Search

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications. Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio-and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Context Impact of lost GLP-1 receptor function in human physiology. Objective Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. Methods We sequenced GLP1R in 8,642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cAMP formation and beta-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signalling (LoS) variants and cardiometabolic phenotypes in 2,930 patients with type 2 diabetes and 5,712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330,566 unrelated Caucasian exome-sequenced participants in the UK Biobank cohort. Results We identified 36 nonsynonymous variants in GLP1R of which 10 had a statistically significant loss in GLP-1-induced cAMP signalling compared to wildtype. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on HbA1c. Conclusion Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as non-carriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

Pulmonary embolism is a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prognostic impact of CTEPH on venous thromboembolism (VTE) mortality remains unclear. We examined the impact of CTEPH and other pulmonary hypertension (PH) subtypes on long-term mortality after VTE. We conducted a nationwide, population-based cohort study of all adult Danish patients alive 2 years after incident VTE without previous PH from 1995 to 2020 (n = 129,040). We used inverse probability of treatment weights in a Cox model to calculate standardized mortality rate ratios (SMRs) of the association between receiving a first-time PH diagnosis ≤2 years after incident VTE and mortality (all-cause, cardiovascular, and cancer). We grouped PH as PH associated with left-sided cardiac disease (group II), PH associated with lung diseases and/or hypoxia (group III), CTEPH (group IV), and unclassified (remaining patients). Total follow-up was 858,954 years. The SMR associated with PH overall was 1.99 (95% confidence interval 1.75 to 2.27) for all-cause, 2.48 (1.90 to 3.23) for cardiovascular, and 0.84 (0.60 to 1.17) for cancer mortality. The SMR for all-cause mortality was 2.62 (1.77 to 3.88) for group II, 3.98 (2.85 to 5.56) for group III, 1.88 (1.11 to 3.20) for group IV, and 1.73 (1.47 to 2.04) for unclassified PH. The cardiovascular mortality rate was increased approximately threefold for groups II and III but was not increased for group IV. Only group III was associated with increased cancer mortality. In conclusion, PH diagnosed ≤2 years after incident VTE was associated with an overall twofold increased long-term mortality driven by cardiovascular causes.

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8–95.4) in Brazil to 315.9 (95% CI 314.0–317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population.

PURPOSE: Refugees are vulnerable to psychiatric disorders because of risk factors linked to migration. Limited evidence exist on the impact of the neighbourhood in which refugee resettle. We examined whether resettling in a socioeconomically disadvantaged neighbourhood increased refugees' risk of psychiatric disorders.METHODS: This register-based cohort study included 42,067 adults aged 18 years and older who came to Denmark as refugees during 1986-1998. Resettlement policies in those years assigned refugees in a quasi-random fashion to neighbourhoods across the country. A neighbourhood disadvantage index was constructed using neighbourhood-level data on income, education, unemployment, and welfare receipt. Main outcomes were psychiatric diagnoses and psychiatric medication usage ascertained from nationwide patient and prescription drug registers, with up to 30-year follow-up. Associations of neighbourhood disadvantage with post-migration risk of psychiatric disorders were examined using Cox proportional hazards and linear probability models adjusted for individual, family, and municipality characteristics.RESULTS: The cumulative risk of psychiatric diagnoses and medication was 13.7% and 46.1%, respectively. Refugees' risk of psychiatric diagnoses and psychiatric medication usage was higher among individuals assigned to high-disadvantage compared with low-disadvantage neighbourhoods in analyses including fixed effects for assigned municipality (psychiatric diagnoses: hazard ratio (HR) = 1.14, 95% CI 1.04, 1.25; psychiatric medication: HR = 1.05, 95% CI 1.00, 1.11). Consistent results were found using linear probability models. Results for diagnostic categories and subclasses of medications suggested that the associations were driven by neurotic and stress-related disorders and use of anxiolytic medications.CONCLUSION: Resettlement in highly disadvantaged neighbourhoods was associated with an increase in refugees' risk of psychiatric disorders, suggesting that targeted placement of newly arrived refugees could benefit refugee mental health. The results contribute quasi-experimental evidence to support links between neighbourhood characteristics and health.

Purpose Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. Methods We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. Results Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98). Conclusion Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Background: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality.Methods: Our cohort included all premenopausal women aged 18-55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007-2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate or high), income (low, medium or high), and employment status (employed, unemployed or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs) and used Poisson regression to compute incidence rate ratios and 95% confidence intervals (95% CIs) of recurrence and death. We stratified on ER status/tamoxifen to evaluate interaction.Results: Our cohort included 2,616 women; 286 (CIP: 13%) experienced recurrence and 223 (CIP: 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased risks of recurrence (IRR: 1.45, 95% CI: 1.11-1.89) and mortality (IRR: 1.83, 95% CI: 1.32-2.52). Furthermore, we observed increased mortality in women with low education (IRR: 1.49, 95% CI: 0.95-2.33), low income (IRR: 1.37, 95% CI: 0.83-2.28), unemployment (IRR: 1.61, 95% CI: 0.83-3.13) or health-related work absenteeism (IRR: 1.80, 95% CI: 1.14-2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen.Conclusions: Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence. Citation Format: Cathrine Hjorth, Per Damkier, Bent Ejlertsen, Timothy L Lash, Henrik T Sørensen, Deirdre Cronin-Fenton. Socioeconomic position and prognosis in premenopausal breast cancer: A population-based cohort study in Denmark [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-22.

Background: Faecal immunochemical tests (FITs) yield many false positives and challenge colonoscopy capacity in colorectal cancer (CRC) screening programmes. We aimed to develop a risk-based selection of participants to undergo diagnostic colonoscopy. Methods: The study was observational and used registry data from the Danish CRC screening programme. We included all participants invited 2014–2016 with a positive FIT (≥ 20 μg fHb/g) who underwent colonoscopy (n = 56,459). We predicted the risk of CRC or advanced neoplasia (AN) from age, gender and FIT value using logistic regression. We evaluated calibration and discrimination and conducted temporal validation. We compared the number of CRCs and adenomas identified by risk cut-offs and by a corresponding FIT cut-off. Results: AUCs were 74.9% (95% CI: 73.6; 76.3) and 67.4% (95% CI: 66.8%; 68.0%) for the models predicting CRC and AN in the validation dataset. The cut-off of CRC risk calculated from age, gender and FIT value identified 1.03 times (95% CI: 1.02; 1.05) more CRCs and 1.01 times (95% CI: 1.01; 1.01) more medium/high-risk adenomas compared with the corresponding FIT cut-off. Conclusions: With existing data, risk-stratified FIT screening using a risk cut-off instead of a FIT cut-off can slightly improve the selection to colonoscopy of those at highest risk of cancer and adenomas.

PDF - 51KB, Shows diagnosis and procedure codes used in the Danish health registries.

PDF - 64KB, Supplementary table showing results for stroke subtypes.

Background: An association between colorectal cancer and acute myocardial infarction (AMI) and stroke has been suggested, but evidence is conflicting.Method: We conducted a population-based cohort study (1978–2010) of the association between AMI/stroke and colorectal cancer by linking nationwide Danish registries. We calculated standardized incidence ratios (SIR) of colorectal cancer after AMI/stroke as the ratios of observed to expected incidence.Results: A total of 297,523 patients with AMI (median age, 69.4 years; 64% men) were followed for a median of 3.1 years (range, 0–33 years) and 4,387 developed colorectal cancer [SIR, 1.08; 95% confidence interval (CI), 1.05–1.11; P < 0.001]. In the first year of follow-up, the SIR was 1.85 (95% CI, 1.73–1.98; P < 0.001), whereas it was 0.98 (95% CI, 0.95–1.02; P = 0.318) in the second and subsequent years. We followed 246,998 patients with stroke (median age, 72.4 years; 52% men) for a median of 2.9 years (range, 0–33 years) and 3,035 developed colorectal cancer (SIR, 1.04; 95% CI, 1.00–1.07; P = 0.053). In the first year of follow-up, the SIR was 1.42 (95% CI, 1.31–1.53; P < 0.001), whereas it was 0.96 (95% CI, 0.93–1.00; P = 0.072) thereafter. We found no difference between the SIRs for ischemic and hemorrhagic stroke. The increased one-year relative risks for AMI and stroke corresponded to a 0.3% absolute risk.Conclusions: Our findings reflect detection of occult cancer at the time of the vascular event. The lack of increased risk after one year suggests that an association based on shared risk factors or chronic inflammation is unlikely.Impact: In patients with AMI/stroke, the diagnostic workup including screening for colorectal cancer should follow that of the general population. Cancer Epidemiol Biomarkers Prev; 22(11); 1994–9. ©2013 AACR.

Supplemental Tables 1-3. Supplementary Table 1. Codes used to identify conditions of interest in the Danish study population. Supplementary Table 2. Tobacco-related cancers according to the International Agency for Research on Cancer (IARC).24 Supplementary Table 3. Standardized incidence ratios (SIRs) for selected cancers among patients (n=53,762) with intermittent claudication in Denmark from 1980-2011.

Background: Intermittent claudication, muscle ischemia due to reduced arterial circulation, may be associated with an increased risk of cancer risk and death due to neoplasm-induced hypercoagulability and angiogenesis, or to shared risk factors, but the relation is not well understood.Methods: We conducted a population-based cohort study using the Danish National Registry of Patients to identify patients with intermittent claudication from 1980 to 2011 and no history of cancer. We followed these patients for incident cancers using the Danish Cancer Registry and compared cancer incidence among patients with intermittent claudication to that expected in the general population. We also compared the survival of patients with cancer with and without claudication, matched for sex, cancer site, stage, age at diagnosis, and diagnosis year.Results: A total of 53,762 patients with intermittent claudication were identified. We observed 6,270 incident cancers over a total 269,430 years of follow-up (mean, 5.0), compared with 4,306 cancer cases expected [standardized incidence ratio = 1.46; 95% confidence interval (CI), 1.42–1.49]. Cancer risk also increased after the exclusion of patients with a prior diagnosis of cerebrovascular disease, myocardial infarction, or diabetes, particularly for tobacco-related cancers. The elevated cancer risk persisted over 10 years of follow-up. For patients with cancer, diagnosis of intermittent claudication within 3 months preceding the cancer diagnosis did not influence survival, but before 3 months, was associated with modestly worse survival (mortality rate ratio = 1.19; 95% CI, 1.14–1.25).Conclusions: Intermittent claudication is associated with an increased risk of cancer and poorer subsequent survival.Impact: Clinical attention following intermittent claudication diagnosis may reveal incident cancers. Cancer Epidemiol Biomarkers Prev; 24(4); 744–8. ©2015 AACR.

Objective: Adult overweight is associated with increased risk of diverticular disease (DD). We investigated associations between birthweight and childhood body mass index (BMI) and DD. Methods: Cohort study of 346,586 persons born during 1930–1996 with records in the Copenhagen School Health Records Register. Data included birthweight, and height and weight from ages 7 through 13. We used Cox proportional hazard regression to examine associations between birthweight and BMI z-scores and DD registered in the Danish National Patient Registry. Due to non-proportionality, we followed participants from age 18–49 and from age 50. Results: During follow-up, 5459 (3.2%) women and 4429 (2.5%) men had DD. For low and high BMI in childhood, we observed a higher risk of DD before age 50. Among women with z-scores

Purpose Breast cancer treatment is associated with adverse effects, which may delay return-to-work. Single nucleotide polymorphisms (SNPs) may influence the risk and severity of treatment toxicities, which in turn could delay return-to-work. We examined the association of 26 SNPs with return-to-work in premenopausal women with breast cancer. Methods Using Danish registries, we identified premenopausal women diagnosed with non-distant metastatic breast cancer during 2007‒2011, assigned adjuvant combination chemotherapy including cyclophosphamide and docetaxel. We genotyped 26 SNPs in 20 genes (ABCB1, ABCC2, ABCG2, CYP1A1, CYP1B1, CYP3A, CYP3A4, CYP3A5, GSTP1, SLCO1B1, SLCO1B3, ARHGEF10, EPHA4, EPHA5, EPHA6, EPHA8, ERCC1, ERCC2, FGD4 and TRPV1) using TaqMan assays. We computed the cumulative incidence of return-to-work (defined as 4 consecutive weeks of work) up to 10 years after surgery, treating death and retirement as competing events and fitted cause-specific Cox regression models to estimate crude hazard ratios (HRs) and 95% confidence intervals (CIs) of return-to-work. We also examined stable labor market attachment (defined as 12 consecutive weeks of work). Results We included 1,964 women. No associations were found for 25 SNPs. The cumulative incidence of return-to-work varied by CYP3A5 rs776746 genotype. From 6 months to 10 years after surgery, return-to-work increased from 25 to 94% in wildtypes (n = 1600), from 17 to 94% in heterozygotes (n = 249), and from 7 to 82% in homozygotes (n = 15). The HR showed delayed return-to-work in CYP3A5 rs776746 homozygotes throughout follow-up (0.48, 95% CI 0.26, 0.86), compared with wildtypes. Estimates were similar for stable labor market attachment. Conclusion Overall, the SNPs examined in the study did not influence return-to-work or stable labor market attachment after breast cancer in premenopausal women. Our findings did suggest that the outcomes were delayed in homozygote carriers of CYP3A5 rs776746, though the number of homozygotes was low.

Background: Little is known about potential health effects of eating organic food in relation to reproduction. Objective: We examined associations between organic food consumption and fecundability. Methods: Data were derived from a preconception cohort study of Danish couples trying to conceive (SnartForældre.dk, SF). Participants completed a baseline questionnaire on socio-demographics, anthropometrics and lifestyle and a validated food-frequency questionnaire, which included questions on proportions of organic food consumed within six food groups. Participants were followed up with bimonthly questionnaires for up to 12 months or until pregnancy. Analyses were restricted to 2061 participants attempting pregnancy for ≤6 cycles at enrollment and 1303 with

AimsRare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants.MethodsThis is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years.ResultsTwenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up.ConclusionsApproximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients. Aims: Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants. Methods: This is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years. Results: Twenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up. Conclusions: Approximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients.

Background: Few studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands. Methods: In this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed. Findings: We included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4–7·1) in Denmark and 4·3 months (0·7–7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6–5·8%) in Denmark and 5·9% (4·7–7·0) in the Netherlands, compared with 0·0% (p

Background: Psychological stress is prevalent among reproductive-aged men. Assessment of semen quality for epidemiological studies is challenging as data collection is expensive and cumbersome, and studies evaluating the effect of perceived stress on semen quality are inconsistent. Objective: To examine the association between perceived stress and semen quality. Material and methods: We analyzed baseline data on 644 men (1,159 semen samples) from two prospective preconception cohort studies during 2015–2021: 592 in Pregnancy Study Online (PRESTO) and 52 in SnartForaeldre.dk (SF). At study entry, men aged ≥21 years (PRESTO) and ≥18 years (SF) trying to conceive without fertility treatment completed a questionnaire on reproductive and medical history, socio-demographics, lifestyle, and the 10-item version of the Perceived Stress Scale (PSS; interquartile range [IQR] of scores: 0–40). After enrollment (median weeks: 2.1, IQR: 1.3–3.7), men were invited to perform in-home semen testing, twice with 7–10 days between tests, using the Trak Male Fertility Testing System. Semen quality was characterized by semen volume, sperm concentration, and total sperm count. We fit generalized estimating equation linear regression models to estimate the percent difference in mean log-transformed semen parameters by four PSS groups (

Introduction: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. Methods: We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015–2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. Results: The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). Conclusions: In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. Registration: The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) (http://www.encepp.eu/encepp/viewResource.htm?id=37726, first protocol registration 4 June 2019), and on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03993132, first posted 20 June 2019).

OBJECTIVE We examined temporal trends in risk of first-time ischemic stroke in patients with incident type 2 diabetes mellitus (T2DM) and no prior atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS Using nationwide health registries, we identified all patients with incident T2DM without a prior hospital diagnosis of ASCVD from 1996 to 2015 in Denmark. Patients were assigned to 5-year periods based on the date of T2DM diagnosis and were followed for 5 years. Each patient was matched by sex and age with up to three individuals from the general population. Temporal trends in ischemic stroke were examined using Cox regression to compute hazard ratios (HRs). Temporal use of prophylactic cardiovascular medications was also assessed. RESULTS The study comprised 288,825 patients with incident T2DM and 782,232 general population individuals. From 1996–2000 to 2011–2015, the 5-year risk of first-time ischemic stroke was approximately halved in the T2DM cohort (5.2% vs. 2.7%; sex- and age-adjusted HR 0.52 [95% CI 0.49–0.55]). Patients diagnosed in 2011–2015 had increased risk of ischemic stroke compared with individuals in the general population; however, the risk difference narrowed over time (5.2% vs. 2.9% in 1996–1999 [difference 2.3%]; 2.7% vs. 2.0% in 2011–2015 [difference 0.7%]). Use of prophylactic cardiovascular medications increased markedly during the overall study period, especially use of statins (from 5% to 50%) and multiple antihypertensive drugs (from 18% to 33%). CONCLUSIONS From 1996 to 2015, the 5-year risk of first-time ischemic stroke was approximately halved in patients with incident T2DM and no prior ASCVD, coinciding with markedly increased use of prophylactic cardiovascular medications.

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100–455 000) early-onset and 162 200 (70 200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500–125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600–96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500–66 200) maternal iGBS cases and 46 200 (20 300–111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. Funding: Bill & Melinda Gates Foundation.

IntroductionPre-diabetes increases the risk of type 2 diabetes, but data are sparse on predictors in a population-based clinical setting. We aimed to develop and validate prediction models for 5-year risks of progressing to type 2 diabetes among individuals with incident HbA1c-defined pre-diabetes.Research design and methodsIn this population-based cohort study, we used data from the Danish National Health Survey (DNHS; n=486 495), linked to healthcare registries and nationwide laboratory data in 2012–2018. We included individuals with a first HbA1c value of 42–47 mmol/mol (6.0%–6.4%), without prior indications of diabetes. To estimate individual 5-year cumulative incidences of type 2 diabetes (HbA1c ≥48 mmol/mol (6.5%)), Fine-Gray survival models were fitted in random 80% development samples and validated in 20% validation samples. Potential predictors were HbA1c, demographics, prescriptions, comorbidities, socioeconomic factors, and self-rated lifestyle.ResultsAmong 335 297 (68.9%) participants in DNHS with HbA1c measurements, 26 007 had pre-diabetes and were included in the study. Median HbA1c was 43.0 mmol/mol (IQR 42.0–44.0 mmol/mol, 6.1% (IQR 6.0%–6.2%)), median age was 69.6 years (IQR 61.0–77.1 years), and 51.9% were women. During a median follow-up of 2.7 years, 11.8% progressed to type 2 diabetes and 10.1% died. The final prediction model included HbA1c, age, sex, body mass index (BMI), any antihypertensive drug use, pancreatic disease, cancer, self-reported diet, doctor’s advice to lose weight or change dietary habits, having someone to talk to, and self-rated health. In the validation sample, the 5-year area under the curve was 72.7 (95% CI 71.2 to 74.3), and the model was well calibrated.ConclusionsIn addition to well-known pre-diabetes predictors such as age, sex, and BMI, we found that measures of self-rated lifestyle, health, and social support are important and modifiable predictors for diabetes. Our model had an acceptable discriminative ability and was well calibrated.

Purpose: Clinical trials have demonstrated efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing risk of cardiovascular disease events, but effectiveness in routine clinical care has not been well-studied. We used negative control outcomes to assess potential confounding in an observational study of PCSK9i versus ezetimibe or high-intensity statin. Methods: Using commercial claims, we identified U.S. adults initiating PCSK9i, ezetimibe, or high-intensity statin in 2015–2018, with other lipid-lowering therapy (LLT) use in the year prior (LLT cohort) or atherosclerotic cardiovascular disease (ASCVD) in the past 90 days (ASCVD cohort). We compared initiators of PCSK9i to ezetimibe and high-intensity statin by estimating one-year risks of negative control outcomes influenced by frailty or health-seeking behaviors. Inverse probability of treatment and censoring weighted estimators of risk differences (RDs) were used to evaluate residual confounding after controlling for covariates. Results: PCSK9i initiators had lower one-year risks of negative control outcomes associated with frailty, such as decubitus ulcer in the ASCVD cohort (PCSK9i vs. high-intensity statin RD = −3.5%, 95% confidence interval (CI): −4.6%, −2.5%; PCSK9i vs. ezetimibe RD = −1.3%, 95% CI: −2.1%, −0.6%), with similar but attenuated associations in the LLT cohort. Lower risks of accidents and fractures were also observed for PCSK9i, varying by cohort. Risks were similar for outcomes associated with health-seeking behaviors, although trended higher for PCSK9i in the ASCVD cohort. Conclusions: Observed associations suggest lower frailty and potentially greater health-seeking behaviors among PCSK9i initiators, particularly those with a recent ASCVD diagnosis, with the potential to bias real-world analyses of treatment effectiveness.

Research on posttraumatic psychopathology has focused primarily on posttraumatic stress disorder (PTSD); other posttraumatic psychiatric diagnoses are less well documented. The present study aimed to (a) develop a methodology to derive a cohort of individuals who experienced potentially traumatic events (PTEs) from registry-based data and (b) examine the risk of psychopathology within 5 years of experiencing a PTE. Using data from Danish national registries, we created a cohort of individuals with no age restrictions (range: 0–108 years) who experienced at least one of eight possible PTEs between 1994 and 2016 (N = 1,406,637). We calculated the 5-year incidence of nine categories of ICD-10 psychiatric disorders among this cohort and examined standardized morbidity ratios (SMRs) comparing the incidence of psychopathology in this group to the incidence in a nontraumatic stressor cohort (i.e., nonsuicide death of a relative; n = 423,270). Stress disorders (2.5%), substance use disorders (4.1%), and depressive disorders (3.0%) were the most common diagnoses following PTEs. Overall, the SMRs for the associations between any PTE and psychopathology varied from 1.9, 95% CI [1.9, 2.0], for stress disorders to 5.2, 95% CI [5.1. 5.3], for personality disorders. All PTEs except pregnancy-related trauma were associated with all forms of psychopathology. Associations were consistent regardless of whether a stress disorder was present. Traumatic experiences have a broad impact on psychiatric health. The present findings demonstrate one approach to capturing trauma exposure in medical record registry data. Increased traumatic experience characterization across studies will help improve the field's understanding of posttraumatic psychopathology.

Background: Risk for nonfatal suicide attempts is heightened in the month after psychiatric hospitalization discharge. Investigations of factors associated with such attempts are limited. Methods: We conducted a case-subcohort study using data from Danish medical, administrative, and social registries to develop sex-specific risk models using two machine learning methods: classification trees and random forests. Cases included individuals who received a diagnostic code for a nonfatal suicide attempt within 30 days of discharge following a psychiatric hospitalization between January 1, 1995 and December 31, 2015 (n = 3166, 56.5% female). The comparison subcohort consisted of a 5% random sample of individuals living in Denmark (n = 24,559, 51.3% female) on January 1, 1995 who had a psychiatric hospitalization during the study period. Results: Histories of self-poisoning, substance-related disorders, and eating disorders were important predictors of nonfatal suicide attempt among women, with notable interactions observed between age, self-poisoning history, and other characteristics (e.g., medication use). Self-poisoning, substance-related disorders, and severe stress reactions were among the most important variables for men, with key interactions noted between self-poisoning history, age, major depressive disorder diagnosis, and prescription classes. Limitations: Findings are based on Danish administrative data, which may be subject to inaccuracies, missingness, etc. It is unclear whether results would generalize to other populations. Conclusions: Markers of behavioral dysregulation were important predictors of nonfatal suicide attempts in the 30 days after psychiatric hospitalization discharge for both sexes. Examining risk markers for nonfatal suicide attempt following discharge is important to enhance support for this vulnerable population.

Background A minority of persons who have traumatic experiences go on to develop post-traumatic stress disorder (PTSD), leading to interest in who is at risk for psychopathology after these experiences. Complicating this effort is the observation that post-traumatic psychopathology is heterogeneous. The goal of this nested case-control study was to identify pre-trauma predictors of severe post-traumatic psychiatric comorbidity, using data from Danish registries. Methods The source population for this study was the population of Denmark from 1994 through 2016. Cases had received three or more psychiatric diagnoses (across all ICD-10 categories) within 5 years of a traumatic experience (n = 20 361); controls were sampled from the parent cohort using risk-set sampling (n = 81 444). Analyses were repeated in samples stratified by pre-trauma psychiatric diagnoses. We used machine learning methods (classification and regression trees and random forest) to determine the important predictors of severe post-trauma psychiatric comorbidity from among hundreds of pre-trauma predictor variables spanning demographic and social variables, psychiatric and somatic diagnoses and filled medication prescriptions. Results In the full sample, pre-trauma psychiatric diagnoses (e.g. stress disorders, alcohol-related disorders, personality disorders) were the most important predictors of severe post-trauma psychiatric comorbidity. Among persons with no pre-trauma psychiatric diagnoses, demographic and social variables (e.g. marital status), type of trauma, medications used primarily to treat psychiatric symptomatology, anti-inflammatory medications and gastrointestinal distress were important to prediction. Results among persons with pre-trauma psychiatric diagnoses were consistent with the overall sample. Conclusions This study builds on the understanding of pre-trauma factors that predict psychopathology following traumatic experiences, by examining a broad range of predictors of post-trauma psychopathology and comorbidity beyond PTSD.