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

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; 2DepartmentofEpidemiology, RollinsSchool ofPublic Health, EmoryUniversity, 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

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

Anne Gulbech Ording, Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital, Denmark Abstract: The proportion of older people in the world population is expected to increase rapidly during the upcoming decades. Consequently, the number of patients with multimorbidity will increase dramatically. In epidemiologic research, the concepts of multimorbidity, comorbidity, and complications have been confusing, and some of these concepts are used interchangeably. In this commentary, the authors propose a clear terminology for clinical concepts describing different aspects of multimorbidity and elucidate the relationship between these clinical concepts and their epidemiologic analogs. Depending on whether a study uses causal or predictive models, a proper distinction between concepts of multimorbidity is important. It can be very difficult to separate complications of the index disease under study from comorbidity. In this context, use of comorbidity indices as confounding scores should be done with caution. Other methodologic issues are type, duration, severity, and number of comorbidities included in the ascertainment methods, as well as sources included in the research. Studies that recognize these challenges have the potential to yield valid estimates of the comorbidity burden and results that can be compared with other studies. Keywords: epidemiology, epidemiologic methods, comorbidity, complications, diagnosis-related groups, risk adjustment

Lone Winther Lietzen1, Gitte Vrelits Sørensen1, Anne Gulbech Ording1, Jens Peter Garne2, Peer Christiansen3, Mette Nørgaard1, Jacob Jacobsen11Department of Clinical Epidemiology, 2Department of Breast Surgery, Aalborg Hospital, 3Breast and Endocrine Section, Department of Surgery P, Aarhus University Hospital, DenmarkObjective: Breast cancer is the most common cancer among women worldwide. The Nordic countries have relatively high survival, but Denmark has a lower survival than neighboring countries. A breast cancer screening program was introduced in 2007 and 2008 in the northern and central regions of Denmark respectively. We aimed to examine possible changes in survival of Danish breast cancer patients in central and northern Denmark in the period 1998–2009.Materials and methods: From the northern and central Denmark regions, we included all women (n = 13,756) with an incident diagnosis of breast cancer, as recorded in the Danish National Registry of Patients during the period January 1, 1998 through December 31, 2009. We calculated age-stratified survival and used Cox proportional hazard regression to estimate mortality rate ratios (MRRs) for all breast cancer patients.Results: Median age was 62 years (21–102 years). The overall 1-year survival improved steadily over the period from 90.9% in 1998–2000 to 94.4% in 2007–2009, corresponding to a 1-year age adjusted MRR of 0.68 in 2007–2009 compared with the reference period 1998–2000. We estimated the 5-year survival to improve from 70.0% in 1998–2000 to 74.7% in 2007–2009, corresponding to a 5-year age adjusted MRR of 0.82 in 2007–2009 compared with the reference period 1998–2000. For middle-aged women (50–74 years) 1-year survival increased from 92.8% in 1998–2000 to 96.6% in 2008–2009, and 5-year survival was expected to increase from 73.9% in 1998–2000 to 80.2% in 2007–2009. Among younger women (15–49 years) and elderly women (>75 years), 1-year survival and 5-year predicted survival did not change over the two time periods.Conclusion: Survival of breast cancer patients has improved in Denmark over the period 1998–2009, and this change was most distinct in women aged 50–74 years. Survival improved even before the implementation of a formal breast cancer screening program.Keywords: breast neoplasm, mortality, epidemiology, population-based