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1.  Multimorbidity and cancer outcomes: a for more research 
Clinical Epidemiology  2013;5(Suppl 1):1-2.
PMCID: PMC3833011  PMID: 24265558
2.  Editor’s choice 
Clinical Epidemiology  2012;4:157-158.
PMCID: PMC3410687  PMID: 22866016
5.  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
6.  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
7.  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
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.  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
12.  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
13.  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
14.  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
16.  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
17.  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
18.  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
19.  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
21.  A Prospective Cohort Study of Menstrual Characteristics and Time to Pregnancy 
American Journal of Epidemiology  2011;174(6):701-709.
The authors examined the association between menstrual characteristics and time to pregnancy among 2,653 Danish women enrolled in a prospective cohort study (2007–2009). Menstrual characteristics were reported at baseline. Outcome data were updated bimonthly until pregnancy, fertility treatment, loss to follow-up, or end of observation (12 cycles). Adjusted fecundability ratios and 95% confidence intervals were estimated by using discrete-time Cox regression models. Relative to average cycle lengths (27–29 days), fecundability ratios for cycle lengths <25, 25–26, 30–31, 32–33, and ≥34 days were 0.64 (95% confidence interval (CI): 0.49, 0.84), 0.94 (95% CI: 0.77, 1.13), 1.10 (95% CI: 0.97, 1.25), 1.35 (95% CI: 1.06, 1.73), and 1.17 (95% CI: 0.91, 1.49), respectively. Compared with cycles that regularized within 2 years after menarche, fecundability ratios for cycles that regularized 2–3 and ≥4 years after menarche were 0.90 (95% CI: 0.80, 1.02) and 0.89 (95% CI: 0.77, 1.03), respectively. Fecundability ratios were 0.87 (95% CI: 0.72, 1.05) comparing <3 with 3–4 days of menstrual bleeding and 0.70 (95% CI: 0.43, 1.13) comparing very heavy with moderate flow. In the present study, shorter cycle length was associated with delayed time to pregnancy. Age at menarche, time to menstrual regularization, and duration or intensity of menstrual flow were not appreciably associated with fecundability.
PMCID: PMC3166706  PMID: 21719742
cohort studies; fertility; menstrual cycle; menstruation; prospective studies
22.  Functional polymorphisms in UDP-glucuronosyltransferases and recurrence in tamoxifen-treated breast cancer survivors 
Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors.
We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype.
No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype.
Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk.
Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.
PMCID: PMC3169710  PMID: 21750172
Epidemiology; breast neoplasms; UDP-glucuronosyltransferases; tamoxifen
23.  The impact of statin use on pneumonia risk and outcome: a combined population-based case-control and cohort study 
Critical Care  2012;16(4):R122.
The impact of statin use on pneumonia risk and outcome remains unclear. We therefore examined this risk in a population-based case-control study and did a 5-year update of our previous 30-day mortality analyses.
We identified 70,953 adults with a first-time hospitalization for pneumonia between 1997 and 2009 in Northern Denmark. Ten age- and sex-matched population controls were selected for each pneumonia patient. To control for potential confounders, we retrieved individual-level data on other medications, comorbidities, recent surgery, socioeconomic indicators, influenza vaccination, and other markers of frailty or health awareness from medical databases. We followed all pneumonia patients for 30 days after hospital admission.
A total of 7,223 pneumonia cases (10.2%) and 64 523 controls (9.1%) were statin users before admission, corresponding to an age- and sex-matched odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.14-1.21). After controlling for higher comorbidity and a wide range of other potential confounders, the adjusted OR for pneumonia associated with current statin use dropped to 0.80 (95% CI: 0.77-0.83). Previous statin use was not associated with decreased pneumonia risk (adjusted OR = 0.97, 95% CI: 0.91-1.02). Decreased risk remained significant after further adjustment for frailty and health awareness markers.
The prevalence of statin use among Danish pneumonia patients increased from 1% in 1997 to 24% in 2009. Thirty-day mortality following pneumonia hospitalization was 11.3% among statin users versus 15.1% among nonusers. This corresponded to a 27% reduced mortality rate (adjusted hazard ratio = 0.73, 95% CI: 0.67-0.79), corroborating our earlier findings.
Current statin use was associated with both a decreased risk of hospitalization for pneumonia and lower 30-day mortality following pneumonia.
PMCID: PMC3580701  PMID: 22789037
24.  One-year mortality among Danish intensive care patients with acute kidney injury: a cohort study 
Critical Care  2012;16(4):R124.
There are few studies on long-term mortality among intensive care unit (ICU) patients with acute kidney injury (AKI). We assessed the prevalence of AKI at ICU admission, its impact on mortality during one year of follow-up, and whether the influence of AKI varied in subgroups of ICU patients.
We identified all adults admitted to any ICU in Northern Denmark (approximately 1.15 million inhabitants) from 2005 through 2010 using population-based medical registries. AKI was defined at ICU admission based on the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) classification, using plasma creatinine changes. We included four severity levels: AKI-risk, AKI-injury, AKI-failure, and without AKI. We estimated cumulative mortality by the Kaplan-Meier method and hazard ratios (HRs) using a Cox model adjusted for potential confounders. We computed estimates for all ICU patients and for subgroups with different comorbidity levels, chronic kidney disease status, surgical status, primary hospital diagnosis, and treatment with mechanical ventilation or with inotropes/vasopressors.
We identified 30,762 ICU patients, of which 4,793 (15.6%) had AKI at ICU admission. Thirty-day mortality was 35.5% for the AKI-risk group, 44.2% for the AKI-injury group, and 41.0% for the AKI-failure group, compared with 12.8% for patients without AKI. The corresponding adjusted HRs were 1.96 (95% confidence interval (CI) 1.80-2.13), 2.60 (95% CI 2.38 to 2.85) and 2.41 (95% CI 2.21 to 2.64), compared to patients without AKI. Among patients surviving 30 days (n = 25,539), 31- to 365 day mortality was 20.5% for the AKI-risk group, 23.8% for the AKI-injury group, and 23.2% for the AKI-failure group, compared with 10.7% for patients without AKI, corresponding to adjusted HRs of 1.33 (95% CI 1.17 to 1.51), 1.60 (95% CI 1.37 to1.87), and 1.64 (95% CI 1.42 to 1.90), respectively. The association between AKI and 30-day mortality was evident in subgroups of the ICU population, with associations persisting in most subgroups during the 31- to 365-day follow-up period, although to a lesser extent than for the 30-day period.
AKI at ICU admission is an important prognostic factor for mortality throughout the subsequent year.
PMCID: PMC3580703  PMID: 22789072
25.  CYP2D6 Inhibition and Breast Cancer Recurrence in a Population-Based Study in Denmark 
Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain.
We conducted a large case–control study nested in the population of 11 251 women aged 35–69 years at diagnosis of stage I–III breast cancer between 1985 and 2001 on Denmark’s Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor–positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER−) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug–drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided.
The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER− tumors, and 22% each in control subjects with ER+ and ER− tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER− tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay.
The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.
PMCID: PMC3057982  PMID: 21325141

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