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1.  Manganese Superoxide Dismutase and Breast Cancer Recurrence: A Danish Clinical Registry-Based Case-Control Study, and a Meta-Analysis 
PLoS ONE  2014;9(1):e87450.
Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses.
We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990–2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR.
The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively.
Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.
PMCID: PMC3909115  PMID: 24498107
2.  A note on arterial to venous oxygen saturation as reference for NIRS-determined frontal lobe oxygen saturation in healthy humans 
PMCID: PMC3897873  PMID: 24478709
cerebral oxygenation; humans; hypocapnia; hypercapnia; hypoxia; jugular vein; NIRS
3.  Elevated Plasma Vitamin B12 Levels as a Marker for Cancer: A Population-Based Cohort Study 
A substantial proportion of patients referred for plasma vitamin B12 (cobalamin [Cbl]) measurement present with high Cbl levels, which have been reported in patients with different cancer types. However, the cancer risk among patients with newly diagnosed high Cbl levels has not been adequately examined.
We conducted this cohort study using population-based Danish medical registries. Patients referred for Cbl measurement with levels greater than the lower reference limit (≥200 pmol/L) were identified from the population of Northern Denmark during the period of 1998 to 2009 using a database of laboratory test results covering the entire population. Data on cancer incidence (follow-up 1998–2010), Cbl treatment, and prior diagnoses were obtained from medical registries. Patients receiving Cbl treatment were excluded. Cancer risks were calculated as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs), stratified by plasma Cbl levels. All statistical tests were two-sided.
We identified 333 667 persons without prevalent cancer and not receiving Cbl treatment. Six percent had Cbl levels greater than the upper reference limit (≥601 pmol/L). Cancer risk increased with higher Cbl levels and was highest during the first year of follow-up (Cbl 601–800 pmol/L: SIR = 3.44, 95% CI = 3.14 to 3.76; Cbl >800 pmol/L: SIR = 6.27, 95% CI = 5.70 to 6.88; both P < .001). The risks were particularly elevated for hematological and smoking- and alcohol-related cancers for persons with high Cbl levels.
High Cbl levels were associated with the risk of subsequently diagnosed cancer, mostly within the first year of follow-up. This may have clinical implications for the interpretation of high Cbl levels.
PMCID: PMC3848986  PMID: 24249744
4.  The impact of comorbidity on cancer survival: a review 
Clinical Epidemiology  2013;5(Suppl 1):3-29.
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.
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.
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.
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.
PMCID: PMC3820483  PMID: 24227920
comorbidity; cancer; diagnosis; treatment; survival
5.  Multimorbidity and cancer outcomes: a for more research 
Clinical Epidemiology  2013;5(Suppl 1):1-2.
PMCID: PMC3833011  PMID: 24265558
6.  Comorbid Diseases Interact with Breast Cancer to Affect Mortality in the First Year after Diagnosis—A Danish Nationwide Matched Cohort Study 
PLoS ONE  2013;8(10):e76013.
Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied.
From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer.
The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up.
There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.
PMCID: PMC3794020  PMID: 24130755
7.  In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study 
BMJ Open  2013;3(9):e003507.
To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD).
Cohort study.
All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription.
Main outcome measures
ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression.
We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4).
This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.
PMCID: PMC3780335  PMID: 24056487
8.  Parental Inflammatory Bowel Disease and Risk of Asthma in Offspring: A Nationwide Cohort Study in Denmark 
Common genetic and environmental risk factors may explain the concurrent increase in the incidence of both inflammatory bowel disease (IBD) and asthma. We examined whether IBD in a parent is associated with an increased asthma risk in offspring.
This was a registry-based cohort study of all children born alive in Denmark in 1979–2009, followed through 2010. IBD and asthma were identified using hospital diagnoses; antiasthma medication was also used to identify asthma. We computed risk of asthma and estimated adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CIs) using Cox proportional-hazards regression. We evaluated asthma risk according to maternal and paternal IBD, Crohn's disease (CD), and ulcerative colitis (UC). Children without parental IBD were the comparison cohort for all comparisons.
We identified 1,845,281 children, of whom 14,952 (0.8%) had a parent with IBD. The 10-year risk of asthma was 6.9% among offspring of parents with CD, 5.6% among offspring of parents with UC, and 5.0% among offspring of parents without IBD. The aIRR for asthma associated with parental IBD was 0.98 (95% CI: 0.91–1.04). The aIRR was 1.09 (95% CI: 0.98–1.22) for parental CD and 0.92 (95% CI: 0.84–1.00) for parental UC. Results were similar regardless of parent of origin or inclusion of antiasthma medication to define asthma.
Our data do not provide evidence for an increased risk of asthma in offspring with a parental history of IBD.
PMCID: PMC3759218  PMID: 23965919
9.  Use of selective serotonin reuptake inhibitors and lifestyle among women of childbearing age: a Danish cross-sectional survey 
BMJ Open  2013;3(7):e003024.
To examine the use of selective serotonin reuptake inhibitors (SSRIs) among Danish women of childbearing age according to lifestyle factors.
Cross-sectional survey.
The Central Denmark Region.
4234 women (71.5% of the invited women) aged 25–44 years who participated in a public health survey in 2006.
Outcome measures
Prevalence and prevalence ratios (PRs) of current and former SSRI use among women characterised by selected lifestyle factors. We obtained information on SSRI use through linkage to the Aarhus University Prescription Database covering all pharmacies in the region.
Of the 4234 women in the study, 161 (3.8%) were current SSRI users, 60 (1.4%) were recent users, 223 (5.3%) were former users and 3790 (89.5%) were never users. Current use of SSRIs was more prevalent in obese women than in non-obese women (PR 1.5, 95% CI 1.0 to 2.3), in current smokers compared with non-current smokers (PR 1.6, 95% CI 1.1 to 2.2), in women who drank more than seven alcoholic drinks weekly compared with women who drank seven or fewer drinks weekly (PR 1.8, 95% CI 1.2 to 2.8) and in women with an unhealthy diet compared with women with a healthy diet (PR 1.7, 95% CI 1.2 to 2.6). Prevalence of former use of SSRIs was similarly increased except in those with an unhealthy diet (PR 1.1, 95% CI 0.8 to 1.7). SSRI use did not differ according to participation in regular physical activity.
Women with an unhealthy lifestyle were about 1.5-fold more likely to be current or former users of SSRIs than those with a healthy lifestyle. These findings may be useful for quantitative assessment of the contribution of lifestyle factors to uncontrolled confounding in studies of SSRI use in pregnancy.
PMCID: PMC3731776  PMID: 23903810
10.  Concepts of comorbidities, multiple morbidities, complications, and their clinical epidemiologic analogs 
Clinical Epidemiology  2013;5:199-203.
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.
PMCID: PMC3704301  PMID: 23861599
epidemiology; epidemiologic methods; comorbidity; complications; diagnosis-related groups; risk adjustment
11.  Changes in walking and running in patients with hip dysplasia 
Acta Orthopaedica  2013;84(3):265-270.
Background and purpose
Earlier studies have suggested that the hip extension angle and the hip flexor moment in walking are affected by hip dysplasia, but to our knowledge there have been no reports on running or evaluations of self-reported health. We evaluated differences in walking, running, and self-reported health between young adults with symptomatic hip dysplasia and healthy controls.
Patients and methods
Walking and running in 32 patients with hip dysplasia, mean 34 (18–53) years old, was compared with walking and running in 32 controls, mean 33 (18–54) years old. Joint kinematics and kinetics—quantified by the peak hip extension angle and the peak net joint moment of hip flexion during walking and running—were recorded using a motion-capture system, and health was evaluated using the Copenhagen Hip and Groin Outcome Score (HAGOS).
The peak hip extension angle during walking was less in the patients than in the controls (–10.4 (SD 4.8) degrees vs. –13.2 (SD 4.5) degrees; p = 0.02). Similarly, the peak net joint moment of hip flexion during walking was lower in the patients than in the controls (0.57 (SD 0.13) N*m/kg vs. 0.70 (SD 0.22) N*m/kg; p = 0.008). In all dimensions of HAGOS, the patients scored lower than the controls. Furthermore, the hip extension angle and the net joint moment of hip flexion correlated with the HAGOS subscales pain and physical function in sport and recreation.
Patients with symptomatic hip dysplasia do modify walking and running, and we therefore suggest that the impairment found in this study should play an important role in the evaluation of later operative and training interventions.
PMCID: PMC3715823  PMID: 23594221
12.  Socioeconomic status in HCV infected patients – risk and prognosis 
Clinical Epidemiology  2013;5:163-172.
Background and aims
It is unknown whether socioeconomic status (SES) is a risk factor for hepatitis C virus (HCV) infection or a prognostic factor following infection.
From Danish nationwide registries, we obtained information on three markers of SES: employment, income, and education. In a case control design, we examined HCV infected patients and controls; conditional logistic regression was employed to obtain odds ratios (ORs) for HCV infection for each of the three SES markers, adjusting for the other two SES markers, comorbidity, and substance abuse. In a cohort design, we used Cox regression analysis to compute mortality rate ratios (MRRs) for each of the three SES markers, adjusting for the other two SES markers, comorbidity level, age, substance abuse, and gender.
When compared to employed persons, ORs for HCV infection were 2.71 (95% confidence interval [CI]: 2.24–3.26) for disability pensioners and 2.24 (95% CI: 1.83–2.72) for the unemployed. When compared to persons with a high income, ORs were 1.64 (95% CI: 1.34–2.01) for low income persons and 1.19 (95% CI: 1.02–1.40) for medium income persons. The OR was 1.35 (95% CI: 1.20–1.52) for low education (no more than basic schooling). When compared to employed patients, MRRs were 1.71 (95% CI: 1.22–2.40) for unemployed patients and 2.24 (95% CI: 1.63–3.08) for disability pensioners. When compared to high income patients, MRRs were 1.47 (95% CI: 1.05–2.05) for medium income patients and 1.64 (95% CI: 1.13–2.34) for low income patients. Educational status was not associated with mortality.
Low SES was associated with an increased risk of HCV infection and with poor prognosis in HCV infected patients.
PMCID: PMC3678712  PMID: 23766659
survival; socioeconomic status; risk factor; prognosis
13.  β-Blockers and Survival among Danish Patients with Malignant Melanoma: A Population-Based Cohort Study 
To study whether use of β-blockers increases survival in patients with malignant melanoma because experimental data suggest that catecholamine hormones may be involved in stimulating the aggressiveness of malignant melanoma.
A total of 4,179 patients diagnosed with malignant melanoma in Denmark with a median follow-up of 4.9 years and identified in the Danish Cancer Registry participated. Data on β-blocker use, comorbidity, and survival were obtained from medical and administrative databases. Cox proportional hazards models were used to estimate HRs for all-cause mortality with 95% CIs with adjustment for prognostic factors.
A total of 372 (8.9%) patients with malignant melanoma were treated with β-blockers within 90 days of melanoma diagnosis. The median β-blocker duration for exposure within 90 days of melanoma diagnosis, more than 90 days, and no prior exposure was 7.6, 1.4, and 0 years, respectively. The patients receiving β-blockers were older, had more comorbidities, and more cardiovascular and psychotropic drug user than the patients receiving no β-blockers prior to melanoma diagnosis. After adjustment for age and comorbidity index, the HR for melanoma death was 0.87 (95% CI: 0.64–1.20) and for all-cause mortality was 0.81 (95% CI: 0.67–0.97).
Increased survival time of patients with melanoma receiving β-blockers suggests that this class of drugs may hold promise in treatment strategy for these patients.
The observations described here suggest that catecholamines may retard melanoma progression and that β-blockers may have unrecognized potential as a therapeutic intervention for melanoma.
PMCID: PMC3652234  PMID: 21933972
14.  Caffeinated Beverage and Soda Consumption and Time to pregnancy 
Epidemiology (Cambridge, Mass.)  2012;23(3):393-401.
Many epidemiologic studies have evaluated the association between caffeine and fertility, with inconsistent results. Some studies suggest that various caffeine-containing beverages may affect fertility differently.
We evaluated the relation of caffeine, coffee, tea, and sodas with time to pregnancy in a prospective cohort study of 3628 women planning a pregnancy in Denmark (2007–2010). Women reported beverage intake at baseline and every eight weeks during follow-up until they became pregnant or for up to 12 cycles. We used discrete-time Cox proportional hazards regression to estimate fecundability ratios (FRs) and 95% confidence intervals (CI), controlling for potential confounders.
There was little relation between fecundability and caffeine intake of 300+mg/day compared with <100 mg/day (FR=1.04 [95% CI= 0.90–1.21]) or coffee intake of 3+ servings/day compared with none (1.05 [0.85–1.33]). Soda consumption was associated with reduced fecundability: for all types of sodas combined, the adjusted FRs were 0.89 (0.80–0.98), 0.85 (0.71–1.02), 0.84 (0.57–1.25), and 0.48 (0.21–1.13) for <1, 1, 2 and 3+ servings per day, respectively, compared with none. Tea drinking was associated with a slight increase in fecundability, with FR=1.27 (0.98–1.64) for 2+ servings/day vs. none.
In this prospective study of time to pregnancy, the association between caffeine intake and fertility differed by beverage type. Although we controlled for many confounders, our findings of reduced fecundability among soda drinkers and increased fecundability among tea drinkers could have resulted from confounding by unmeasured lifestyle characteristics.
PMCID: PMC3321066  PMID: 22407137
15.  A prospective cohort study of physical activity and time-to-pregnancy 
Fertility and Sterility  2012;97(5):1136-1142.e4.
To investigate the association between leisure-time physical activity (PA) and fecundability.
Prospective cohort study.
Internet-based observational study of Danish women who were planning a pregnancy (2007–2009).
3,628 women aged 18–40 years at baseline.
Main outcome measure(s)
Time-to-pregnancy (TTP). Fecundability ratios (FR) and 95% confidence intervals (CI) were derived from discrete-time Cox models, with adjustment for potential confounders such as body mass index (BMI).
We observed an inverse monotonic association between vigorous PA and fecundability (≥5 hours/week vs. none: FR=0.68, 95% CI: 0.54, 0.85), and a weak positive association between moderate PA and fecundability (≥5 vs. <1 hours/week: FR=1.18, 95% CI: 0.98, 1.43), after mutual adjustment for both PA types. Inverse associations between high vigorous PA and fecundability were observed within subgroups of age, parity status, and cycle regularity, but not among overweight or obese women (BMI ≥ 25 kg/m2).
There was evidence for a dose-response relation between increasing vigorous PA and delayed TTP in all subgroups of women, with the exception of overweight and obese women. Moderate PA was associated with a small increase in fecundability regardless of BMI. These findings indicate that PA of any type might improve fertility among overweight and obese women, a subgroup at higher risk of infertility. Lean women who substitute vigorous PA with moderate PA may also improve their fertility.
PMCID: PMC3340509  PMID: 22425198
fecundability; fertility; physical activity; prospective study; cohort study
Background and Purpose:
Many researchers acknowledge the importance of “training errors” as the main cause of running‐related injuries. The purpose of this clinical commentary is to present a theoretical framework for the assumption that some running‐related injuries among rear‐foot strikers develop due to rapidly changing running volume, while others develop due to rapidly changing running pace.
Description of Topic with Related Evidence:
Evidence from clinical and experimental studies is presented to support the assertion that rapid change in running volume may lead to the development of patellofemoral pain syndrome, iliotibial band syndrome, and patellar tendinopathy, while change in running pace may be associated with the development of achilles tendinopathy, gastrocnemius injuries, and plantar fasciitis.
Discussion/Relation to Clinical Practice:
If this assertion is correct, bias may be prevented in future studies by categorizing injuries into volume or pacing injuries. However, more work is needed to provide further evidence in support of this approach. Future investigations of the link between training patterns and injury development should be designed as large‐scale prospective studies using objective methods to quantify training patterns.
Level of evidence:
PMCID: PMC3625796  PMID: 23593555
Etiology; running pace; running‐related injury; training volume
18.  Development and validation of a registry-based definition of eosinophilic esophagitis in Denmark 
AIM: To develop and validate a case definition of eosinophilic esophagitis (EoE) in the linked Danish health registries.
METHODS: For case definition development, we queried the Danish medical registries from 2006-2007 to identify candidate cases of EoE in Northern Denmark. All International Classification of Diseases-10 (ICD-10) and prescription codes were obtained, and archived pathology slides were obtained and re-reviewed to determine case status. We used an iterative process to select inclusion/exclusion codes, refine the case definition, and optimize sensitivity and specificity. We then re-queried the registries from 2008-2009 to yield a validation set. The case definition algorithm was applied, and sensitivity and specificity were calculated.
RESULTS: Of the 51 and 49 candidate cases identified in both the development and validation sets, 21 and 24 had EoE, respectively. Characteristics of EoE cases in the development set [mean age 35 years; 76% male; 86% dysphagia; 103 eosinophils per high-power field (eos/hpf)] were similar to those in the validation set (mean age 42 years; 83% male; 67% dysphagia; 77 eos/hpf). Re-review of archived slides confirmed that the pathology coding for esophageal eosinophilia was correct in greater than 90% of cases. Two registry-based case algorithms based on pathology, ICD-10, and pharmacy codes were successfully generated in the development set, one that was sensitive (90%) and one that was specific (97%). When these algorithms were applied to the validation set, they remained sensitive (88%) and specific (96%).
CONCLUSION: Two registry-based definitions, one highly sensitive and one highly specific, were developed and validated for the linked Danish national health databases, making future population-based studies feasible.
PMCID: PMC3558573  PMID: 23382628
Eosinophilic esophagitis; Denmark; Epidemiology; Case definition; Sensitivity; Specificity
19.  The Association Between Vitamin K Antagonist Therapy and Site-specific Cancer Incidence Estimated by Using Heart Valve Replacement as an Instrumental Variable 
American Journal of Epidemiology  2011;174(12):1382-1390.
Earlier studies suggest a protective association between vitamin K antagonist (VKA) anticoagulants and the incidence of cancer. The authors examined the associations between VKA therapy and incidence of 24 site-specific cancers with a Danish population-based cohort study, using heart valve replacement as an instrumental variable. The authors enrolled 9,727 Danish residents who received a replacement heart valve between 1989 and 2006. The heart valve recipients were matched with 95,481 unexposed individuals on age and sex. The authors used the heart valve replacement instrument to estimate rate ratios associating VKA therapy with incidence of the 24 site-specific cancers using Poisson regression models. Direct associations between VKA therapy and incidence of the 24 cancers were estimated in a prescription validation subset. The instrumental variable associations were plotted according to the inverse normal of rank percentile and subjected to semi-Bayes shrinkage adjustment for multiple comparisons. The pattern of associations was consistent with a null-centered Gaussian distribution. No individual cancer site showed a substantial positive or negative association with VKA therapy in the prescription validation subset, the instrumental variable analysis, or the analysis with semi-Bayes adjustment. These results do not support the existing hypothesis that VKA therapy is associated with reduced cancer risk.
PMCID: PMC3276295  PMID: 22047822
anticoagulants; bias (epidemiology); heart valves; instrumental variable; neoplasms; vitamin K
20.  Diabetes, Glycemic Control, and Risk of Tuberculosis 
Diabetes Care  2011;34(12):2530-2535.
To examine the association between diabetes, glycemic control, and risk of tuberculosis (TB).
We conducted a population-based case-control study in Northern Denmark. Cases of active TB were all individuals with a first-time principal hospital diagnosis of TB between 1980 and 2008. Each case subject was matched with up to five population control subjects with similar age, sex, place and length of residence in Denmark, and country of emigration. We computed odds ratios (ORs) for a first-time TB diagnosis among people with and without diabetes using regression to control for other comorbidities, alcoholism, immunosuppressive medications, and socioeconomic markers.
We identified 2,950 patients, including 156 diabetic individuals (5.3%), with active TB, and 14,274 population control subjects, of which 539 had diabetes (3.8%). The adjusted OR for active TB among subjects with diabetes was 1.18 (95% CI 0.96–1.45) compared with nondiabetic individuals. We found a similar risk increase from diabetes in the 843 (29%) TB case subjects who were immigrants; adjusted OR = 1.23 (95% CI 0.78–1.93). In a subset with laboratory data, diabetic individuals with an HbA1c <7.0, 7–7.9, and ≥8.0% had ORs of 0.91 (0.51–1.63), 1.05 (0.41–2.66), and 1.19 (CI 0.61–2.30), respectively, compared with individuals without diabetes.
In the low TB–burden country of Denmark, the TB risk increase associated with diabetes is substantially lower than previously suggested. We found no evidence for any association between TB and dysglycemia.
PMCID: PMC3220855  PMID: 21972407
21.  Existing data sources for clinical epidemiology: The Danish National Database of Reimbursed Prescriptions 
Clinical Epidemiology  2012;4:303-313.
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.
PMCID: PMC3508607  PMID: 23204870
Denmark; patient registration; pharmacoepidemiology; registry-based research
22.  Hospital Recorded Morbidity and Breast Cancer Incidence: A Nationwide Population-Based Case-Control Study 
PLoS ONE  2012;7(10):e47329.
Chronic diseases and their complications may increase breast cancer risk through known or still unknown mechanisms, or by shared causes. The association between morbidities and breast cancer risk has not been studied in depth.
Data on all Danish women aged 45 to 85 years, diagnosed with breast cancer between 1994 and 2008 and data on preceding morbidities were retrieved from nationwide medical registries. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression associating the Charlson comorbidity score (measured using both the original and an updated Charlson Comorbidity Index (CCI)) with incident breast cancer. Furthermore, we estimated associations between 202 morbidity categories and incident breast cancer, adjusting for multiple comparisons using empirical Bayes (EB) methods.
The study included 46,324 cases and 463,240 population controls. Increasing CCI score, up to a score of six, was associated with slightly increased breast cancer risk. Among the Charlson diseases, preceding moderate to severe renal disease (OR = 1.25, 95% CI: 1.06, 1.48), any tumor (OR = 1.17, 95% CI: 1.10, 1.25), moderate to severe liver disease (OR = 1.86, 95% CI: 1.32, 2.62), and metastatic solid tumors (OR = 1.49, 95% CI: 1.17, 1.89), were most strongly associated with subsequent breast cancer. Preceding myocardial infarction (OR = 0.89, 95% CI: 0.81, 0.99), connective tissue disease (OR = 0.87, 95% CI: 0.80, 0.94), and ulcer disease (OR = 0.91, 95% CI: 0.83, 0.99) were most strongly inversely associated with subsequent breast cancer. A history of breast disorders was associated with breast cancer after EB adjustment. Anemias were inversely associated with breast cancer, but the association was near null after EB adjustment.
There was no substantial association between morbidity measured with the CCI and breast cancer risk.
PMCID: PMC3477157  PMID: 23094045
23.  Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study 
Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied.
We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I–III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided.
Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = −0.10, 95% confidence interval = −0.11 to −0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = −0.01 to 0.11).
Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.
PMCID: PMC3186780  PMID: 21813413
24.  Comparison of zotarolimus-eluting and sirolimus-eluting coronary stents: a study from the Western Denmark Heart Registry 
We evaluated the effectiveness and safety of a zotarolimus-eluting (ZES) versus a sirolimus-eluting (SES) coronary stent in a large cohort of patients treated with one of these stents in Western Denmark.
A total of 6,122 patients treated with ZES (n=2,282) or SES (n=3,840) were followed for up to 27 months. We ascertained clinical outcomes based on national medical databases.
Incidence of target lesion revascularization (no. per 100 person-years) was 5.3 in the ZES group compared to 1.9 in the SES group (adjusted hazard ratio (HR)=2.19, 95% confidence intervals (CI): 1.39-3.47; p=0.001). All-cause mortality was also higher in the ZES group (ZES: 6.3; SES: 3.3; adjusted HR=1.34, 95% CI: 1.05-1.72; p=0.02), while stent thrombosis (ZES: 1.2; SES: 0.5; adjusted HR=1.98, 95% CI: 0.75-5.23; p=0.14) did not differ significantly.
In agreement with previously published randomised data, this observational study indicated that the ZES was associated with an increased risk of death and TLR in a large cohort of consecutive patients.
PMCID: PMC3518209  PMID: 23031197
Zotarolimus; Sirolimus; Stent; Mortality; Stent thrombosis; Diabetes mellitus

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