Søren Korsgaard,1,2 Christian Fynbo Christiansen,1,2 Morten Schmidt,1– 3 Henrik Toft Sørensen1,2 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Cardiology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Søren KorsgaardDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N, Aarhus, 8200, DenmarkTel +45 87167212Fax +45 87167215Email soren@clin.au.dkPurpose: Studies examining myocardial infarction (MI) often seek to include only incident MIs by excluding recurrent MIs. When based on historical data, identification of previous MI depends on the length of the look-back period. However, international registries often cover a short time period, consequently containing left-censored data, making it impossible to determine if a first MI in a period is truly an incident MI. We evaluated whether the proportion of MIs identified as recurrent MIs depends on the look-back period, and how including recurrent MIs in a planned incident MI cohort impacts survival estimates.Patients and Methods: We used the Danish National Patient Registry, covering all Danish hospitals since 1977 to identify first MIs during 2010– 2016 (index events). The hospital registry history preceding the index event was then searched for previous MIs. We plotted the proportion of index events identified as recurrent MIs as a function of the look-back period. Moreover, we calculated 5-year all-cause mortality and confidence intervals (CIs) using the 1-Kaplan–Meier method for five cohorts based on the index events and defined by look-back periods of 0, 5, 10, 20, and up to 39 years.Results: Among 63,885 index events, 3.4% were identified as recurrent MIs with 5 years of look-back, 7.9% with 10 years, 14% with 24 years, and 15% with up to 39 years. All-cause mortality risk was 36% (95% CI: 36– 37%) with 0 years of look-back, 35% (95% CI: 35– 36%) with 5 years, 35% (95% CI: 35– 36%) with 10 years, 34% (95% CI: 34– 35%) with 20 years, and 34% (95% CI: 33– 34%) with up to 39 years.Conclusion: Most recurrent MIs were identified with a look-back period of 24 years. Including recurrent MIs in a planned incident MI cohort, due to shorter look-back periods, overestimated the mortality risk.Keywords: acute myocardial infarction, bias, cardiology, cohort, epidemiology, methodology

Lau Caspar Thygesen,1 Kaare Christensen,2 Mikael Rørth,3,4 Henrik Toft Sørensen,3,4 Jan P Vandenbroucke,3,5,6 Rudi GJ Westendorp7 1National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; 2The Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark; 3Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 4Aarhus University Hospital, Aarhus, Denmark; 5Department of Medical Statistics and Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; 6Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 7Department of Public Health and Center for Healthy Aging, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Lau Caspar ThygesenNational Institute of Public Health, University of Southern Denmark, Studiestræde 6, Copenhagen, DK-1455, DenmarkTel +45 65 50 77 71Email lct@sdu.dkAbstract: Aging of the population is a pressing challenge for healthcare systems and knowledge of a patient’s prognosis is a key to shaping effective interventions. As the prevalence of multimorbidity strongly increases with age, the prognostic value of multiple disease diagnoses for survival among older people may diminish, whereas other measures of health, such as functional status (defined as a measure of an individual’s ability to perform activities of daily living), may become more important. In this commentary, the impact of age on the prognostic value of multimorbidity is discussed, with the aim of identifying relevant alternative risk indicators for different age groups. The key question is to determine at what age the prognostic value of multimorbidity for meaningful clinical outcomes decreases and is overridden by the prognostic value of functional status. This tipping point likely depends on age, calendar time, and birth cohort. The public health and clinical implications of these tipping points are important. Among younger and middle-aged persons, interventions could be directed towards prevention and treatment of specific diseases, while among older persons efforts should focus more on improving functional levels that include physical, emotional, and social dimensions.Keywords: chronic disease, health services, public health, aged, multimorbidity

Kristina Laugesen,1 Jonas F Ludvigsson,2,3 Morten Schmidt,1,4 Mika Gissler,5– 7 Unnur Anna Valdimarsdottir,2,8,9 Astrid Lunde,10 Henrik Toft Sørensen1,11 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 3Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 4Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 5Information Services Department, THL Finnish Institute for Health and Welfare, Helsinki, Finland; 6Research Centre for Child Psychiatry, University of Turku, Turku, Finland; 7Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden and Region Stockholm, Academic Primary Health Care Centre, Stockholm, Sweden; 8Center of Public Health Science, Faculty of Medicine, University of Iceland, Reykjavik, Iceland; 9Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA; 10Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 11KOR, The Danish Advisory Board on Register Based Research, the Danish e-infrastructure Cooperation, Copenhagen, DenmarkCorrespondence: Kristina LaugesenDepartment of Clinical Epidemiology, Aarhus University Hospital, Aurhus, DenmarkTel +45 87167212Email Kristina.laugesen@clin.au.dkAbstract: The Nordic countries are Denmark, Finland, Iceland, Norway, and Sweden and comprise a total population of approximately 27 million. The countries provide unique opportunities for joint health registry-based research in large populations with long and complete follow-up, facilitated by shared features, such as the tax-funded and public health care systems, the similar population-based registries, and the personal identity number as unique identifier of all citizens. In this review, we provide an introduction to the health care systems, key registries, and how to navigate the practical and ethical aspects of setting up such studies. For each country, we provide an overview of population statistics and health care expenditures, and describe the operational and administrative organization of the health care system. The Nordic registries provide population-based, routine, and prospective data on individuals lives and health with virtually complete follow-up and exact censoring information. We briefly describe the total population registries, birth registries, patient registries, cancer registries, prescription registries, and causes of death registries with a focus on period of coverage, selected key variables, and potential limitations. Lastly, we discuss some practical and legal perspectives. The potential of joint research is not fully exploited, mainly due to legal and practical difficulties in, for example, cross-border sharing of data. Future tasks include clear and transparent legal pathways and a framework by which practical aspects are facilitated.Keywords: health care system, population characteristics, registries, epidemiology, Scandinavian and Nordic countries

Julie Barberio,1 Thomas P Ahern,2 Richard F MacLehose,3 Lindsay J Collin,1 Deirdre P Cronin-Fenton,4 Per Damkier,5 Henrik Toft Sørensen,4 Timothy L Lash1 1Rollins School of Public Health, Emory University, Atlanta, GA, USA; 2The Robert Larner College of Medicine, University of Vermont, Burlington, VT, USA; 3University of Minnesota, Minneapolis, MN, USA; 4Aarhus University Hospital, Aarhus, Denmark; 5Odense University Hospital, Odense, DenmarkCorrespondence: Julie BarberioRollins School of Public Health, Emory University, Atlanta, GA, USAEmail julie.barberio@emory.eduPurpose: To compare the magnitude of bias due to unmeasured confounding estimated from various techniques in an applied example.Patients and Methods: We examined the association between dibutyl phthalate (DBP) and incident estrogen receptor (ER)-positive breast cancer in a Danish nationwide cohort (N=1,122,042). Cox regression analyses were adjusted for age and active drug compounds contributing to DBP exposure. We estimated the hazard ratios (HRs) that would have been observed had one of the DBP sources been unmeasured and calculated the strength of confounding by comparing to the fully adjusted HR. We performed a quantitative bias analysis (QBA) of the “unmeasured” confounder, using external information to specify the bias parameters. Upper bounds on the bias were estimated and E-values were calculated.Results: The adjusted HR for incident ER-positive breast cancer among women with high-level (≥ 10,000 cumulative milligrams) versus no DBP exposure was 2.12 (95% confidence interval 1.12 to 4.05). Removing each DBP source in isolation resulted in negligible change in the HR. The bias estimates from the QBA ranged from 1.00 to 1.01. The estimated maximum impact of unmeasured confounding ranged from 1.01 to 1.51. E-values ranged from 3.46 to 3.68.Conclusion: The impact of bias due to simulated unmeasured confounding was negligible, in part, because the unmeasured variable was not independent of controlled variables. When a suspected confounder cannot be measured in the study data, our exercise suggests that QBA is the most informative method for assessing the impact. E-values may best be reserved for situations where uncontrolled confounding emanates from an unknown confounder.Keywords: bias analysis, unmeasured confounding, the E-value

Linn Håkonsen Arendt,1– 3 Lars Henning Pedersen,1,4 Lars Pedersen,5 Per Glud Ovesen,1,6 Tine Brink Henriksen,7 Morten Søndergaard Lindhard,8 Jørn Olsen,2,5 Henrik Toft Sørensen,5 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 3Department of Obstetrics and Gynecology, Regional Hospital Horsens, Horsens, Denmark; 4Department of Biomedicine, Aarhus University, Aarhus, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 6Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 7Department of Child and Adolescent Health, Aarhus University Hospital, Aarhus, Denmark; 8Department of Child and Adolescent Health, Regional Hospital Randers, Aarhus, DenmarkCorrespondence: Linn Håkonsen ArendtDepartment of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; Department of Public Health, Research Unit for Epidemiology, Aarhus, DenmarkTel +45 27 21 09 81Email lha@clin.au.dkPurpose: To study the occurrence of major congenital abnormalities in children of women with type 1 and type 2 diabetes and investigate the association between glycated haemoglobin (HbA1c) and major congenital malformations according to type 1 diabetes and type 2 diabetes separately.Patients and methods: In this register-based study, all singletons born alive from January 1, 2000 to December 31, 2015 in the North Denmark and Central Denmark regions of Denmark and their mothers were included. We used data from Danish health registers and the LABKA database. Logistic regression models were used to compute crude and adjusted prevalence odds ratios (cORs and aORs) with 95% confidence intervals (CIs) for major congenital malformations overall and for subtypes, by type of maternal pre-existing diabetes and HbA1c levels.Results: Among 314,245 infants included, 2020 (0.64%) had mothers with type 1 diabetes and 498 (0.16%) had mothers with type 2 diabetes. We found an aOR of 2.9 (95% CI: 2.5, 3.5) and 1.9 (95% CI: 1.3; 2.8) for major malformations for type 1 and type 2 diabetes, respectively. The highest occurrence was seen for major congenital heart diseases, but we also observed higher occurrence of several other non-cardiac malformations. For both type 1 and type 2 diabetes, the prevalence of major congenital malformations increased with higher levels of maternal HbA1c with no safe threshold level. Mothers with type 1 diabetes had higher risks than those without diabetes irrespective of HbA1c, and women with HbA1c levels ≥ 9.5% had 8 times the odds of major congenital malformations [aOR 8.7 (95% CI: 5.4; 14.5)].Conclusions: The prevalence of major congenital malformations progressively increased with poorer glycemic control during pregnancy, with no obvious safe threshold level, for both type 1 and type 2 diabetes.Keywords: congenital heart diseases, diabetes, epidemiology, malformations, pregnancy, register-based research

Lisbeth Wellejus Albertsen,1 Uffe Heide-Jørgensen,1 Sigrun Alba Johannesdottir Schmidt,1 Corina Grey,2 Rod Jackson,2 Henrik Toft Sørensen,1 Morten Schmidt1,3,4 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New Zealand; 3Department of Cardiology, Regional Hospital West Jutland, Herning, Denmark; 4Department of Cardiology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Morten Schmidt Email Morten.schmidt@clin.au.dkObjective: To develop and validate the DANish Comorbidity index for Acute Myocardial Infarction (DANCAMI) for adjustment of comorbidity burden in studies of myocardial infarction prognosis.Methods: Using medical registries, we identified patients with first-time myocardial infarction in Denmark during 2000– 2013 (n=36,685). We developed comorbidity indices predicting 1-year all-cause mortality from all comorbidities (DANCAMI) and restricted to non-cardiovascular comorbidities (rDANCAMI). For variable selection, we eliminated comorbidities stepwise using hazard ratios from multivariable Cox models. We compared DANCAMI/rDANCAMI with Charlson and Elixhauser comorbidity indices using standard performance measures (Nagelkerke’s R2, Harrell’s C-statistic, the Integrated Discrimination Improvement, and the continuous Net Reclassification Index). We assessed the significance of the novel DANCAMI variables not included in the Charlson Comorbidity Index. External validation was performed in patients with myocardial infarction in New Zealand during 2007– 2016 (n=75,069).Results: The DANCAMI included 24 comorbidities. The rDANCAMI included 17 non-cardiovascular comorbidities. In the Danish cohort, the DANCAMI indices outperformed both the Charlson and the Elixhauser comorbidity indices on all performance measures. The DANCAMI indices included multiple variables that were significant predictors of 1-year mortality even after controlling for all variables in the Charlson Comorbidity Index. These novel variables included valvular heart disease (hazard ratio for 1-year mortality=1.25, 95% CI: 1.14– 1.35), coagulopathy (1.13, 95% CI: 1.05– 1.22), alcohol and drug abuse (1.35, 95% CI: 1.15– 1.58), schizophrenia (1.60, 95% CI: 1.46– 1.76), affective disorder (1.29, 95% CI: 1.22– 1.36), epilepsy (1.26, 95% CI: 1.05– 1.50), neurodegenerative disorder (1.30, 95% CI: 1.10– 1.54) and chronic pancreatitis (1.71, 95% CI: 1.14– 2.56). The results were supported by the external validation in New Zealand.Conclusion: DANCAMI assessed comorbidity burden of patients with first-time myocardial infarction, outperformed existing comorbidity indices, and was generalizable to patients outside Denmark. DANCAMI is recommended as a standard approach for comorbidity adjustment in studies of myocardial infarction prognosis.Keywords: comorbidity, myocardial infarction, prognosis, risk score

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

Holly Michelle Crowe,1 Lauren Anne Wise,1 Amelia Kent Wesselink,1 Kenneth Jay Rothman,1,2 Ellen Margrethe Mikkelsen,3 Henrik Toft Sørensen,3 Allan Jay Walkey,4 Elizabeth Elliott Hatch1 1Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA; 2RTI International, Raleigh, NC 27709, USA; 3Department of Clinical Epidemiology, Aarhus University, Aarhus N 8200, Denmark; 4Boston University School of Medicine, Boston, MA 02118, USACorrespondence: Holly Michelle Crowe Email hcrowe@bu.eduPurpose: Asthma has been positively associated with irregular menses and infertility in some studies, but data are limited on the relation between asthma medication use and fecundability (i.e., average per-cycle probability of conception among non-contracepting couples). This study examines the extent to which a history of asthma, asthma medication use, and age at first asthma diagnosis are associated with fecundability among female pregnancy planners.Participants and Methods: Pregnancy Study Online (PRESTO) is an ongoing, web-based preconception cohort study of couples aged 21– 45 years from North America. Between July 2013 and July 2019, a total of 10,436 participants enrolled in PRESTO, and 8286 were included in the present analysis. At study enrollment, women reported whether they had ever been diagnosed with asthma and, if so, the year they were first diagnosed. Women who reported ever being diagnosed with asthma were asked about medication use, including medication type and frequency of use. Participants completed follow-up questionnaires every 8 weeks for up to 12 months or until pregnancy. Proportional probabilities regression models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Fecundability ratios below 1.00 indicate reduced probability of conception.Results: There was little association between a history of asthma diagnosis or asthma medication use and fecundability. Compared with no history of asthma, the FR for ever-diagnosis of asthma with medication use was 1.02 (95% CI: 0.91– 1.15) and for ever-diagnosis of asthma without medication use was 1.00 (95% CI: 0.91– 1.09). Highest intensity asthma medication use (daily plus extra dosing for symptoms), combination inhaled corticosteroid and long-acting beta-agonist inhaler use, and a first diagnosis of asthma after age 17 years were associated with small reductions in fecundability.Conclusion: The present study provides little evidence that asthma or asthma medication use is adversely associated with fecundability.Keywords: corticosteroid, beta agonist, time to pregnancy, fertility

Johan Frederik Håkonsen Arendt,1,2 Anette Tarp Hansen,1,3 Søren Andreas Ladefoged,2 Henrik Toft Sørensen,1 Lars Pedersen,1 Kasper Adelborg1,2 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, DenmarkCorrespondence: Johan Frederik Håkonsen ArendtDepartment of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N 8200, DenmarkTel +45 87 16 80 63Fax +45 87 16 72 15Email jfba@clin.au.dkAbstract: Routine biomarker results from hospital laboratory information systems, covering hospitals and general practitioners, in Denmark are available to researchers through access to the regional Clinical Laboratory Information System Research Database at Aarhus University and the nationwide Register of Laboratory Results for Research. This review describes these two data sources. The laboratory databases have different geographical and temporal coverage. They both include individual-level biomarker results that are electronically transferred from laboratory information systems. The biomarker results can be linked to all other Danish registries at the individual level, using the unique identifier, the CPR number. The databases include variables such as the CPR number, date and time (hour and minute) of sampling, NPU code, and name of the biomarker, identification code for the laboratory and the requisitioner, the test result with the corresponding unit, and the lower and upper reference limits. Access to the two databases differs since they are hosted by two different institutions. Data cannot be transferred outside Denmark, and direct access is provided only to Danish institutions. It is concluded that access to data on routine biomarkers expands the detailed biological and clinical information available on patients in the Danish healthcare system. The full potential is enabled through linkage to other Danish healthcare registries.Keywords: biomarkers, database, data resource, laboratory information systems

Christine Gyldenkerne,1 Kevin Kris Warnakula Olesen,1,2 Morten Madsen,2 Troels Thim,1 Lisette Okkels Jensen,3 Bent Raungaard,4 Henrik Toft Sørensen,2 Hans Erik Bøtker,1 Michael Maeng11Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Odense University Hospital, Odense, Denmark; 4Department of Cardiology, Aalborg University Hospital, Aalborg, DenmarkPurpose: We examined risk of myocardial infarction and all-cause death associated with the extent of coronary artery disease ascertained by coronary angiography in patients with diabetes mellitus. We hypothesized that risks of myocardial infarction and death were associated with extent of coronary artery disease in diabetes patients.Patients and methods: We conducted a cohort study of patients with type 1 and type 2 diabetes, who underwent coronary angiography from 2004 to 2012. Patients were stratified according to extent of coronary artery disease: 0-, 1-, 2- or 3-vessel disease or diffuse vessel disease. Endpoints were myocardial infarction, all-cause death, and major adverse cardiovascular events (MACE), defined as the composite of myocardial infarction, cardiac death, or ischemic stroke. Adjusted incidence and mortality rate ratios (IRRsadj) were calculated using patients with 0-vessel disease as the reference group. Median follow-up was 3 years for a total of 45,164 person-years.Results: The study included 12,594 diabetes patients. Of these, 3,147 (25.0%) had 0-vessel disease, 1,195 (9.5%) had diffuse vessel disease, 3,001 (23.8%) had 1-vessel disease, 2,220 (17.6%) had 2-vessel disease, and 3,031 (24.1%) had 3-vessel disease. The myocardial infarction rate was 0.4 per 100 person-years (95% CI: 0.3–0.5) in patients with 0-vessel disease. Using patients with 0-vessel disease as reference, the risk of myocardial infarction increased according to the number of diseased vessels (diffuse vessel disease: 1.4 per 100 person-years, IRRadj 3.87, 95% CI: 2.41–6.23; 1-vessel disease: 1.9 per 100 person-years, IRRadj 4.99, 95% CI: 3.33–7.46; 2-vessel disease: 2.7 per 100 person-years, IRRadj 7.14, 95% CI: 4.78–10.65; and 3-vessel disease: 4.3 per 100 person-years, IRRadj 11.42, 95% CI: 7.76–16.82; ptrend

Jens Sundbøll,1 Sandra Kruchov Thygesen,1 Katalin Veres,1 Donghua Liao,2 Jingbo Zhao,2 Hans Gregersen,3 Henrik Toft Sørensen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2GIOME Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3GIOME, Department of Surgery, Chinese University of Hong Kong, Shatin, Hong KongBackground: It remains unclear whether constipation is associated with cancer. We evaluated the risk of malignancies in patients with constipation requiring hospitalization.Methods: Using Danish medical registries, we calculated cumulative incidences and standardized incidence ratios (SIRs) for cancer. SIRs were computed as the observed number of gastrointestinal (GI) cancers and selected non-GI cancers in patients with constipation compared with the expected number based on national incidence rates by sex, age, and calendar year (1978–2013).Results: We identified 1,75,901 patients with constipation (59% females, median age 54 years). The cumulative incidences of GI cancers and non-GI cancers after 15 years of follow-up were 2.5% and 2.6%, respectively. During the first year of follow-up, the SIR for any GI cancer was 5.0 (95% confidence interval (CI): 4.8–5.3), driven by colon and pancreas cancers and higher for younger age groups. Beyond 1 year of follow-up, the risk declined to near unity for colorectal cancer. The risk of other GI cancers (including cancers of the esophagus, stomach, small intestine, liver, and pancreas) remained moderately increased (overall SIR =1.3, 95% CI: 1.2–1.4). Except for ovarian cancer (SIR =7.3, 95% CI: 6.3–8.4), the risk of non-GI cancers was only slightly increased during the first year of follow-up and declined to unity thereafter.Conclusions: Patients with constipation had increased short-term risk of a diagnosis of GI cancer. Beyond 1 year of follow-up, a moderately elevated risk persisted only for GI cancers other than colorectal cancer. The risk of non-GI cancers was elevated only during the first year of follow-up, particularly for ovarian cancer.Keywords: constipation, cancer, cohort study

Greg Ridgeway,1–3 Mette Nørgaard,4 Thomas Bøjer Rasmussen,4 William D Finkle,3 Lars Pedersen,4 Hans Erik Bøtker,5 Henrik Toft Sørensen4 1Department of Criminology, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Statistics, University of Pennsylvania, Philadelphia, PA, USA; 3Consolidated Research, Inc., Los Angeles, CA, USA; 4Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Objective: The aim of this study was to examine hospital performance measures that account more comprehensively for unique mixes of patients’ characteristics. Design: Nationwide cohort registry-based study within a population-based health care system. Participants: In this study, 331,513 patients discharged with a primary cardiovascular diagnosis from 1 of 26 Danish hospitals during 2011–2015 were included. Data covering all Danish hospitals were drawn from the Danish National Patient Registry and the Danish National Health Service Prescription Database. Main outcome measures: Thirty-day post-admission mortality rates, 30-day post-discharge readmission rates, and the associated numbers needed to harm were measured. Methods: For each index hospital, we used a non-parametric logistic regression model to compute propensity scores. Propensity score weighted patients treated at other hospitals collectively resembled patients treated at the index hospital in terms of age, sex, primary discharge diagnosis, diagnosis history, medications, previous cardiac procedures, and comorbidities. Outcomes for the weighted patients treated at other hospitals formed benchmarks for the index hospital. Doubly robust regression formally tested whether the outcomes of patients at the index hospital differed from the outcomes of the patients used to form the benchmarks. For each index hospital, we computed the false discovery rate, ie, the probability of being incorrect if we claimed the hospital differed from its benchmark. Results: Five hospitals exceeded their benchmark for 30-day mortality rates, with the number needed to harm ranging between 55 and 137. Seven hospitals exceeded their benchmark for readmission, with the number needed to harm ranging from 22 to 71. Our benchmarking approach flagged fewer hospitals as outliers compared with conventional regression methods. Conclusion: Conventional methods flag more hospitals as outliers than our benchmarking approach. Our benchmarking approach accounts more thoroughly for differences in hospitals’ patient case mix, reducing the risk of false-positive selection of suspected outliers. A more comprehensive system of hospital performance measurement could be based on this approach. Keywords: performance measurement, propensity score, doubly robust estimation, case mix adjustment, cohort study

Erzsébet Horváth-Puhó,1 Marit M Suttorp,2 Henrik Frederiksen,1,3 Tiny Hoekstra,2 Olaf M Dekkers,1,2 Lars Pedersen,1 Suzanne C Cannegieter,2 Friedo W Dekker,2 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Haematology, Odense University Hospital, Odense, Denmark Introduction: Erythropoiesis-stimulating agent (ESA) treatment has been associated with an increased risk of venous thromboembolism (VTE) in patients with solid tumors and with an increased risk of cardiovascular events in patients with chronic kidney disease. The ESA-related risk in patients with hematological neoplasms remains unclear. We, therefore, aimed to assess the ESA-related risk of VTE, myocardial infarction (MI), and stroke in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). Materials and methods: We conducted a population-based cohort study in Denmark, using medical databases to identify 2,114 MDS patients and 3,105 MM patients diagnosed in 2004–2013. Incidence rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE, MI, and stroke associated with ESA treatment were computed. HRs were calculated in time-dependent Cox regression and adjusted for age, sex, MDS prognosis group, comorbidities, and treatments. Results: Incidence rates per 1,000 person-years for VTE, MI, and stroke were 10.8, 8.2, and 16.0 in MDS patients, and 21.9, 10.2 and 9.9 in MM patients without ESA treatment, respectively. MDS patients with ESA treatment had a 1.6-fold increased risk of MI (HR 1.60 [95% CI 0.90–2.86]) and an almost twofold increased risk of stroke (HR 1.94 [95% CI 1.28–2.94]). Adjusted HR for VTE was 1.04 (95% CI 0.57–1.89) compared with MDS patients without ESAs. In MM patients with ESAs compared with patients without ESAs, HRs were 1.41 (95% CI 0.96–2.08) for VTE, 1.23 (95% CI 0.68–2.20) for MI, and 1.63 (95% CI 0.96–2.77) for stroke. Conclusion: ESA use was associated with stroke in MDS patients. Among MM patients, ESA treatment was associated with a higher risk of all cardiovascular events, although all CIs included equivalence. Keywords: cohort study, epidemiology, erythropoietin, multiple myeloma, myelodysplastic syndromes, myocardial infarction, stroke, pulmonary embolism, venous thrombosis

Uffe Heide-Jørgensen, Kasper Adelborg, Johnny Kahlert, Henrik Toft Sørensen, Lars Pedersen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: For a patient cohort, access to linkable population-based registries permits sampling of a comparison cohort from the general population, thereby contributing to the understanding of the disease in a population context. However, sampling without replacement in random order can lead to immortal time bias by conditioning on the future.Aim: We compared the following strategies for sampling comparison cohorts in matched cohort studies with respect to time to ischemic stroke and mortality: sampling without replacement in random order; sampling with replacement; and sampling without replacement in chronological order.Methods: We constructed index cohorts of individuals from the Danish general population with no particular trait, except being alive and without ischemic stroke on the index date. We also constructed index cohorts of persons aged >50 years from the general population. We then applied the sampling strategies to sample comparison cohorts (5:1 or 1:1) from the Danish general population and compared outcome risks between the index and comparison cohorts. Finally, we sampled comparison cohorts for a heart failure cohort using each strategy.Results: We observed increased outcome risks in comparison cohorts sampled 5:1 without replacement in random order compared to the index cohorts. However, these increases were minuscule unless index persons were aged >50 years. In this setting, sampling without replacement in chronological order failed to sample a sufficient number of comparators, and the mortality risks in these comparison cohorts were lower than in the index cohorts. Sampling 1:1 showed no systematic difference between comparison and index cohorts. When we sampled comparison cohorts for the heart failure patients, we observed a pattern similar to when index persons were aged >50 years.Conclusion: When index persons were aged >50 years, ie, had high outcome risks, sampling 5:1 without replacement introduced bias. Sampling with replacement or 1:1 did not introduce bias. Keywords: matched cohort study, survival analysis, population-based registry, observational study

Fu-Chao Liu,1,2,* Huan-Tang Lin,1,2,* Chang-Fu Kuo,2–4 Mei-Yun Hsieh,4 Lai-Chu See,3,5,6 Huang-Ping Yu1,2,7 1Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Office for Big Data Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 7Department of Anesthesiology, Xiamen Changgung Hospital, Xiamen, China *These authors contributed equally to this work Background: Individuals with a family history of Parkinson’s disease (PD) appear to have a higher risk of developing PD and other neuropsychiatric diseases. However, estimates of the relative risks (RRs) of PD and the roles of genetic and environmental factors in PD susceptibility are unclear. The aim of this study was to examine familial aggregation and genetic contributions to PD and the RRs of other neuropsychiatric diseases in relatives of PD patients. Methods: In this population-based family cohort study, the records of all individuals actively registered in the Taiwan National Health Insurance Research Database in 2015 were queried (N=24,349,599). In total, 149,187 individuals with a PD-affected parent, 3,698 with an affected offspring, 3,495 with an affected sibling, and 15 with an affected twin were identified. Diagnoses of PD were ascertained between January 1, 1999, and December 31, 2015. The prevalence and RRs of PD and other neuropsychiatric diseases in individuals with first-degree relatives with PD, as well as the contributions of heritability and environmental factors to PD susceptibility were investigated. Results: The prevalence of PD was 0.46% in the general population and 0.52% in individuals with first-degree relatives with PD. The RR (95% CI) for PD was 2.20 (1.41–3.45) for siblings, 1.59 (1.47–1.73) for parents, 1.86 (1.63–2.11) for offspring, 63.12 (16.45–242.16) for twins, and 1.46 (1.41–1.52) for spouses. The RR (95% CI) in individuals with first-degree relatives with PD was 1.66 (1.57–1.76) for essential tremor, 1.68 (1.61–1.75) for schizophrenia, and 1.20 (1.12–1.28) for Alzheimer’s disease. The estimated contribution to the phenotypic variance of PD was 11.0% for heritability, 9.1% for shared environmental factors, and 79.9% for non-shared environmental factors. Conclusion: First-degree relatives of PD patients are more likely to develop PD and other neuropsychiatric diseases. Environmental factors account for a high proportion of the phenotypic variance of PD. Keywords: Parkinson’s disease, familial risk, population-based family study

Kasper Adelborg,1 Jens Sundbøll,1,2 Morten Schmidt,1,3 Hans Erik Bøtker,2 Noel S Weiss,4 Lars Pedersen,1 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Regional Hospital West Jutland, Herning, Denmark; 4Department of Epidemiology, University of Washington, Seattle, WA, USA Background: Histamine H2 receptor activation promotes cardiac fibrosis and apoptosis in mice. However, the potential effectiveness of histamine H2 receptor antagonists (H2RAs) in humans with heart failure is largely unknown. We examined the association between H2RA initiation and all-cause mortality among patients with heart failure. Methods: Using Danish medical registries, we conducted a nationwide population-based active-comparator cohort study of new users of H2RAs and proton pump inhibitors (PPIs) after first-time hospitalization for heart failure during the period 1995−2014. Hazard ratios (HRs) for all-cause mortality and hospitalization due to worsening of heart failure, adjusting for age, sex, and time between heart failure diagnosis and initiation of PPI or H2RA therapy, index year, comorbidity, cardiac surgery, comedications, and socioeconomic status were computed based on Cox regression analysis. Results: Our analysis included 42,902 PPI initiators (median age 78 years, 46% female) and 3,296 H2RA initiators (median age 76 years, 48% female). Mortality risk was lower among H2RA initiators than PPI initiators after 1 year (26% vs 31%) and 5 years (60% vs 66%). In multivariable analyses, the 1-year HR was 0.80 (95% CI, 0.74–0.86) and the 5-year HR was 0.85 (95% CI, 0.80–0.89). These findings were consistent after propensity score matching and for ischemic and nonischemic heart failure, as for sex and age groups. The rate of hospitalization due to worsening of heart failure was lower among H2RA initiators than PPI initiators. Conclusion: In patients with heart failure, H2RA initiation was associated with 15%–20% lower mortality than PPI initiation. Keywords: heart failure, epidemiology, histamine H2 receptor, mortality

Kristina Laugesen,1 Henrik Støvring,2 Jesper Hallas,3 Anton Pottegård,3 Jens Otto Lunde Jørgensen,4 Henrik Toft Sørensen,1 Irene Petersen1,5 1Department of Clinical Epidemiology, Aarhus University Hospital, 2Department of Public Health, Aarhus University, Aarhus, 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, 4Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Department of Primary Care and Population Health, University College London, London, UK Purpose: Glucocorticoids are widely used medications. In many pharmacoepidemiological studies, duration of individual prescriptions and definition of treatment episodes are important issues. However, many data sources lack this information. We aimed to estimate duration of individual prescriptions for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution.Methods: We used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996–2014. We applied the parametric waiting time distribution to estimate duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan–Meier survival function to estimate length of first continuous treatment episodes by assigning estimated prescription duration to each prescription and thereby create treatment episodes from overlapping prescriptions.Results: We identified 5,691,985 prescriptions issued to 854,429 individuals of whom 351,202 (41%) only redeemed 1 prescription in the whole study period. The 80th percentile for prescription duration ranged from 87 to 120 days, the 90th percentile from 116 to 150 days, the 95th percentile from 147 to 181 days, and the 99th percentile from 228 to 259 days during 1996–2014. Based on the 80th, 90th, 95th and 99th percentiles of prescription duration, the median length of continuous treatment was 113, 141, 170 and 243 days, respectively.Conclusion: Our method and results may provide an important framework for future pharmacoepidemiological studies. The choice of which percentile of the interarrival distribution to apply as prescription duration has an impact on the level of misclassification. Use of the 80th percentile provides a measure of drug exposure that is specific, while the 99th percentile provides a sensitive measure. Keywords: glucocorticoids, pharmacoepidemiology, prescription duration, parametric waiting time distribution

Jennifer L Lund,1,2 Erzsébet Horváth-Puhó,2 Szimonetta Komjáthiné Szépligeti,2 Henrik Toft Sørensen,2 Lars Pedersen,2 Vera Ehrenstein,2 Til Stürmer1,2 1Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Background: A principle of cohort studies is that cohort membership is defined by current rather than future exposure information. Pharmacoepidemiologic studies using existing databases are vulnerable to violation of this principle. We evaluated the impact of using data on future redemption of prescriptions to determine cohort membership, motivated by a published example seeking to emulate a “per-protocol” association between continuous versus never use of low-dose acetylsalicylic acid (ASA) and major bleeding (e.g., cerebral hemorrhage or gastrointestinal bleeding). Materials and methods: Danish medical registry data from 2004 to 2011 were used to construct two analytic cohorts. In Cohort 1, we used information about future redemption of low-dose ASA prescriptions to identify cohorts of continuous and never-ASA users. In Cohort 2, we identified ASA initiators and non-initiators using only contemporaneous data and censored follow-up for changes in use over time. We implemented propensity score-matched Poisson regression to evaluate associations between ASA use and major bleeding and estimated adjusted incidence rate differences (IRDs) per 1,000 person-years and ratios (IRRs) overall and stratified by time since initiation. Results: Among >6 million eligible Danish adults, we identified 403,693 low-dose ASA initiators (Cohort 2), of whom 189,150 were defined as continuous users (Cohort 1). Overall, IRDs and IRRs were similar across cohorts. However, the IRD for major bleeding in the first 90 days was substantially larger in Cohort 1 (IRD=25 per 1,000 person-years) compared with Cohort 2 (IRD=10 per 1,000 person-years). Conclusion: Using future medication redemption data to define baseline cohorts violates basic epidemiologic principles. Compared with an approach using only contemporaneous data to define cohorts, the approach based on future redemption data generated a substantially higher short-term association between low-dose ASA use and major bleeding on the absolute, but not the relative, scale possibly due to selection and immortal time biases. Keywords: pharmacoepidemiology, cohort studies, immortal time bias, selection bias

Anne Gulbech Ording,1 Deirdre Cronin-Fenton,1 Vera Ehrenstein,1 Timothy L Lash,1,2 John Acquavella,1 Mikael Rørth,1 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA Abstract: Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. Keywords: endpoint determination, medical oncology, treatment outcome, neoplasms, research design

Pernilla Hansdotter Andersson,1 Peer Wille-Jørgensen,2 Erzsébet Horváth-Puhó,3 Sune Høirup Petersen,2 Anna Martling,4 Henrik Toft Sørensen,3 Ingvar Syk1 On behalf of the COLOFOL Study Group 1Department of Surgery, Skåne University Hospital, Malmö, Sweden; 2Abdominal Disease Center K, Bispebjerg University Hospital, Copenhagen, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden Introduction: The COLOFOL trial, a prospective randomized multicenter trial comparing two follow-up regimes after curative surgical treatment for colorectal cancer, focuses on detection of asymptomatic recurrences. This paper aims to describe the design and recruitment procedure in the COLOFOL trial, comparing demographic characteristics between randomized patients and eligible patients not included in the study. Materials and methods: COLOFOL was designed as a pragmatic trial with wide inclusion criteria and few exclusion criteria, in order to obtain a sample reflecting the general patient population. To be eligible, patients had to be 75 years or younger and curatively resected for stage II or III colorectal cancer. Exclusion criteria were hereditary colorectal cancer, no signed consent, other malignancy, and life expectancy less than 2 years due to concomitant disease. In four of the 24 participating centers, we scrutinized hospital inpatient data to identify all colorectal cancer patients who underwent surgery, in order to ascertain all eligible patients who were not included in the study and to compare them with enrolled patients. Results: Of a total of 4,445 eligible patients, 2,509 patients were randomized (56.4% inclusion rate). A total of 1,221 eligible patients were identified in the scrutinized hospitals, of which 684 (56%) were randomized. No difference in age or sex distribution was observed between randomized and nonrandomized eligible patients. However, a difference was noted in tumor location and stage distribution, with 5.6% more patients in the randomized group having colon cancer and 6.7% more patients having stage II disease. Conclusion: Patients in the two study arms were not only demographically similar, but also similar to nonincluded eligible patients, apart from stage and localization. The analyses will be stratified by these variables. Taken together, we conclude that our trial results will be robust and possible to extrapolate to the target population. Keywords: trial design, source population, colorectal cancer, follow-up

Kevin Kris Warnakula Olesen,1,2 Christine Gyldenkerne,1 Morten Madsen,2 Troels Thim,1 Lisette Okkels Jensen,3 Bent Raungaard,4 Henrik Toft Sørensen,2 Hans Erik Bøtker,1 Michael Maeng11Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Odense University Hospital, Odense, Denmark; 4Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark We thank Xu et al for their interest in our study.1 First, we unfortunately did not have access to LDL measurements which we acknowledge potentially could have provided valuable information. We found that statin treatment increased with the extent of coronary artery disease (CAD) which may lead to underestimation of the actual effect of CAD extent. This is in response to the Letter to the Editor

Kimberly M Shea,1,2 Timothy L Lash,3,4 Sussie Antonsen,4 Susan S Jick,1,5 Henrik T Sørensen1,41Department of Epidemiology, Boston University School of Public Health, 2Department of Pediatrics, Boston University School of Medicine, Boston, MA, 3Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Boston Collaborative Drug Surveillance Program, Boston University, Boston, MA, USABackground: Although asthma has recently been established as a risk factor for pneumococcal disease (PD), few studies have specifically evaluated this association in children.Methods: We conducted a nation-wide population-based cohort study of the effect of asthma on childhood PD among all singleton live births in Denmark from 1994 to 2007, before the introduction of the 7-valent pneumococcal conjugate vaccine. All data were abstracted from Danish medical registries. Because underlying comorbidity substantially increases the PD risk in children, standard methods were used to assess the evidence of biologic interaction between comorbidity and asthma on the risk of PD.Results: There were 2,253 cases of childhood PD among 888,655 children born in Denmark from 1994 to 2007. The adjusted incidence rate ratio of the effect of asthma on childhood PD was 2.2 (95% confidence interval [CI]: 2.0, 2.5). Age-stratified incidence rate ratios were 2.1 (95% CI: 1.8, 2.9) in children 6 months to

Henrik Toft Sørensen,1 Lars Pedersen,1 Jørgen Jørgensen,2 Vera Ehrenstein11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 2Danish Regions, Copenhagen, DenmarkThe health care systems in many countries are facing several challenges: the aging population,the need for personalized medicine, evolving treatment modalities, quality andsafety imperatives, and unsustainable costs, to mention only a few. Population aging in the face of significant pressure to contain costs is perhaps the most immediate challenge. The proportion of people aged 65 years or older in Western Europe and North America is expected to increase to 26% in 2025. Furthermore, clinical medicine in the Western world is confronting an evolving set of diseases, as smoking becomes less prevalent and obesity more common. Diagnostics and treatment of chronic disease have improved, while the threshold for initiating preventive treatment of asymptomatic conditions has been lowered. Consequently, the number of patients with multimorbidity, that is, the coexistence of several chronic diseases, will increase dramatically.1 To treat a disease or prevent its progression, patients with several chronic diseases often take multiple drugs, each with potentially severe side effects. In patients with multiple morbidities, “polypharmacy” is a challenging clinical issue, often associated with iatrogenic harm.2 A call for innovative approaches to polypharmacy has been the focus of recent editorials in high-impact medical journals.3–5 Randomized trials rarely address multimorbidity, adherence to treatments, co-intervention (polypharmacy), or their long-term risks.6 These challenges underscore the need for population-based long-term longitudinal clinical data available for clinical care and research.

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

Charlotte Höybye,1 Lars Sävendahl,2 Henrik Thybo Christesen,3 Peter Lee,4 Birgitte Tønnes Pedersen,5 Michael Schlumpf,6 John Germak,7 Judith Ross8 1Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Endocrinology, Metabolism and Diabetes, 2Department of Women’s and Children’s Health, Karolinska Institute and Division of Pediatrics, Karolinska University Hospital, Stockholm, Sweden; 3Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 4Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA; 5Global Development, Novo Nordisk A/S, Søborg, Denmark; 6Global Medical Affairs Biopharm, Novo Nordisk Health Care AG, Zurich, Switzerland; 7Clinical Development and Medical Affairs, Novo Nordisk Inc, Princeton, NJ, USA; 8Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA Objective: Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. Design: The NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web Enabled Research (ANSWER Program®) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. Patients: The studies include pediatric and adult patients receiving Norditropin®, as prescribed by their physicians. Measurements: The studies gather long-term data on the safety and effectiveness of real-life treatment with the recombinant human GH, Norditropin®. We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. Conclusion: The NordiNet® IOS and ANSWER Program® studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines. Keywords: growth hormone replacement therapy, treatment outcome, pharmacoepidemiology, survey

Sigrun Alba Johannesdottir, Erzsébet Horváth-Puhó, Vera Ehrenstein, Morten Schmidt, Lars Pedersen, Henrik Toft SørensenDepartment of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, DenmarkAbstract: The Danish health care system provides partial reimbursement of most prescription medications in Denmark. The dispensation of prescription medications is registered in administrative databases. Each time a prescription is redeemed at a pharmacy, an electronic record is generated with information related to the user, prescriber, the pharmacy, and the dispensed drug. The National Health Service gathers this information for administration of the drug reimbursement plan. Recently, this information became the basis for the establishment of a new research database, the Danish National Database of Reimbursed Prescriptions (DNDRP). In this paper, we review the content, coverage, quality, linkage, access, and research possibilities of this new database. The database encompasses the reimbursement records of all reimbursed drugs sold in community pharmacies and hospital-based outpatient pharmacies in Denmark since 2004. On average, approximately 3.5 million users are recorded in the database each year. During the coverage period, the number of annual prescription redemptions increased by 15%. Most dispensed prescriptions are in the categories “alimentary tract and metabolism”, “cardiovascular system”, “nervous system”, and “respiratory system”. Individuals are identified by the unique central personal registration (CPR) number assigned to all persons born in or immigrating to Denmark. The new database fully complies with Denmark’s Act on Processing of Personal Data, while avoiding additional restrictions imposed on data use at the Danish National Prescription Registry, administered by Statistics Denmark. Most importantly, CPR numbers are reversibly encrypted, which allows re-identification of drug users; furthermore, the data access is possible outside the servers of Statistics Denmark. These features open additional opportunities for international collaboration, validation studies, studies on adverse drug effects requiring review of medical records, studies involving contact to general practitioners, and linkage of prescription data to other clinical and research databases. The DNDRP thus is a valuable data source for pharmacoepidemiological research.Keywords: Denmark, patient registration, pharmacoepidemiology, registry-based research

Henrik Toft Sørensen,1 Søren Friborg,2 Jørgen Rungby,3 Jens Sandahl Christensen,4 Allan Vaag,5 Henning Beck-Nielsen61Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 2Department of Endocrinology M, Odense University Hospital, Odense, Denmark, 3Department of Pharmacology, University of Aarhus, Aarhus, 4Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, 5Department of Endocrinology, Rigshospitalet and Copenhagen University, 6Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, DenmarkType 2 diabetes is a pandemic and an enormous public health problem. This supplemental issue of Clinical Epidemiology describes the rationale, design, and implementation of the establishment of a large cohort of all Danes with type 2 diabetes (the DD2 study) and of a biobank to bridge the scientific disciplines of epidemiology, clinical medicine, genetics, epigenetics, and pharmacology. This will most likely result in great benefits for the application of evidence-based medicine to the care of, and improved outcomes for, Danish type 2 diabetes patients.

Sinéad M Langan,1 Eric I Benchimol,2,3 Astrid Guttmann,2 David Moher,4 Irene Petersen,5 Liam Smeeth,1 Henrik Toft Sørensen,6 Fiona Stanley,7 Erik Von Elm81Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom; 2Institute for Clinical Evaluative Sciences, University of Toronto, Toronto, Canada; 3Department of Pediatrics and Epidemiology and Community Medicine University of Ottawa, Ottawa, Canada; 4Ottawa Hospital Research Institute, Ottawa, Canada; 5Department of Primary Care and Population Health, University College London, London, United Kingdom; 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; 7Telethon Department of Child Health, University of Western Australia, Perth, Australia; 8Institut Universitaire de Médecine Sociale et Préventive, University of Lausanne, Switzerland Recent technological developments in recording health care delivery have led to major research opportunities for epidemiologists and others. There has been a dramatic increase in the availability of "routine data" for research purposes, including data from electronic medical records, administrative data for billing purposes, disease registries, and sources of sociodemographic data. Examples of routine data include data from medical records in the UK in the Clinical Practice Research Database, administrative data from Surveillance, Epidemiology and End Results Medicare, and registry data from the Danish National Registry of Patients. The key aspect that differentiates routine data from other research data sources is the reasons for which the data were collected, since routine data are not specifically collected for research purposes. These data are increasingly available from various health care settings and geographic locations. They present innovative, efficient, and cost-effective prospects with which to answer key research questions. However, use of these data for research leads to specific challenges for researchers and for policymakers and clinicians in using studies based on such data.

Omland LH, Legarth R, Ahlström MG, et al. Clin Epidemiol. 2016;8:333–340. On page 338, Table 1 was referenced in error under the heading “Patient categories with a particularly high FYRHD”. The incorrect sentence read as “The ten combinations of indicator diseases, age, and sex with the highest FYRDH among individuals of Danish origin, as well as the ten indicator diseases with the highest FYRHD among individuals of African origin, are shown in Table 1.” The correct sentence should read “The ten combinations of indicator diseases, age, and sex with the highest FYRHD among individuals of Danish origin, as well as the ten indicator diseases with the highest FYRHD among individuals of African origin, are shown in Table 2.” Table 2 was missed from being included in the paper.Read the original article