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1.  Relationship of HbA1c variability, absolute changes in HbA1c, and all-cause mortality in type 2 diabetes: a Danish population-based prospective observational study 
We assessed the relationship of mortality with glycated hemoglobin (HbA1c) variability and with absolute change in HbA1c.
A population-based prospective observational study with a median follow-up time of 6 years.
Based on a validated algorithm, 11 205 Danish individuals with type 2 diabetes during 2001–2006 were identified from public data files, with at least three HbA1c measurements: one index measure, one closing measure 22–26 months later, and one measurement in-between. Medium index HbA1c was 7.3%, median age was 63.9 years, and 48% were women. HbA1c variability was defined as the mean absolute residual around the line connecting index value with closing value. Cox proportional hazard models with restricted cubic splines were used, with all-cause mortality as the outcome.
Variability between 0 and 0.5 HbA1c percentage point was not associated with mortality, but for index HbA1c ≤8% (64 mmol/mol), a variability above 0.5 was associated with increased mortality (HR of 1 HbA1c percentage point variability was 1.3 (95% CI 1.1 to 1.5) for index HbA1c 6.6–7.4%). For index HbA1c≤8%, mortality increased when HbA1c declined, but was stable when HbA1c rose. For index HbA1c>8%, change in HbA1c was associated with mortality, with the lowest mortality for greatest decline (HR=0.9 (95% CI 0.80 to 0.98) for a 2-percentage point decrease).
For individuals with an index HbA1c below 8%, both high HbA1c variability and a decline in HbA1c were associated with increased mortality. For individuals with index HbA1c above 8%, change in HbA1c was associated with mortality, whereas variability was not.
PMCID: PMC4317527  PMID: 25664182
HbA1c; Type 2 Diabetes; Mortality; Change
2.  Risk and prognosis of Staphylococcus aureus bacteremia among individuals with and without end-stage renal disease: a Danish, population-based cohort study 
Staphylococcus aureus is a leading cause of bloodstream infections among hemodialysis patients and of exit-site infections among peritoneal dialysis patients. However, the risk and prognosis of Staphylococcus aureus bacteremia among end-stage renal disease patients have not been delineated.
In this Danish nationwide, population-based cohort study patients with end-stage renal disease and matched population controls were observed from end-stage renal disease diagnosis/sampling until first episode of Staphylococcus aureus bacteremia, death, or end of study period. Staphylococcus aureus positive blood cultures, hospitalization, comorbidity, and case fatality were obtained from nationwide microbiological, clinical, and administrative databases. Incidence rates and risk factors were assessed by regression analysis.
The incidence rate of Staphylococcus aureus bacteremia was very high for end-stage renal disease patients (35.7 per 1,000 person-years; 95% CI, 33.8-37.6) compared to population controls (0.5 per 1,000 person-years; 95% CI, 0.5-0.6), yielding a relative risk of 65.1 (95% CI, 59.6-71.2) which fell to 28.6 (95% CI, 23.3-35.3) after adjustment for sex, age, and comorbidity. After stratification for type of renal replacement therapy, we found the highest incidence rate of Staphylococcus aureus bacteremia among hemodialysis patients (46.3 per 1,000 person-years) compared to peritoneal dialysis patients (22.0 per 1,000 person-years) and renal transplant recipients (8.9 per 1,000 person-years). In persons with Staphylococcus aureus bacteremia, ninety-day case fatality was 18.2% (95% CI, 16.2%-20.3%) for end-stage renal disease patients and 33.7% (95% CI, 30.3-37.3) for population controls.
Patients with end-stage renal disease, and hemodialysis patients in particular, have greatly increased risk of Staphylococcus aureus bacteremia compared to population controls. Future challenges will be to develop strategies to reduce Staphylococcus aureus bacteremia-related morbidity and death in this high-risk population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0740-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4296555  PMID: 25566857
Bacteremia; Staphylococcus aureus; End-stage renal disease; Dialysis
3.  In utero exposure to persistent organochlorine pollutants and reproductive health in the human male 
Reproduction (Cambridge, England)  2014;148(6):635-646.
Persistent organochlorine pollutants (POPs) are ubiquitous, bioaccumulative compounds with potential endocrine-disrupting effects. They cross the placental barrier thereby resulting in in utero exposure of the developing fetus. The objective of this study was to investigate whether maternal serum concentrations of polychlorinated biphenyls (PCBs) and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) during pregnancy are associated with son's semen quality and reproductive hormone levels. During 2008–2009, we recruited 176 male offspring from a Danish cohort of pregnant women who participated in a study in 1988–1989. Each provided semen and blood samples that were analyzed for sperm concentration, total sperm count, motility, and morphology, and reproductive hormone levels, respectively. The maternal blood samples were collected in pregnancy week 30 and were analyzed for the concentrations of six PCBs (PCB-118, -138, -153, -156, -170, and -180) and p,p′-DDE. The potential associations between in utero exposure to ΣPCBs (pmol/ml), Σdioxin like-(DL) PCBs (PCB-118 and -156) (pmol/ml), and p,p′-DDE and semen quality and reproductive hormone levels were investigated using multiple regression. Maternal median (range) exposure levels of ΣPCB, ΣDL-PCB, and p,p′-DDE were 10.0 (2.1–35.0) pmol/ml, 0.8 (0.2–2.7) pmol/ml, and 8.0 (0.7–55.3) pmol/ml, respectively, reflecting typical background exposure levels in the late 1980s in Denmark. Results suggested that in utero exposure to ΣPCB, ΣDL-PCB, and p,p′-DDE was not statistically significantly associated with semen quality measures or reproductive hormone levels. Thus, results based on maternal PCB and p,p′-DDE concentrations alone are not indicative of long-term consequences for male reproductive health; however, we cannot exclude that these POPs in concert with other endocrine-modulating compounds may have adverse effects.
PMCID: PMC4241711  PMID: 25190505
4.  Effectiveness of the population-based Check your health preventive programme conducted in primary care with 4 years follow-up [the CORE trial]: study protocol for a randomised controlled trial 
Trials  2014;15(1):341.
The periodic health check-up has been a fundamental part of routine medical practice for decades, despite a lack of consensus regarding its value in health promotion and disease prevention. A large-scale Danish population-based preventive programme ‘Check your health’ was developed based on available evidence of screening and successive accepted treatment, prevention for diseases and health promotion, and is closely aligned with the current health care system.
The objective of the ‘Check your health’ [CORE] trial is to investigate effectiveness on health outcomes of a preventive health check offered at a population-level to all individuals aged 30–49 years, and to establish the cost-effectiveness.
The trial will be conducted as a pragmatic household-cluster randomised controlled trial involving 10,505 individuals. All individuals within a well-defined geographical area in the Central Denmark Region, Denmark (DK) were randomised to be offered a preventive health check (Intervention group, n = 5250) or to maintain routine access to healthcare until a delayed intervention (Comparison group, n = 5255). The programme consists of a health examination which yields an individual risk profile, and according to this participants are assigned to one of the following interventions: (a) referral to a health promoting consultation in general practice, (b) behavioural programmes at the local Health Centre, or (c) no need for follow-up.
The primary outcomes at 4 years follow-up are: ten-year-risk of fatal cardiovascular event (Heart-SCORE model), physical activity level (self-report and cardiorespiratory fitness), quality of life (SF12), sick leave and labour market attachment. Cost-effectiveness will be evaluated according to life years gained, direct costs and total health costs. Intention to treat analysis will be performed.
Results from the largest Danish health check programme conducted within the current healthcare system, spanning the sectors which share responsibility for the individual, will provide a scientific basis to be used in the development of systems to optimise population health in the 21st century.
Trial registration
The trial has registered at with an ID: NCT02028195 (7. March 2014).
PMCID: PMC4158060  PMID: 25169211
5.  Maternal Pre-Pregnancy BMI and Intelligence Quotient (IQ) in 5-Year-Old Children: A Cohort Based Study 
PLoS ONE  2014;9(4):e94498.
An association between maternal pre-pregnancy BMI and childhood intelligence quotient (IQ) has repeatedly been found but it is unknown if this association is causal or due to confounding caused by genetic or social factors.
We used a cohort of 1,783 mothers and their 5-year-old children sampled from the Danish National Birth Cohort. The children participated between 2003 and 2008 in a neuropsychological assessment of cognitive ability including IQ tests taken by both the mother and the child. Linear regression analyses were used to estimate the associations between parental BMI and child IQ adjusted for a comprehensive set of potential confounders. Child IQ was assessed with the Wechsler Primary and Preschool Scales of Intelligence – Revised (WPPSI-R).
The crude association between maternal BMI and child IQ showed that BMI was adversely associated with child IQ with a reduction in IQ of −0.40 point for each one unit increase in BMI. This association was attenuated after adjustment for social factors and maternal IQ to a value of −0.27 (−0.50 to −0.03). After mutual adjustment for the father's BMI and all other factors except maternal IQ, the association between paternal BMI and child IQ yielded a regression coefficient of −0.26 (−0.59 to 0.07), which was comparable to that seen for maternal BMI (−0.20 (−0.44 to 0.04)).
Although maternal pre-pregnancy BMI was inversely associated with the IQ of her child, the similar association with paternal BMI suggests that it is not a specific pregnancy related adiposity effect.
PMCID: PMC3984139  PMID: 24727836
6.  Impact of effectiveness information format on patient choice of therapy and satisfaction with decisions about chronic disease medication: the "Influence of intervention Methodologies on Patient Choice of Therapy (IMPACT)" cluster-randomised trial in general practice 
Risk communication is an integral part of shared decision-making in health care. In the context of interventions for chronic diseases it represents a particular challenge for all health practitioners. By using two different quantitative formats to communicate risk level and effectiveness of a cholesterol-lowering drug, we posed the research question: how does the format of risk information influence patients’ decisions concerning therapy, patients’ satisfaction with the communication as well as confidence in the decision. We hypothesise that patients are less prone to accept therapy when the benefits of long-term intervention are presented in terms of prolongation of life (POL) in months compared to the absolute risk reduction (ARR). We hypothesise that patients presented with POL will be more satisfied with the communication and confident in their decision, suggesting understanding of the time-related term.
In 2009 a sample of 328 general practitioners (GPs) in the Region of Southern Denmark was invited to participate in a primary care-based clinical trial among patients making real-life clinical decisions together with their GP. Interested GPs were cluster-randomised to inform patients about cardiovascular disease (CVD) risk and the effectiveness of statin therapy using either POL or ARR. The GPs attended a training session before informing their patients. Before training and after the trial period they received a questionnaire about their attitudes to risk communication and the use of numerical information. Patients’ redemptions of statin prescriptions will be registered in a regional prescription database to evaluate a possible association between redemption rates and effectiveness format. The Combined Outcome Measure for Risk Communication And Treatment Decision Making Effectiveness (COMRADE) questionnaire will be used to measure patients’ confidence and satisfaction with the risk communication immediately after the conversation with their GPs.
This randomised clinical trial compares the impact of two effectiveness formats on real-life risk communication between patients and GPs, including affective patient outcomes and actual choices about acceptance of therapy. Though we found difficulties in recruiting GPs, according to the study protocol we have succeeded in engaging sufficient GPs for the trial, enabling us to perform the planned analyses.
Trial registration Protocol Registration System
PMCID: PMC3599428  PMID: 23442351
RCT; Shared decision making; Risk communication; Prognosis; Absolute risk reduction; Prolongation of life; Cardiovascular disease; Primary prevention; Health behaviour; General practice
7.  Associations between reporting of cancer alarm symptoms and socioeconomic and demographic determinants: a population-based, cross-sectional study 
BMC Public Health  2012;12:686.
Reporting of symptoms which may signal cancer is the first step in the diagnostic pathway of cancer diseases. Cancer alarm symptoms are common in the general population. Public awareness and knowledge of cancer symptoms are sparse, however, and many people do not seek medical help when having possible cancer symptoms. As social inequality is associated with cancer knowledge, cancer awareness, and information-seeking, our hypothesis is that social inequality may also exist in the general population with respect to reporting of cancer alarm symptoms. The aim of this study was to investigate possible associations between socioeconomic and demographic determinants and reporting of common cancer alarm symptoms.
A cross-sectional questionnaire survey was performed based on a stratified sample of the Danish general population. A total of 13 777 randomly selected persons aged 20 years and older participated. Our main outcome measures were weighted prevalence estimates of self-reporting one of the following cancer alarm symptoms during the preceding 12 months: a lump in the breast, coughing for more than 6 weeks, seen blood in urine, or seen blood in stool. Logistic regression models were used to calculate unadjusted and adjusted odds ratios with 95% confidence intervals for the associations between each covariate and reporting of cancer alarm symptoms.
A total of 2 098 (15.7%) of the participants reported one or more cancer alarm symptoms within the preceding 12 months.
Women, subjects out of the workforce, and subjects with a cancer diagnosis had statistically significantly higher odds of reporting one or more cancer alarm symptoms. Subjects with older age and subjects living with a partner had lower odds of reporting one or more cancer alarm symptoms. When analysing the four alarm symptoms of cancer separately most tendencies persisted.
Socioeconomic and demographic determinants are associated with self-reporting of common cancer alarm symptoms.
PMCID: PMC3560107  PMID: 22914003
Breast cancer; Colorectal cancer; Cross-sectional survey; Lung cancer; Socioeconomic factors; Signs and symptoms; Urinary tract cancer
8.  Medication effectiveness may not be the major reason for accepting cardiovascular preventive medication: A population-based survey 
Shared decision-making and patients’ choice of interventions are areas of increasing importance, not least seen in the light of the fact that chronic conditions are increasing, interventions considered important for public health, and still non-acceptance of especially risk-reducing treatments of cardiovascular diseases (CVD) is prevalent. A better understanding of patients’ medication-taking behavior is needed and may be reached by studying the reasons why people accept or decline medication recommendations. The aim of this paper was to identify factors that may influence people’s decisions and reasoning for accepting or declining a cardiovascular preventive medication offer.
From a random sample of 4,000 people aged 40–59 years in a Danish population, 1,169 participants were asked to imagine being at increased risk of cardiovascular disease and being offered a preventive medication. After receiving ‘complete’ information about effectiveness of the medication they were asked whether they would accept medication. Finally, they were asked about reasons for the decision.
A total of 725 (67%) of 1,082 participants accepted the medication offer. Even quite large effects of medication (up to 8 percentage points absolute risk reduction) had a smaller impact on acceptance to medication than personal experience with cardiovascular disease. Furthermore, increasing age of the participant and living with a partner were significantly associated with acceptance. Some 45% of the respondents accepting justified their choice as being for health reasons, and they were more likely to be women, live alone, have higher income and higher education levels. Among those who did not accept the medication offer, 56% indicated that they would rather prefer to change lifestyle.
Medication effectiveness seems to have a moderate influence on people’s decisions to accept preventive medication, while factors such as personal experience with cardiovascular disease may have an equally strong or stronger influence, indicating that practitioners could do well to carefully identify the reasons for their patients’ treatment decisions.
PMCID: PMC3465182  PMID: 22873796
Decision-making; Risk assessment; Risk communication; Preventive health services; Primary prevention; Cardiovascular disease; Health behavior
9.  Therapeutic decisions by number needed to treat and survival gains: a cross-sectional survey of lipid-lowering drug recommendations 
The British Journal of General Practice  2011;61(589):e477-e483.
Previous studies suggest that lay people have difficulties with evaluating effect size in terms of number needed to treat (NNT), but theyare sensitive to effect size in terms of survival gains.
To explore whether GPs and internists are sensitive to NNT and survival gains when considering a lipid-lowering drug therapy.
Design and setting
Cross-sectional survey of primary prevention of cardiovascular disease with random allocation to different scenarios.
GPs (n = 450) and internists (n = 450) were posted a vignette presenting a high-risk patient and a novel drug, ‘neostatin’. The benefit was described in terms of NNT or mean gain in disease-free survival. Each physician was randomly allocated to one version of the vignette. Outcome measures were evaluation of ‘neostatin’ on a Likert scale (0: very poor choice, 10: very good choice) and the proportion recommending ‘neostatin’.
A total of 477 responses (53%) were received. Among responders to NNT scenarios, 26%, 31%, and 43% recommended ‘neostatin’ for NNT values of 34, 17, and 9 respectively. With equivalent disease-free survival gains of 9, 17, and 32 months, 40%, 49%, and 52% respectively recommended the drug. On the rating scale, mean values were 4.7, 5.0, and 5.5 across the respective NNT scenarios and 5.2, 6.2, and 6.1 across the scenarios presenting survival gains. Differences in trends between the two formats were not statistically significant. In total, 33% recommended ‘neostatin’ when presented with NNT values, compared to 47% when presented with survival gain (χ2 = 9.2, P= 0.002).
Physicians presented with survival gains were more likely to recommend the therapy than those presented with NNT. Sensitivity to effect size was similarfor both effect formats.
PMCID: PMC3145531  PMID: 21801540
cardiovascular diseases; decision making; health communication; primary prevention
10.  Simple parametric survival analysis with anonymized register data: A cohort study with truncated and interval censored event and censoring times 
BMC Research Notes  2011;4:308.
To preserve patient anonymity, health register data may be provided as binned data only. Here we consider as example, how to estimate mean survival time after a diagnosis of metastatic colorectal cancer from Norwegian register data on time to death or censoring binned into 30 day intervals. All events occurring in the first three months (90 days) after diagnosis were removed to achieve comparability with a clinical trial. The aim of the paper is to develop and implement a simple, and yet flexible method for analyzing such interval censored and truncated data.
Considering interval censoring a missing data problem, we implement a simple multiple imputation strategy that allows flexible sensitivity analyses with respect to the shape of the censoring distribution. To allow identification of appropriate parametric models, a χ2-goodness-of-fit test--also imputation based--is derived and supplemented with diagnostic plots. Uncertainty estimates for mean survival times are obtained via a simulation strategy. The validity and statistical efficiency of the proposed method for varying interval lengths is investigated in a simulation study and compared with simpler alternatives.
Mean survival times estimated from the register data ranged from 1.2 (SE = 0.09) to 3.2 (0.31) years depending on period of diagnosis and choice of parametric model. The shape of the censoring distribution within intervals did generally not influence results, whereas the choice of parametric model did, even when different models fit the data equally well. In simulation studies both simple midpoint imputation and multiple imputation yielded nearly unbiased analyses (relative biases of -0.6% to 9.4%) and confidence intervals with near-nominal coverage probabilities (93.4% to 95.7%) for censoring intervals shorter than six months. For 12 month censoring intervals, multiple imputation provided better protection against bias, and coverage probabilities closer to nominal values than simple midpoint imputation.
Binning of event and censoring times should be considered a viable strategy for anonymizing register data on survival times, as they may be readily analyzed with methods based on multiple imputation.
PMCID: PMC3748025  PMID: 21867515
11.  Endotoxemia Is Associated with Altered Innate and Adaptive Immune Responses in Untreated HIV-1 Infected Individuals 
PLoS ONE  2011;6(6):e21275.
Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV.
Methodology/Principal Findings
This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies) and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10) with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC) from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA) were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART), 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals.
LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our results suggest that microbial translocation may be associated with innate and adaptive immune dysfunction in untreated HIV infection.
PMCID: PMC3123300  PMID: 21731690
12.  Prevalence of cancer alarm symptoms: A population-based cross-sectional study 
To estimate the prevalence of alarm symptoms for breast, colorectal, urinary tract, and lung cancer in the general population.
Cross-sectional questionnaire survey.
The former County of Funen, Denmark, with 480 000 inhabitants.
A total of 13 777 randomly selected persons aged 20 years and older.
Main outcome measures
Prevalence estimates of having experienced cancer alarm symptoms during the past 12 months: a lump in the breast, blood in bowel movements, blood in urine, or coughing for more than six weeks. The number of alarm symptoms experienced within the past 12 months was also calculated.
With a response rate of 69%, 3.3% of responders (95% CI 2.9% to 3.7%) reported a lump in their breast, 5.7% (5.2% to 6.3%) reported blood in bowel movements, 2.2% (1.9% to 2.5%) reported blood in urine, and 6.5% (6.1% to 7.5%) reported coughing for more than six weeks within the past 12 months. Overall, 15.3% (95% confidence interval 14.3% to 16.3%) of the females and 12.7% (11.6% to 13.7%) of the males reported having experienced at least one cancer alarm symptom within the past 12 months.
Alarm symptoms of breast, colorectal, urinary tract, and lung cancer are common in the general population and approximately 15% of the population have experienced at least one of these cancer alarm symptom within the past 12 months.
PMCID: PMC3442327  PMID: 20698729
Breast cancer; colorectal cancer; cross-sectional survey; health surveys; lung cancer; signs and symptoms; urinary tract cancer
13.  Use of a Prescribed Ephedrine/Caffeine Combination and the Risk of Serious Cardiovascular Events: A Registry-based Case-Crossover Study 
American Journal of Epidemiology  2008;168(8):966-973.
Ephedrine and herbal ephedra preparations have been shown to induce a small-to-moderate weight loss. Owing to reports on serious cardiovascular events, they were banned from the US market in 2004. There have been no large controlled studies on the possible association between prescribed ephedrine/caffeine and cardiovascular events in general. The authors linked data from four different sources within Statistics Denmark, using data on 257,364 users of prescribed ephedrine/caffeine for the period 1995–2002. The data were analyzed using a case-crossover technique with a composite endpoint: death outside of a hospital, myocardial infarction, or stroke. To account for effects of chronic exposure and effects in naïve users, the authors performed a secondary case-control study nested within the cohort of ephedrine/caffeine ever users. Among 2,316 case subjects, 282 (12.2%) were current users of ephedrine/caffeine. The case-crossover analysis yielded an odds ratio of 0.84 (95% confidence interval: 0.71, 1.00); after adjustment for trends in ephedrine/caffeine use, it was 0.95 (95% confidence interval: 0.79, 1.16). Subgroup analyses revealed no strata with significantly elevated risk. In the case-control substudy, there was no increased risk among naïve users or users with large cumulative doses. Prescribed ephedrine/caffeine was not associated with a substantially increased risk of adverse cardiovascular outcomes in this study.
PMCID: PMC2565736  PMID: 18756018
Ephedra sinica; ephedrine; mortality; myocardial infarction; stroke
14.  A new approach of nonparametric estimation of incidence and lifetime risk based on birth rates and incident events 
Incidence and lifetime risk of diabetes are important public health measures. Traditionally, nonparametric estimates are obtained from survey data by means of a Nelson-Aalen estimator which requires data information on both incident events and risk sets from the entire cohort. Such data information is rarely available in real studies.
We compare two different approaches for obtaining nonparametric estimates of age-specific incidence and lifetime risk with emphasis on required assumptions. The first and novel approach only considers incident cases occurring within a fixed time window–we have termed this cohort-of-cases data–which is linked explicitly to the birth process in the past. The second approach is the usual Nelson-Aalen estimate which requires knowledge on observed time at risk for the entire cohort and their incident events. Both approaches are used on data on anti-diabetic medications obtained from Odense Pharmacoepidemiological Database, which covers a population of approximately 470,000 over the period 1993–2003. For both methods we investigate if and how incidence rates can be projected.
Both the new and standard method yield similar sigmoidal shaped estimates of the cumulative distribution function of age-specific incidence. The Nelson-Aalen estimator gives somewhat higher estimates of lifetime risk (15.65% (15.14%; 16.16%) for females, and 17.91% (17.38%; 18.44%) for males) than the estimate based on cohort-of-cases data (13.77% (13.74%; 13.81%) for females, 15.61% (15.58%; 15.65%) for males). Accordingly the projected incidence rates are higher based on the Nelson-Aalen estimate–also too high when compared to observed rates. In contrast, the cohort-of-cases approach gives projections that fit observed rates better.
The developed methodology for analysis of cohort-of-cases data has potential to become a cost-effective alternative to a traditional survey based study of incidence. To allow more general use of the methodology, more research is needed on how to relax stationarity assumptions.
PMCID: PMC2265722  PMID: 18096045
15.  Counting drugs to understand the disease: The case of measuring the diabetes epidemic 
Diabetes prevalence increases globally with severe consequences for afflicted individuals and societies. Data on diabetes incidence and diabetes related mortality on a population level are, however, scarce. As an alternative to dedicated studies it has been suggested to use pharmacoepidemiological databases that are readily available, at least in the Nordic countries.
For all 470,000 inhabitants in Funen County, Denmark, in the period 1992–2003, data on gender, date of birth, death and migration to and from the county, and any filled prescriptions of an anti-diabetic medication was obtained from the Odense Pharmaco-Epidemiological Database.
Prevalence odds for use of an anti-diabetic medication rose annually 3.5% (95% confidence interval: 3.1%, 3.9%) for females, 4.5% (4.0%, 4.9%) for males. Corresponding incidence rates annually rose 4.8% (3.8%, 5.8%) for females, 4.5% (3.5%, 5.4%) for males. Mortality rates among treated annually declined 2.8% (1.4%, 4.1%) among females, 2.2% (0.9%, 3.5%) among males. The disequilibrium in absolute numbers between incidence and mortality among treated was the main driver for the increasing prevalence, while concurrent trends in incidence and diabetes related mortality only marginally affected prevalence trends. Trend estimates were insensitive to varying the length of the run-in period used for determining treatment status, except when using the naive and methodologically flawed run-in period of variable length.
While pharmacoepidemiological databases provide a useful tool for monitoring pharmacologically treated diabetes, a dedicated diabetes database covering all prevalents and incidents is needed for a more detailed analysis of underlying causes and trends.
PMCID: PMC1805738  PMID: 17313683
16.  Population-based study of place of death of patients with cancer: implications for GPs 
A majority of patients with cancer who are seriously ill have a preference of dying at home. However, only a minority of patients actually die at home in most Western countries.
To explore factors associated with place of death in an unselected population of patients with cancer.
Design of study
Case-control study.
County of Funen, Denmark.
Register linkage from six Danish healthcare registers.
The GP's home visit during the last 3 months before death was inversely associated with dying in hospital (adjusted odds ratio [OR] = 0.08, 95% confidence interval [CI] = 0.06 to 0.12) and so were community nurses visiting the home (OR = 0.36, 95% CI = 0.26 to 0.48). Furthermore, being married (OR = 0.68, 95% CI = 0.56 to 0.85), and age at death of 40–65 years (OR = 0.70, 95% CI = 0.56 to 0.90) seemed to have an effect. Hospital death was associated with survival time of less than 1 month (OR = 2.27, 95% CI = 1.69 to 3.13). Type of cancer, sex, or residence (urban versus rural) were not associated with a hospital death in this multivariate analysis.
Dying at home was, to a higher extent, associated with GP visit and, to a lesser extent, community nurse visit than with clinical and sociodemographic characteristics of patients with cancer. In our view, these findings indicate the importance of the GP in particular. To increase the opportunity to die at home, more research is needed on the role of the GP and the interface between GPs and other providers of health care at home for patients who are terminally ill with cancer.
PMCID: PMC1464074  PMID: 16176735
family practice; health services research; neoplasm; palliative care; place of death
17.  Use of population based background rates of disease to assess vaccine safety in childhood and mass immunisation in Denmark: nationwide population based cohort study 
Objectives To predict the number of selected outcomes temporally associated but not caused by vaccination, to aid causality assessment of adverse events arising after mass immunisation in a paediatric population.
Design Nationwide population based cohort study.
Setting Denmark.
Participants All liveborn infants delivered after 1 January 1980. Study population was followed from date of birth until hospital admission for selected outcome diagnoses, death, first emigration, age 18 years, or 31 December 2009. The study population was subject to vaccines used in standard childhood immunisation in Denmark, with 82-93% vaccine coverage.
Main outcome measures Incidence of acute infectious and post-infectious polyneuritis (Guillain-Barré syndrome), acute transverse myelitis, optic polyneuritis, facial nerve palsy, anaphylactic shock, seizure, multiple sclerosis, autoimmune thrombocytopenia, type 1 diabetes mellitus, juvenile and rheumatoid arthritis, narcolepsy, and death of unknown cause stratified by sex, age, and season. We predicted the number of events for a hypothetical vaccine cohort of 1 000 000 people for follow-up periods of up to 182 days.
Results The study included 2 300 227 liveborn infants, yielding 37 262 404 person years of follow-up; median follow-up was 16.8 person years. Incidence of outcome diagnoses spanned from 0.32 per 100 000 patient years for autoimmune thrombocytopenia to 189.82 per 100 000 patient years for seizure. Seasonal differences were most pronounced for anaphylactic shock, seizure, and multiple sclerosis. Even for rare outcomes, numerous events were predicted in the hypothetical vaccine cohort. We predicted that 20 cases of type 1 diabetes mellitus, 19 of juvenile or rheumatoid arthritis, eight of facial nerve palsy, and five of multiple sclerosis per 1 000 000 children would occur within 42 days after vaccination.
Conclusions Incorporating exact background rates of disease based on age, sex, and seasonal distribution could strengthen vaccine safety assessment, and provides an evidence based focus for discussing the incremental risk of newly introduced vaccines.
PMCID: PMC3444137  PMID: 22988304

Results 1-17 (17)