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Kathrine Dyhr Lycke,1,2 Johnny Kahlert,3 Rikke Damgaard,1,2 Ole Mogensen,2,4 Anne Hammer1,2,4 1Department of Obstetrics and Gynecology, NIDO | Denmark, Gødstrup Hospital, Herning, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Kathrine Dyhr LyckeDepartment of Obstetrics and Gynecology, NIDO | Denmark, Gødstrup Hospital, Gl. Landevej 61, Herning, DK-7400, DenmarkEmail katlyc@clin.au.dkBackground: Hysterectomy (removal of the uterus) is a common surgical procedure in gynecology. Although minimally invasive surgical procedures have been introduced, hysterectomy is still associated with risk of short- and long-term complications. Given that hysterectomized women are no longer at risk of either hysterectomy or being diagnosed with endometrial or cervical cancer, it is important to describe trends in hysterectomy rates.Objective: To describe trends in hysterectomy incidence rates overall and stratified by age, indication, and procedure.Methods: Nationwide population-based cohort study using Danish national registries, 2000– 2015, was conducted. We calculated the overall hysterectomy-corrected and age-standardized incidence rates of hysterectomy among women ≥ 20 years old. Incidence rates were stratified by age group, indication, and surgical procedure. We performed trend analyses using Joinpoint regression, thereby estimating the average annual percentage change (AAPC).Results: A total of 98,484 women had a hysterectomy during the study period, corresponding to an overall age-standardized, hysterectomy-corrected hysterectomy incidence rate (SIR) of 351.1 per 100,000 person-years (95% CI 348.9;353.3). SIR of hysterectomy declined over time (AAPC − 1.4; 95% CI − 1.9;-1.0), which was driven by a decline in rates of benign hysterectomy (AAPC − 2.1; 95% CI − 2.7;-1.6). Irrespective of indication, rates of abdominal hysterectomy declined substantially during the study period and were surpassed by rates of minimally invasive procedures (ie, laparoscopy and robot-assisted laparoscopy) in 2013.Conclusion: Hysterectomy-corrected incidence rates of benign hysterectomy declined over time. Irrespective of indication, we observed a shift in surgical procedure over time, from abdominal hysterectomy to minimally invasive surgical procedures.Keywords: hysterectomy, incidence, surgical procedure, indication, epidemiology

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

Troels Munch,1 Lotte B Christensen,1 Kasper Adelborg,1 Grethe S Tell,2 Ellen M Apalset,2,3 Anna Westerlund,3,4 Ylva T Lagerros,5,6 Johnny Kahlert,1 Fei Xue,7 Vera Ehrenstein1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 3Department of Rheumatology, Bergen Group of Epidemiology and Biomarkers in Rheumatic Disease, Haukeland University Hospital, Bergen, Norway; 4Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden; 5Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden; 6Department of Medicine, Clinic of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Sweden; 7Center for Observational Research, Amgen Inc., Thousand Oaks, CA, USA Background: Validation of definitions used to identify conditions of interest is imperative to epidemiologic studies based on routinely collected data. The objective of the study was thus to estimate positive predictive values (PPVs) of International Classification of Diseases, 10th Revision (ICD-10) codes to identify cases of incident acute pancreatitis leading to hospitalization and incident primary malignancy in the Scandinavian (Denmark, Norway, and Sweden) national patient registries in women with postmenopausal osteoporosis (PMO). Methods: This validation study included postmenopausal (defined as 55 years or older) women with osteoporosis, identified between 2005–2014. Potential cases were sampled based on ICD-10 codes from the three national patient registries. Cases were adjudicated by physicians, using medical record review as gold standard. PPVs with corresponding 95% CIs were computed. Results: Medical records of 286 of 325 (retrieval rate 88%) women with PMO were available for adjudication. Acute pancreatitis leading to hospitalization had a PPV of 87.6% (95% CI: 80.8%–90.2%). Incident primary malignancy had a PPV of 88.1% (95% CI: 81.3%–92.7%). The PPVs did not vary substantially across the three countries. Conclusion: ICD-10 codes to identify acute pancreatitis leading to hospitalization, and incident primary malignancy in the Scandinavian national patient registries had high PPVs among women with PMO. This allows identification of cases of acute pancreatitis and incident primary malignancy with reasonable validity and to use these as outcomes in comparative analyses. Keywords: validation, primary malignancy, acute pancreatitis, positive predictive value, postmenopausal women

Kasper Adelborg,1 Lotte Brix Christensen,1 Troels Munch,1 Johnny Kahlert,1 Ylva Trolle Lagerros,2,3 Grethe S Tell,4 Ellen M Apalset,4,5 Fei Xue,6 Vera Ehrenstein1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark; 2Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, 3Department of Medicine, Clinic of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden; 4Department of Global Public Health and Primary Care, University of Bergen, 5Department of Rheumatology, Haukeland University Hospital, Bergen, Norway; 6Center for Observational Research, Amgen Inc. Thousand Oaks, CA, USA Background: Clinical epidemiology research studies, including pharmacoepidemiology and pharmacovigilance studies, use routinely collected health data, such as diagnoses recorded in national health and administrative registries, to assess clinical effectiveness and safety of treatments. We estimated positive predictive values (PPVs) of International Classification of Diseases, 10th revision (ICD-10) codes for primary diagnoses of dermatologic events and hypersensitivity recorded at hospitalization or emergency room visit in the national patient registries of Denmark and Sweden among women with postmenopausal osteoporosis (PMO). Methods: This validation study included women with PMO identified from the Danish and Swedish national patient registries (2005–2014). Medical charts of the potential cases served as the gold standard for the diagnosis confirmation and were reviewed and adjudicated by physicians. Results: We obtained and reviewed 189 of 221 sampled medical records (86%). The overall PPV was 92.4% (95% confidence interval [CI], 85.1%–96.3%) for dermatologic events, while the PPVs for bullous events and erythematous dermatologic events were 52.5% (95% CI, 37.5%–67.1%) and 12.5% (95% CI, 2.2%–47.1%), respectively. The PPV was 59.0% (95% CI, 48.3%–69.0%) for hypersensitivity; however, the PPV of hypersensitivity increased to 100.0% (95% CI, 67.6%–100.0%) when restricting to diagnostic codes for anaphylaxis. The overall results did not vary by country. Conclusion: Among women with PMO, the PPV for any dermatologic event recorded as the primary diagnosis at hospitalization or at an emergency room visit was high and acceptable for epidemiologic research in the Danish and Swedish national patient registries. The PPV was substantially lower for hypersensitivity leading to hospitalization or emergency room visit. Keywords: dermatology, positive predictive value, validation, pharmacoepidemiology

Johnny Kahlert,1 Sigrid Bjerge Gribsholt,1,2 Henrik Gammelager,1,3 Olaf M Dekkers,1,4,5 George Luta1,6 1Department of Clinical Epidemiology, Institute of Clinical Medicine, 2Department of Endocrinology and Internal Medicine, 3Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Epidemiology, 5Department of Medicine, Section Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; 6Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA Abstract: In observational studies, control of confounding can be done in the design and analysis phases. Using examples from large health care database studies, this article provides the clinicians with an overview of standard methods in the analysis phase, such as stratification, standardization, multivariable regression analysis and propensity score (PS) methods, together with the more advanced high-dimensional propensity score (HD-PS) method. We describe the progression from simple stratification confined to the inclusion of a few potential confounders to complex modeling procedures such as the HD-PS approach by which hundreds of potential confounders are extracted from large health care databases. Stratification and standardization assist in the understanding of the data at a detailed level, while accounting for potential confounders. Incorporating several potential confounders in the analysis typically implies the choice between multivariable analysis and PS methods. Although PS methods have gained remarkable popularity in recent years, there is an ongoing discussion on the advantages and disadvantages of PS methods as compared to those of multivariable analysis. Furthermore, the HD-PS method, despite its generous inclusion of potential confounders, is also associated with potential pitfalls. All methods are dependent on the assumption of no unknown, unmeasured and residual confounding and suffer from the difficulty of identifying true confounders. Even in large health care databases, insufficient or poor data may contribute to these challenges. The trend in data collection is to compile more fine-grained data on lifestyle and severity of diseases, based on self-reporting and modern technologies. This will surely improve our ability to incorporate relevant confounders or their proxies. However, despite a remarkable development of methods that account for confounding and new data opportunities, confounding will remain a serious issue. Considering the advantages and disadvantages of different methods, we emphasize the importance of the clinical input and of the interplay between clinicians and analysts to ensure a proper analysis. Keywords: observational studies, confounding, adjustment, stratification, multivariable analysis, propensity score

Vera Ehrenstein,1 Rohini K Hernandez,2 Merete Lund Maegbaek,1 Johnny Kahlert,1 Mary Nguyen-Nielsen,1 Mette Nørgaard,1 Alexander Liede2 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Center for Observational Research, Amgen, Thousand Oaks, CA, USA Objective: Among patients with prostate cancer, diagnostic codes for bone metastases in the Danish National Registry of Patients have a sensitivity of 44%. In an attempt to improve the sensitivity of registry-based identification of metastases from prostate cancer, we tested a series of algorithms, combining elevated prostate-specific antigen (PSA) levels, use of antiresorptive therapy, and performed bone scintigraphy. Patients and methods: We randomly selected 212 men diagnosed with prostate cancer in 2005–2010 in the Central Denmark Region with prespecified PSA values, antiresorptive therapy, and bone scintigraphy who did not have a registry-based diagnostic code indicating presence of distant metastases. We defined three candidate algorithms for bone metastases: 1) PSA >50 µg/L and bone scintigraphy, 2) PSA >50 µg/L and antiresorptive therapy, and 3) PSA ≤50 µg/L with antiresorptive therapy or bone scintigraphy. An algorithm for distant metastasis site other than bone was defined as PSA >50 µg/L alone. Medical chart review was used as the reference standard to establish the presence or absence of metastases. Validity was expressed as a positive predictive value (PPV) or a negative predictive value, based on whether the algorithms correctly classified metastases compared with the reference standard. Results: We identified 113 men with evidence of metastases according to the candidate algorithms, and 99 men without evidence of metastases according to the candidate algorithm. The PPVs of PSA >50 µg/L were 0.10 (95% confidence interval [CI] 0.04–0.19) for bone metastases and 0.14 (95% CI 0.07–0.24) for nonbone metastases, regardless of receipt of antiresorptive therapy or presence of bone scintigraphy. The PPVs for any metastases were 0.16 (95% CI 0.06–0.32) for PSA >50 µg/L and 0.28 (95% CI 0.14–0.47) for PSA >50 µg/L with bone scintigraphy. Adding antiresorptive treatment to the algorithm did not improve PPV. All negative predictive values approached 1.00. Conclusion: Algorithms based on elevated PSA, antiresorptive therapy, or bone scintigraphy are not suitable for supplementing diagnostic codes to identify additional cases of distant metastases among men with prostate cancer. However, it is possible that in this setting, medical chart review is not a gold standard to identify metastases. Keywords: algorithm, bone metastases, prostate-specific antigen, validation, Danish databases

Background: Intensified insulin therapy may increase body weight and cause obesity. This study compared body mass index standard deviation score (BMISDS) and obesity rate in children with type 1 diabetes (T1D) in Denmark, Iceland, Norway and Sweden, and uncovered predictors for increasing BMISDS. Methods: Data registered in the Nordic national childhood diabetes databases during the period 2008‐2012 on children below 15 years with T1D for more than 3 months were compiled, including information on gender, age, diabetes duration, hemoglobin A1c (HbA1c), insulin dose, severe hypoglycemia (SH), treatment modality, height and weight. The Swedish reference chart for BMI was used for calculating BMISDS. Results: Totally, 11 025 children (48% females) (30 994 registrations) were included. Medians by the last recorded examination were: age, 13.5 years; diabetes duration, 4.3 years; HbA1c, 7.9% (63 mmol/mol); insulin dose, 0.8 IU/kg/d and BMISDS, 0.70. Obesity rate was 18.5%. Adjusted mean BMISDS (BMISDS adj) was inversely related to HbA1c and directly to diabetes duration. Higher BMISDS adj was found in those with an insulin dose above 0.6 IU/kg/d, and in girls above 10 years. Pump users had higher BMISDS adj than pen users, and patients with registered SH had higher BMISDS adj than patients without SH (both P < .001). Conclusion: Obesity rate in children with T1D in the Nordic countries is high, however, with country differences. Low HbA1c, long diabetes duration, higher insulin dose, pump treatment and experiencing a SH predicted higher BMISDS. Diabetes caregivers should balance the risk of obesity and the benefit of a very low HbA1c. [ABSTRACT FROM AUTHOR]