European Journal of Epidemiology最新文献

{"title":"Revisiting the hazards of hazard ratios through simulations and case studies.","authors":"Michal Abrahamowicz,Marie-Eve Beauchamp,Emily K Roberts,Jeremy M G Taylor","doi":"10.1007/s10654-025-01245-6","DOIUrl":"https://doi.org/10.1007/s10654-025-01245-6","url":null,"abstract":"The hazard has been a central concept in the analysis and interpretation of time-to-event data for over 50 years. At any follow-up time, the hazard is the probability of the event happening in the next unit of time amongst those still at risk. Hazard ratios (HRs) between groups are frequently used to quantify the exposure/treatment's association with the failure time. In a highly cited paper, Hernán criticized HRs, asserting that their decreases over time may reflect simply a built-in selection bias, induced by an unmeasured susceptibility, and should not be interpreted as genuine changes in treatment effect. Hernán supports his arguments mainly by the results of a hormone therapy trial, where the HR for coronary heart events decreased largely during follow-up, with hazards crossing from harmful to protective treatment effect. However, he did not present simulations or algebraic derivations to demonstrate that these changes may reflect just an unmeasured susceptibility. We use simulations and real-world case studies to systematically explore this issue. The first simulation series reveals how the underestimation bias and changes over time in Cox proportional hazards model-based HRs depend on the joint impact of susceptibility on the hazard, its distribution, and the incidence of events; with important bias toward the null occurring only for a very strong susceptibility. Further simulations mimic the hormone therapy trial highlighted by Hernán, to demonstrate that the reported bias and crossing hazards are extremely unlikely to reflect just an unmeasured susceptibility, which suggests some biological reasons for decaying treatment HR, possibly including decreasing treatment adherence. Finally, we present real-world examples of interpretable and clinically plausible time-dependent HRs in cancer research. In conclusion, results of our simulations and real-world case studies suggest that concerns about HR limitations may be overstated, and we encourage researchers to model time-dependent HRs and consider potential biological and clinical causes thereof.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"51 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of systemic hormonal contraception and risk of depression: a registry-based study from Finland.","authors":"Elena Toffol,Timo Partonen,Oskari Heikinheimo,Anna But,Antti Latvala,Jari Haukka","doi":"10.1007/s10654-025-01267-0","DOIUrl":"https://doi.org/10.1007/s10654-025-01267-0","url":null,"abstract":"Earlier findings on the relationship between use of hormonal contraception (HC) and depressive symptoms and disorders are contradictory. Thus, we assessed the associations of use of different types of systemic hormonal contraceptives in the six preceding months with the risk of depression in women aged 15-49 years. Data were obtained from national registers in Finland. All cases of depression in the years 2018-2019 were identified in a population-based cohort of women. We used a nested case-control design with 1:4 ratio (n = 117,360 cases) and applied multivariable conditional logistic regression models. During the follow-up a total of 23,480 new cases with the diagnosis of depression were observed (incidence rate: 21.7, 95% confidence interval = 21.5-22.0 per 1000 person-years). Use of HC in the six preceding months, specifically that of combined hormonal contraceptives (containing gestodene and ethinylestradiol, drospirenone and ethinylestradiol, and nomegestrol and estradiol), was significantly associated with a lower risk of depression compared to non-use when controlling for marital status, socioeconomic status, education, recent delivery, recent psychiatric hospitalization, chronic diseases, use of psychiatric medications (excluding antidepressants) and former use of HC (odds ratio: 0.90, 95% confidence interval = 0.85-0.95; 0.86, 95% confidence interval = 0.81-0.91, respectively). Current use of progestogen-only preparations (norethisterone, levonorgestrel, desogestrel) was not associated with depression. This pattern was evident in all age groups, including adolescent girls. HC use appeared not associated with an increased risk of depression in fertile-aged women and across all age groups, including adolescent girls.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"26 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ingestion of titanium dioxide as an excipient in medicines and the risk of cancer: a nationwide study within the French National health data system.","authors":"Manon Cairat,Gianluca Severi,Inge Huybrechts,Agnès Fournier","doi":"10.1007/s10654-025-01263-4","DOIUrl":"https://doi.org/10.1007/s10654-025-01263-4","url":null,"abstract":"Concerns about the safety of titanium dioxide (TiO2), including potential carcinogenicity, have prompted its ban in foods in the European Union, while remaining allowed as pharmaceutical excipient. We aimed to evaluate whether ingesting increasing quantities of TiO2 through medicines is associated with higher cancer risk. Data were derived from the French National Health Data System, a nationwide medico-administrative database. A case-control study was nested within two cohorts: users of metformin (all doses) and users of 200 mg acebutolol, both available in TiO2-containing and TiO2-free formulations. During 2013-2021, 293,101 cancer cases were identified and matched to 2,930,633 controls. TiO2 exposure through metformin and acebutolol consumption was calculated based on drug claims from 2006 up to five years before the index date. Conditional logistic regression models estimated linear associations between TiO2 exposure and cancer risk. RRs of overall cancer per 1000 TiO2-containing tablets and per 10,000 mg of TiO2 increments were both 1.00 (95% CI: 0.99-1.01). Analyses by cancer site also yielded RRs very close to 1.00 or slightly different but not statistically significant, except for breast (RR per 10,000 mg: 1.03, 95% CI:1.00-1.07) and lymphoid/hematopoietic (RR per 1000 tablets: 0.97, 95% CI: 0.95-1.00) cancers, which however lost significance after Bonferroni correction. There was a suggestion of non-linear positive association for central nervous system cancers. This first epidemiological study on TiO2 ingestion and cancer found no meaningful linear association between increasing TiO2 exposure through medicines and overall or site-specific cancer risk. Non-linear associations cannot be excluded.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"2 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TransplantLines, a biobank and cohort study of solid organ transplant recipients and donors.","authors":"Anna M Posthumus,Tim J Knobbe,Daan Kremer,Antonio W Gomes-Neto,Isabelle J C Dielwart,Jip Jonker,Caecilia S E Doorenbos,Michele F Eisenga,Marco van Londen,Rianne M Douwes,Lianne M Nieuwenhuis,Coby Annema,Marieke T de Boer,Martin H de Borst,Kevin Damman,Robert A Pol,C Tji Gan,Erik A M Verschuuren,Hans Blokzijl,Vincent E de Meijer,Stephan J L Bakker,","doi":"10.1007/s10654-025-01258-1","DOIUrl":"https://doi.org/10.1007/s10654-025-01258-1","url":null,"abstract":"The TransplantLines Biobank and Cohort Study (NCT03272841) is an ongoing prospective study conducted at the University Medical Centre Groningen, The Netherlands. TransplantLines aims to identify risk factors and biomarkers associated with health problems following solid organ transplantation and donation. Additionally, the study seeks to develop new interventions to reduce symptom burden and improve long-term outcomes, including health-related quality of life, cardiovascular complications, graft failure, and mortality. It includes recipients of (combined) heart, liver, lung, kidney, pancreas, and small bowel transplants, as well as living liver and kidney donors, and deceased (multi-)organ donors. The biobank contains a wide range of biomaterials including whole blood, serum, EDTA-plasma, buffy coat, 24-h urine samples, faeces, hair, nails, and tissues. Data collection includes physical and cognitive assessments, extensive laboratory analysis, metagenomic sequencing, and questionnaires. TransplantLines, initiated in 2015, consists of 5143 participants as of October 2024, among 2312 (45%) females. The mean age was 50 (± 16) years at transplantation, 55 (± 11) years at living donation and 56 (± 15) years at deceased donation. Both cross-sectional and longitudinal biomaterials and data are included. For recipients, longitudinal biomaterials and data were collected at: pre-transplantation, at transplantation, and at 3, 6, 12, 24, and 60 months post-transplantation. For living donors, data were collected at pre-donation, donation, 3 months post-donation, and/or 5 or 10 years post-donation.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"41 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triangulation in biomedical research: navigating an ocean of uncertainty.","authors":"Frank J Wolters","doi":"10.1007/s10654-025-01265-2","DOIUrl":"https://doi.org/10.1007/s10654-025-01265-2","url":null,"abstract":"","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"11 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How hazard ratios can mislead and why it matters in practice.","authors":"Elise Dumas,Mats J Stensrud","doi":"10.1007/s10654-025-01250-9","DOIUrl":"https://doi.org/10.1007/s10654-025-01250-9","url":null,"abstract":"Hazard ratios are routinely reported as effect measures in clinical trials and observational studies. However, many methodological works have raised concerns about the interpretation of hazard ratios as causal effects. These concerns are often related to three points: (i) depletion of susceptible individuals leads to selection bias and complicates the causal interpretation of the hazard ratio, (ii) the hazard ratio is not collapsible, and (iii) the conventional proportional hazards assumption rarely holds in medical studies. We discuss the relation between these three points. We ground our presentation on an example about effect of endocrine therapy in reducing the risk of recurrence or death in a population of patients with breast cancer. We also describe why survival curves and risk differences do not exhibit any of the undesirable properties of hazard ratios.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"18 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of individuals who benefit from omega-3 fatty acid supplementation to prevent coronary heart disease: a machine-learning analysis of the VITAL.","authors":"Rikuta Hamaya,Nancy R Cook,Howard D Sesso,Samia Mora,Julie E Buring,JoAnn E Manson","doi":"10.1007/s10654-025-01259-0","DOIUrl":"https://doi.org/10.1007/s10654-025-01259-0","url":null,"abstract":"Randomized controlled trials (RCTs) have demonstrated benefits of marine omega-3 polyunsaturated fatty acids (omega-3 FA) supplementation for the prevention of coronary heart disease (CHD). However, it has not been clear which individuals benefit the most from supplementation. We sought to develop an omega-3 effect score to stratify individuals according to their expected benefit from supplementation. Among the 25,871 randomized participants without a history of cardiovascular disease in the VITamin D and OmegA-3 TriaL (VITAL), we applied machine-learning (ML) approaches to predict individual treatment effect of omega-3 FA supplementation on 5-year CHD risk using 11 covariates pre-specified in the VITAL protocol. An omega-3 effect score was developed such that each covariate contributed linearly. ML algorithms effectively stratified participants by their expected benefit according to individual factors; for example, there was 1.21% absolute CHD risk reduction in the top tertile of the expected benefit, compared with the average effect of 0.47% risk reduction. Baseline diabetes, race, hypertension, sex, and fish intake contributed the most to the omega-3 effect score. Five-year CHD risk was 2.5% among those in the omega-3 arm and 3.2% among those in the placebo arm with omega-3 effect score ≥ 4 (upper 70th percentile), and 1.4% among the omega-3 arm and 1.3% among the placebo arm in those with the score < 4, respectively. The transportability of the score to the National Health and Nutrition Examination Survey (NHANES) data was confirmed. Although testing of the score in a new RCT is warranted, the proposed omega-3 effect score holds promise for guiding decision making for omega-3 FA supplementation in the US primary prevention population.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"13 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Traditional and advanced electrocardiographic measures of autonomic function in the population-based KORA-F3 study.","authors":"Aenne S von Falkenhausen,Felix N Wenner,Luisa Freyer,Lauren E Sams,Margit Heier,Annette Peters,Birgit Linkohr,Steffen Massberg,Axel Bauer,Stefan Kääb,Konstantinos D Rizas,Moritz F Sinner","doi":"10.1007/s10654-025-01248-3","DOIUrl":"https://doi.org/10.1007/s10654-025-01248-3","url":null,"abstract":"AIMSHeart-rate variability (HRV) measures are surrogates of autonomic function at the level of the sinus node and have evolved as markers of cardiovascular mortality in patients after myocardial infarction (MI). Traditionally, HRV is assessed in time-domain and frequency domain. Advanced measures of autonomic function include deceleration capacity (DC) and periodic repolarization dynamics (PRD). DC predominantly quantifies the influence of parasympathetic tone. PRD captures low-frequency oscillations of repolarization instability and is considered to reflect sympathetic activity at the level of the left ventricular myocardium. However, population-based reference values are missing.METHODS AND RESULTSIn 505 participants of the population-based KORA F3 study (Cooperative Health Research in the Region of Augsburg) with extant digital 24-h Holter electrocardiograms we assessed markers of HRV in time and frequency domains. Additionally, we determined advanced measures of autonomic function including DC and PRD applying previously established technologies. We used standard, pre-defined cut-off values to define high-risk groups. The cohort's mean age was 63.6 ± 5.5 years, and 256 (50.1%) were women. Among HRV measures, exemplarily the median standard deviation of all normal-to-normal intervals (SDNN) was 141 ms [119;165] and the median low frequency to high frequency ratio (LF/HF-ratio) was 3.92 [2.69;6.18]. Regarding autonomic function, median DC was 5.32 ms [2.69;6.18], and median PRD was 2.92 ms [2.06;4.14]. Among these measures LF/HF-ratio was significantly higher among men (5.15 [3.23; 7.20]) than women (3.37 [2.36;4.53], p < 0.001). Measured distribution is also provided in a cohort subset without overt cardiovascular conditions. While DC decreased with age, SDNN, LF/HF-ratio, and PRD were stable across age-groups. For participants with comorbidities including hypertension, intake of betablockers, history of MI, stroke, or diabetes mellitus significantly lower SDNN, LF/HF-ratio, and DC were observed.CONCLUSIONIn a large population-based cohort, we systematically present traditional and advanced measures of HRV of cardiac autonomic function. We report reference values in the overall cohort, as well as stratified by sex, age, and concomitant cardiovascular conditions.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"1 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetal programming of early-onset type 2 diabetes: a Swedish nationwide cohort and sibling analysis.","authors":"Coralie Amadou,Yuxia Wei,Tiinamaija Tuomi,Maria Feychting,Sofia Carlsson","doi":"10.1007/s10654-025-01261-6","DOIUrl":"https://doi.org/10.1007/s10654-025-01261-6","url":null,"abstract":"Incidence of early-onset (< 40 years) type 2 diabetes (T2D) is increasing. While multiple risk factors have been identified, particularly obesity and low socioeconomic status, early-life factors are hypothesised to play a role via fetal programming. We investigated sociodemographic and early-life factors in relation to early-onset T2D using a family-based design that accounts for shared genetic and environmental factors. We included 1,814,062 individuals born in Sweden 1983 to 2002 with follow-up data until 2020, and identified early-onset (age 19-39) T2D cases (n = 3505) through National Diabetes, Patient and Prescribed Drug Registers. Perinatal and sociodemographic factors were retrieved from registers. We used a cohort and sibling design, with multivariable-adjusted Cox proportional hazards regression. Sociodemographic factors associated with early-onset T2D included low parental education, single parenthood, younger parental age and non-Swedish origin. The latter association did not remain after mutual adjustment. Regarding perinatal factors, a higher incidence was noted in relation to lower birth weight (hazard ratio 2.38 [95% confidence interval: 1.98-2.87] and 1.43[1.33-1.54] for < 2500 g and 2500-3500 g, respectively, vs 3500-4500 g), small-for-gestational-age (SGA) (2.24[1.96-2.56]), large-for-gestational-age (LGA) (1.19[1.01-1.39]), and maternal obesity (2.34[2.04-2.69]), diabetes (1.59[1.36-1.85]), smoking (1.59[1.48-1.71]), and infection (1.21[1.03-1.41]) during pregnancy. In the sibling analysis, only low birth weight and SGA remained associated with early-onset T2D. Early-onset T2D is associated with sociodemographic and multiple perinatal factors; only growth restriction likely reflects fetal programming, while other perinatal-related associations might involve confounders. This study highlights the need for early-life, targeted strategies to prevent T2D and reduce health inequities.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"16 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A population-based cohort to evaluate drug safety during pregnancy (PREGVAL): rationale, design, and baseline characteristics.","authors":"Francisco Sánchez-Sáez,Gabriel Sanfélix-Gimeno,Isabel Hurtado,Aníbal García-Sempere,María Garcés-Sánchez,Fran Llopis-Cardona,Salvador Peiró,Clara L Rodríguez-Bernal","doi":"10.1007/s10654-025-01260-7","DOIUrl":"https://doi.org/10.1007/s10654-025-01260-7","url":null,"abstract":"The main aim of the PREGVAL cohort is to evaluate and monitor the in-utero safety of medication administered to pregnant women, as usually this population is excluded from clinical trials assessing drugs. It is a population-based cohort, comprised by pregnant women and their offspring in the Valencia Region (Spain), between July 1st 2009 and December 31st 2021, which will be followed from 6 months pre-conception until death, loss of coverage or end of study, with over 520.000 pregnancies for the study period. The data source will be the Valencia Integrated Database (VID), which links records at the individual level using a unique personal identification code, with exhaustive data on comorbidities (diabetes, hypertension, etc.) and other clinical variables, sociodemographic variables (age, socio-economic status, risk of social exclusion) and other potential confounders (smoking, alcohol intake). It also provides accurate data on timing of exposure for most livebirths and all of the stillbirths occurred in the region, and partially for spontaneous abortions and elective terminations (due to the availability of gestational age by ultrasound or last menstrual period for these outcomes allowing the calculation of the date of conception) and allows the identification of medications prescription and dispensation data with a very high detail, avoiding the problem of potential exposure misclassification present in many of the existent registries/cohorts. Regarding outcomes, there is exhaustive and accurate data on pregnancy complications, spontaneous abortions, terminations (in this case, those occurred within the public health system), birth weight, preterm birth, congenital anomalies, and perinatal mortality; as well as the availability of post-natal long-term follow-up. These features make the PREGVAL study one of the largest and most exhaustive cohorts to assess real-world in-utero safety of medications to date.","PeriodicalId":11907,"journal":{"name":"European Journal of Epidemiology","volume":"640 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}