Showing papers in "European Journal of Epidemiology in 2017"
TL;DR: There are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants.
Abstract: Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). Simon G. Thompson is supported by the British Heart Foundation (Grant Number CH/12/2/ 29428).
1,066 citations
TL;DR: The origins and composition of the Swedish cause of death register are described, the key strengths and weaknesses of the register are set out, and the main causes of death across age groups and over time in Sweden are presented.
Abstract: Sweden has a long tradition of recording cause of death data. The Swedish cause of death register is a high quality virtually complete register of all deaths in Sweden since 1952. Although originally created for official statistics, it is a highly important data source for medical research since it can be linked to many other national registers, which contain data on social and health factors in the Swedish population. For the appropriate use of this register, it is fundamental to understand its origins and composition. In this paper we describe the origins and composition of the Swedish cause of death register, set out the key strengths and weaknesses of the register, and present the main causes of death across age groups and over time in Sweden. This paper provides a guide and reference to individuals and organisations interested in data from the Swedish cause of death register.
774 citations
TL;DR: There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk, and selecting specific optimal intakes can lead to a considerable change in risk of T1D.
Abstract: The aim of this systematic review and meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups and risk of type 2 diabetes (T2D). We conducted a systematic search in PubMed, Embase, Medline (Ovid), Cochrane Central, and Google Scholar for prospective studies investigating the association between whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSB) on risk of T2D. Summary relative risks were estimated using a random effects model by contrasting categories, and for linear and non-linear dose-response relationships. Six out of the 12 food-groups showed a significant relation with risk of T2D, three of them a decrease of risk with increasing consumption (whole grains, fruits, and dairy), and three an increase of risk with increasing consumption (red meat, processed meat, and SSB) in the linear dose-response meta-analysis. There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk. Optimal consumption of risk-decreasing foods resulted in a 42% reduction, and consumption of risk-increasing foods was associated with a threefold T2D risk, compared to non-consumption. The meta-evidence was graded "low" for legumes and nuts; "moderate" for refined grains, vegetables, fruit, eggs, dairy, and fish; and "high" for processed meat, red meat, whole grains, and SSB. Among the investigated food groups, selecting specific optimal intakes can lead to a considerable change in risk of T2D.
490 citations
TL;DR: The rationale of the study and its design is given, a summary of the major findings and an update of the objectives and methods are presented and the cohort is being expanded by persons aged 40 years and over.
Abstract: The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy
). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
401 citations
TL;DR: This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality and how dairy products can be replaced by other foods.
Abstract: With a growing number of prospective cohort studies, an updated dose–response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose–response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associations were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk products, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97–0.99; I2 = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97–0.99; I2 = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95–1.00; I2 = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods.
259 citations
TL;DR: It is important to recognise that epidemiology and public health have a crucial role to play in providing evidence to improve health of society and reduce inequalities, and evidence strongly supports social causation.
Abstract: A lifetime spent studying how social determinants of health lead to health inequalities has clarified many issues. First is that social stratification is an appropriate topic of study for epidemiologists. To ignore it would be to ignore a major source of variation in health in society. Not only is the social gradient in health appropriate to study but we have made progress both in understanding its causes and what can be done to address them. Post-modern ‘critical theory’ raises questions about the social construction of science. Given the attack on science by politicians of bad faith, it is important to recognise that epidemiology and public health have a crucial role to play in providing evidence to improve health of society and reduce inequalities. Evidence gives grounds for optimism that progress can be made both in improving the health of the worst-off in society and narrowing health inequalities. Theoretical debates about ‘inequality of what’ have been helpful in clarifying theories that drive further gathering of evidence. While it is important to consider alternative explanations of the social gradient in health—principal among them reverse causation—evidence strongly supports social causation. Social action is by its nature political. It is, though, a vital function to provide the evidence that underpins action.
235 citations
TL;DR: It is observed that the effect of alcohol may be greater in younger adults (<60 years old) with regard to fighting against dementia, and Modest alcohol consumption is associated with a reduced risk of dementia with 6 g/day of alcohol conferring a lower risk than other levels while excessive drinking may instead elevate the risk.
Abstract: It is widely believed that light-to-moderate alcohol intake may protect against dementia while excessive drinking may instead increase the risk. Nonetheless, these findings need cautious interpretations due to varying methodologies and lack of standard definition, which hindered our transferring into preventative practice. The objective of this study is to investigate the potential dose–response association between alcohol consumption and risk of dementia. A systematic search was conducted in electronic databases to identify relevant studies. Risk estimates were combined using a random-effect model. Eleven studies with 73,330 participants and 4586 cases for all-cause dementia (ACD), five studies with 52,715 participants and 1267 cases for Alzheimer’s dementia (AD) and four studies with 49,535 participants and 542 cases for vascular dementia were included. We observed a nonlinear association between alcohol consumption and ACD risk (p
nonlinearity < 0.05). The alcohol dose associated with lower risk of dementia was confined to at most 12.5 g/day, with the risk hitting bottom (RR ≈ 0.9) at roughly 6 g/day. Of note, the ACD risk seemed to be elevated (≈10%) when the dose surpasses certain levels: 23 drinks/week or 38 g/day. For the alcohol type, recommendation for wine is prioritized. The subgroup analysis further indicated that the effect of alcohol may be greater in younger adults (<60 years old) with regard to fighting against dementia. Modest alcohol consumption (≤12.5 g/day) is associated with a reduced risk of dementia with 6 g/day of alcohol conferring a lower risk than other levels while excessive drinking (≥38 g/day) may instead elevate the risk.
169 citations
TL;DR: The number of available and analyzable data is reported and demonstrates the high relevance and potential of the LIFE Child study.
Abstract: The LIFE Child study is a large population-based longitudinal childhood cohort study conducted in the city of Leipzig, Germany. As a part of LIFE, a research project conducted at the Leipzig Research Center for Civilization Diseases, it aims to monitor healthy child development from birth to adulthood and to understand the development of lifestyle diseases such as obesity. The study consists of three interrelated cohorts; the birth cohort, the health cohort, and the obesity cohort. Depending on age and cohort, the comprehensive study program comprises different medical, psychological, and sociodemographic assessments as well as the collection of biological samples. Optimal data acquisition, process management, and data analysis are guaranteed by a professional team of physicians, certified study assistants, quality managers, scientists and statisticians. Due to the high popularity of the study, more than 3000 children have already participated until the end of 2015, and two-thirds of them participate continuously. The large quantity of acquired data allows LIFE Child to gain profound knowledge on the development of children growing up in the twenty-first century. This article reports the number of available and analyzable data and demonstrates the high relevance and potential of the study.
139 citations
TL;DR: The impact of all major transportation noise sources on cardiovascular diseases is demonstrated, including mid-range IR levels at night, which are potentially more harmful than continuous noise levels of the same average level.
Abstract: Most studies published to date consider single noise sources and the reported noise metrics are not informative about the peaking characteristics of the source under investigation. Our study focuses on the association between cardiovascular mortality in Switzerland and the three major transportation noise sources—road, railway and aircraft traffic—along with a novel noise metric termed intermittency ratio (IR), expressing the percentage contribution of individual noise events to the total noise energy from all sources above background levels. We generated Swiss-wide exposure models for road, railway and aircraft noise for 2001. Noise from the most exposed facade was linked to geocodes at the residential floor height for each of the 4.41 million adult (>30 y) Swiss National Cohort participants. For the follow-up period 2000–2008, we investigated the association between all noise exposure variables [Lden(Road), Lden(Rail), Lden(Air), and IR at night] and various cardiovascular primary causes of death by multipollutant Cox regression models adjusted for potential confounders including NO2. The most consistent associations were seen for myocardial infarction: adjusted hazard ratios (HR) (95% CI) per 10 dB increase of exposure were 1.038 (1.019–1.058), 1.018 (1.004–1.031), and 1.026 (1.004–1.048) respectively for Lden(Road), Lden(Rail), and Lden(Air). In addition, total IR at night played a role: HRs for CVD were non-significant in the 1st, 2nd and 5th quintiles whereas they were 1.019 (1.002–1.037) and 1.021 (1.003–1.038) for the 3rd and 4th quintiles. Our study demonstrates the impact of all major transportation noise sources on cardiovascular diseases. Mid-range IR levels at night (i.e. between continuous and highly intermittent) are potentially more harmful than continuous noise levels of the same average level.
135 citations
TL;DR: To conclude, adherence to the Dutch dietary guidelines was associated with a lower mortality risk and a lower risk of developing some but not all of the chronic diseases on which the guidelines were based.
Abstract: We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. We studied 9701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45 years and over [median 64.1 years (95%-range 49.0–82.8)]. Dietary intake was assessed at baseline with a food-frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (≥200 g/day), fruit (≥200 g/day), whole-grains (≥90 g/day), legumes (≥135 g/week), nuts (≥15 g/day), dairy (≥350 g/day), fish (≥100 g/week), tea (≥450 mL/day), ratio whole-grains:total grains (≥50%), ratio unsaturated fats and oils:total fats (≥50%), red and processed meat (<300 g/week), sugar-containing beverages (≤150 mL/day), alcohol (≤10 g/day) and salt (≤6 g/day). Total adherence was calculated as sum-score of the adherence to the individual items (0–14). Information on disease incidence and all-cause mortality during a median follow-up period of 13.5 years (range 0–27.0) was obtained from data collected at our research center and from medical records. Using Cox proportional-hazards models adjusted for confounders, we observed every additional component adhered to was associated with a 3% lower mortality risk (HR 0.97, 95% CI 0.95; 0.98), lower risk of stroke (HR 0.95, 95% CI 0.92; 0.99), chronic obstructive pulmonary disease (HR 0.94, 95% CI 0.91; 0.98), colorectal cancer (HR 0.90, 95% CI 0.84; 0.96), and depression (HR 0.97, 95% CI 0.95; 0.999), but not with incidence of coronary heart disease, type 2 diabetes, heart failure, lung cancer, breast cancer, or dementia. These associations were not driven by any of the individual dietary components. To conclude, adherence to the Dutch dietary guidelines was associated with a lower mortality risk and a lower risk of developing some but not all of the chronic diseases on which the guidelines were based.
111 citations
TL;DR: The present meta-analysis demonstrated an association between periodontitis and ischemic stroke, however, well-designed prospective studies should be carried out to provide robust evidence of the link between both diseases.
Abstract: Several observational studies have suggested an association between periodontitis and cerebral ischemia. This meta-analysis aimed to investigate whether this link exists, and if so, the degree to which it is significant. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline for systematic review was used. The search strategy included using electronic databases and hand searching works published up to March 2015. MEDLINE via PubMed, EMBASE, Proceedings Web of Science and Current Contents Connect were searched by two independent reviewers. Case-control, cross-sectional or cohort studies including patients with measures of periodontitis and ischemic stroke were eligible to be included in the analysis. Quality assessments of selected studies were performed. From a total of 414 titles and abstracts, 57 potentially relevant full text papers were identified. After inclusion criteria were applied, 8 studies were included in the present systematic review (5 case-control and 3 cohort studies). Although it was not the intention, cross-sectional studies were excluded due to eligibility criteria were not accomplished. Therefore, meta-analyses were conducted with data retrieved from the 8 studies included. These meta-analyses showed statistically significant association between periodontitis and ischemic stroke in both cohort pooled relative risks at 2.52 (1.77-3.58), and case-control studies pooled relative risks at 3.04 (1.10-8.43). In conclusion, the present meta-analysis demonstrated an association between periodontitis and ischemic stroke. However, well-designed prospective studies should be carried out to provide robust evidence of the link between both diseases. In regards to ischemic stroke subtypes, further case-control studies should be carried out to investigate whether there is any association between the different subtypes of cerebral infarcts and periodontitis.
TL;DR: In conclusion, general and abdominal adiposity and higher body fat mass increase the risk of atrial fibrillation, with a stronger association at higher BMI levels.
Abstract: Different adiposity measures have been associated with increased risk of atrial fibrillation, however, results have previously only been summarized for BMI. We therefore conducted a systematic review and meta-analysis of prospective studies to clarify the association between different adiposity measures and risk of atrial fibrillation. PubMed and Embase databases were searched up to October 24th 2016. Summary relative risks (RRs) were calculated using random effects models. Twenty-nine unique prospective studies (32 publications) were included. Twenty-five studies (83,006 cases, 2,405,381 participants) were included in the analysis of BMI and atrial fibrillation. The summary RR was 1.28 (95% confidence interval: 1.20–1.38, I2 = 97%) per 5 unit increment in BMI, 1.18 (95% CI: 1.12–1.25, I2 = 73%, n = 5) and 1.32 (95% CI: 1.16–1.51, I2 = 91%, n = 3) per 10 cm increase in waist and hip circumference, respectively, 1.09 (95% CI: 1.02–1.16, I2 = 44%, n = 4) per 0.1 unit increase in waist-to-hip ratio, 1.09 (95% CI: 1.02–1.16, I2 = 94%, n = 4) per 5 kg increase in fat mass, 1.10 (95% CI: 0.92–1.33, I2 = 90%, n = 3) per 10% increase in fat percentage, 1.10 (95% CI: 1.08–1.13, I2 = 74%, n = 10) per 5 kg increase in weight, and 1.08 (95% CI: 0.97–1.19, I2 = 86%, n = 2) per 5% increase in weight gain. The association between BMI and atrial fibrillation was nonlinear, pnonlinearity < 0.0001, with a stronger association at higher BMI levels, however, increased risk was observed even at a BMI of 22–24 compared to 20. In conclusion, general and abdominal adiposity and higher body fat mass increase the risk of atrial fibrillation.
TL;DR: A recent observational analysis that explicitly emulated a target trial of screening colonoscopy using insurance claims from U.S. Medicare is reviewed, suggesting that lack of an explicit emulation of the target trial leads to biased estimates, and shows that allowing for repeated eligibility increases the statistical efficiency of the estimates.
Abstract: Observational analyses for causal inference often rely on real world data collected for purposes other than research. A frequent goal of these observational analyses is to use the data to emulate a hypothetical randomized experiment, i.e., the target trial, that mimics the design features of a true experiment, including a clear definition of time zero with synchronization of treatment assignment and determination of eligibility. We review a recent observational analysis that explicitly emulated a target trial of screening colonoscopy using insurance claims from U.S. Medicare. We then compare this explicit emulation with alternative, simpler observational analyses that do not synchronize treatment assignment and eligibility determination at time zero and/or do not allow for repeated eligibility. This empirical comparison suggests that lack of an explicit emulation of the target trial leads to biased estimates, and shows that allowing for repeated eligibility increases the statistical efficiency of the estimates.
TL;DR: Despite advances in prophylaxis, the IR of VTE has increased slightly during the last 15 years, mainly due to an increase in PE.
Abstract: Changes in the incidence of venous thromboembolism (VTE) during the last two decades have not been extensively studied. Therefore, we studied time trends in the incidence rates (IRs) of deep vein thrombosis (DVT) and pulmonary embolism (PE) in a cohort of 26,855 subjects, aged 25–97 years, enrolled in the Tromso study in 1994/1995. The subject were followed-up throughout 2012, and all symptomatic, objectively confirmed, incident VTEs were identified using multiple sources (hospital discharge-, radiology procedure- and autopsy registry) and validated by review of medical records. Age-adjusted biennial IR per 100,000 person years (PY) with 95% confidence intervals (CI) were calculated using Poisson regression. Between January 1996 and December 2012, 693 VTEs occurred during 368,150 PY of follow up. The IR of VTE increased from 158 (95% CI 116–199) in 1996/1997 to 201 (95% CI 160–243) in 2010/2011. There was a marked increase in the rates of PE (with/without concurrent DVT) ranging from 45 (95% CI 23–67) in 1996/1997 to 113 (95% CI 82–144) in 2010/2011, whereas the rates of isolated DVT decreased (112, 95% CI 77–146 in 1996/1997 and 88, 95% CI 61–115 in 2010/2011). Despite advances in prophylaxis, the IR of VTE has increased slightly during the last 15 years, mainly due to an increase in PE. Although the introduction of better diagnostic tools to some extent may explain the increase in PE rates, our findings suggest that there is still a need for improvement in risk factor management and prevention strategies of first time VTE.
TL;DR: Recent increases in outdoor air pollutants such as PM10 or O3 can trigger suicide, particularly during warm periods, even at concentrations below the European thresholds, and PM10 may have strong trigger effects among children and elderly population.
Abstract: In addition to underlying health disorders and socio-economic or community factors, air pollution may trigger suicide mortality. This study evaluates the association between short-term variation in air pollution and 10 years of suicide mortality in Belgium. In a bidirectional time-stratified case-crossover design, 20,533 suicide deaths registered between January 1st 2002 and December 31st 2011 were matched by temperature with control days from the same month and year. We used municipality-level air pollution [particulate matter (PM10) and O3 concentrations] data and meteorology data. We applied conditional logistic regression models adjusted for duration of sunshine and day of the week to obtain odds ratios (OR) and their 95% CI for an increase of 10 µg/m3 in pollutant concentrations over different lag periods (lag 0, 0–1, 0–2, 0–3, 0–4, 0–5, and 0–6 days). Effect modification by season and age was investigated by including interaction terms. We observed significant associations of PM10 and O3 with suicide during summer (OR ranging from 1.02 to 1.07, p-values <0.05). For O3, significant associations were also observed during spring and autumn. Age significantly modified the associations with PM10, with statistically significant associations observed only among 5–14 year old children (lag 0–6: OR = 1.45; 95% CI: 1.03–2.04) and ≥85 years old (e.g. lag 0–4: OR = 1.17; 95% CI: 1.06–1.29). Recent increases in outdoor air pollutants such as PM10 or O3 can trigger suicide, particularly during warm periods, even at concentrations below the European thresholds. Furthermore, PM10 may have strong trigger effects among children and elderly population.
TL;DR: In this article, the authors analyzed the life course history of pre-diagnostic body mass index (BMI) in patients with amyotrophic lateral sclerosis (ALS) and found that a sharp decrease was evident in the BMI of ALS patients about 10 years before disease onset.
Abstract: Weight loss appears as a strong predictor of survival of patients with amyotrophic lateral sclerosis, yet no data are currently available to describe the life course history of pre-diagnostic body mass index (BMI) in these patients. 393 ALS cases (mean age: 65.8 years, 57.3% men) and 791 controls matched by age and sex from a population-based case–control study of the ALS Registry Swabia were analyzed. Differences of BMI change in cases and controls over time were modeled using a multilevel additive model. In addition, survival in ALS cases by BMI change was modeled using an accelerated failure time model adjusted for prognostic factors. In ALS cases, BMI was consistently higher than in controls in the 20–70 years before the interview. Conditional logistic regression revealed an odds ratio of 1.05 (95% confidence interval (CI) 1.00–1.11, p = 0.041) per 1 kg/m2 higher BMI 35–45 years before interview. However, a sharp decrease was evident in the BMI of ALS cases about 10 years before disease onset. Moreover, weight loss was strongly associated with shorter survival in ALS patients. Illustrating this, patients with stable weight showed a median survival time of 22.1 (95%-CI 19.2–25.0) months, as compared to 13.4 (95%-CI 10.5–16.3) months for patients with weight loss of 2.5 kg/m2 over the last 3 months before the interview. Thus, alterations in body weight are present in ALS patients already decades before clinical manifestation of ALS, while weight loss precedes motor symptoms of several years and is associated with poor prognosis.
TL;DR: This study can help policy makers and Non-Governmental Organizations decide which health care is needed most in the current European refugee crisis and there is an urgent need for mental and dental healthcare.
Abstract: To assess current medical problems at two Greek refugee sites at Lesbos island (Camp Moria and Caritas hotel), to explore which care is needed and to assess how the provided healthcare can be improved. In this dynamic cohort study all consecutive patients who visited doctors from the Boat Refugee Foundation were included. Treatment Rates (TR) with 95% Confidence Intervals (95% CI) were calculated for all major health issues. Additionally, the provided health care was evaluated using the SPHERE project standards. During the observation period of 30 March 2016 to 15 May 2016, 2291 persons were followed for a total of 289 person years (py). The median age of patients was 23.0 (IQR 8–38) years, 30.0% was aged <18. The healthcare demand was high with 3.6 patient visits per py. Upper respiratory tract infections were most commonly diagnosed with a TR of 89.6/100py (95% CI 78.7–10.1) followed by dental problems (TR 18.0/100py, 95% CI 13.1–22.9). The rate of suicide attempts was high at TR 1.4/100py (95% CI 0.03–2.8), and many psychological problems were diagnosed, TR 19.4/100py (95% CI 14.3–24.4). Major health care threats are the lack of a vaccination program, inadequate sanitation and hygiene, and severe overcrowding. This study can help policy makers and Non-Governmental Organizations decide which health care is needed most in the current European refugee crisis. There is an urgent need for mental and dental healthcare. Furthermore, it is crucial that vaccination programs are initiated and “hotspot” camps should transform in camps designed for long-stay situations.
TL;DR: It is argued that, once these misconceptions are removed, most elements of the opposing views can be reconciled and the chief problem of causal inference becomes one of how to teach sound use of formal methods and how to apply them without generating the overconfidence and misinterpretations that have ruined so many statistical practices.
Abstract: I present an overview of two methods controversies that are central to analysis and inference: That surrounding causal modeling as reflected in the "causal inference" movement, and that surrounding null bias in statistical methods as applied to causal questions. Human factors have expanded what might otherwise have been narrow technical discussions into broad philosophical debates. There seem to be misconceptions about the requirements and capabilities of formal methods, especially in notions that certain assumptions or models (such as potential-outcome models) are necessary or sufficient for valid inference. I argue that, once these misconceptions are removed, most elements of the opposing views can be reconciled. The chief problem of causal inference then becomes one of how to teach sound use of formal methods (such as causal modeling, statistical inference, and sensitivity analysis), and how to apply them without generating the overconfidence and misinterpretations that have ruined so many statistical practices.
TL;DR: In middle-aged Caucasian men, low serum magnesium is strongly and independently associated with an increased risk of fractures and further research is needed to assess the potential relevance of serum magnesium in the prevention of fractures.
Abstract: Magnesium, which is an essential trace element that plays a key role in several cellular processes, is a major component of bone; however, its relationship with risk of major bone fractures is uncertain. We aimed to investigate the association of baseline serum magnesium concentrations with risk of incident fractures. We analyzed data on 2245 men aged 42–61 years in the Kuopio Ischemic Heart Disease prospective cohort study, with the assessment of serum magnesium measurements and dietary intakes made at baseline. Hazard ratios [95% confidence intervals (CI)] for incident total (femoral, humeral, and forearm) and femoral fractures were assessed. During a median follow-up of 25.6 years, 123 total fractures were recorded. Serum magnesium was non-linearly associated with risk of total fractures. In age-adjusted Cox regression analysis, the hazard ratio (HR) (95% CIs) for total fractures in a comparison of the bottom quartile versus top quartile of magnesium concentrations was 2.10 (1.30–3.41), which persisted on adjustment for several established risk factors 1.99 (1.23–3.24). The association remained consistent on further adjustment for renal function, socioeconomic status, total energy intake, and several trace elements 1.80 (1.10–2.94). The corresponding adjusted HRs for femoral fractures were 2.56 (1.38–4.76), 2.43 (1.30–4.53) and 2.13 (1.13–3.99) respectively. There was no evidence of an association of dietary magnesium intake with risk of any fractures. In middle-aged Caucasian men, low serum magnesium is strongly and independently associated with an increased risk of fractures. Further research is needed to assess the potential relevance of serum magnesium in the prevention of fractures.
TL;DR: This article proposed explicit target trial emulation, which emulates the design and methods of a target trial in an observational study and then compares the results of the observational study to previous trials in the discussion.
Abstract: textObservational epidemiology is continually held to thestandard of randomized trials. A typical epidemiology article references previous trials in the introduction (or reasons why trials are not feasible) and, when possible, compares the results to previous trials in the discussion. When the results from an observational study and trial disagree, we nearly always begin by questioning the former. Curiously, the methods section of an observational study — an undeniably crucial part of an article — rarely references trial methods or designs. Explicit target trial emulation aims to remedy this.
TL;DR: Pooled evidence suggests that elevated CRP is associated with greater VTE risk, consistent with a linear dose–response relationship.
Abstract: Evolving debate suggests that C-reactive protein (CRP) might be associated with the development of venous thromboembolism (VTE); however, the evidence is conflicting. We aimed to assess the prospective association of CRP with VTE risk. C-reactive protein was measured in serum samples at baseline from 2420 men aged 42–61 years, from the Kuopio Ischemic Heart Disease study. Within-person variability in CRP levels was corrected for using repeat measurements of CRP taken 11 years after baseline. Incident VTE events (n = 119) were recorded during a median follow-up of 24.7 years. The age-adjusted regression dilution ratio for loge CRP was 0.57 [95% confidence interval (CIs): 0.51–0.64]. In age-adjusted Cox regression analysis, the hazard ratio (95% CIs) for VTE per 1 standard deviation (SD) increase in loge baseline CRP was 1.17 (0.98–1.40). Further adjustment for several established and emerging risk factors did not alter the association. In a meta-analysis of nine population-based studies (including the current study) comprising 81,625 participants and 2225 VTE cases, the fully-adjusted risk estimate for VTE was 1.14 (1.08–1.19) per SD increase in loge baseline CRP. In a pooled dose–response analysis, a linear association between CRP and VTE risk was suggested (P for nonlinearity = 0.272). The pooled risk estimate for VTE per 5 mg/l increment in CRP levels was 1.23 (1.09–1.38). C-reactive protein was only modestly associated with VTE risk in the primary analysis. Pooled evidence, however, suggests that elevated CRP is associated with greater VTE risk, consistent with a linear dose–response relationship.
TL;DR: The conceptual framework of SSA is presented and advantages and potential pitfalls of the method in practice are discussed and it is confirmed that SSA has moderate sensitivity and high specificity, and controls time-constant confounders.
Abstract: Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice. SSA is based on analyzing the sequences of medications; if one medication (drug B) is more often initiated after another medication (drug A) than before, it may be an indication of an adverse effect of drug A. The main advantage of the method is that it requires a minimal dataset and is computationally efficient. By design, SSA controls time-constant confounders. However, the validity of SSA may be affected by time-varying confounders, as well as by time trends in the occurrence of exposure or outcome events. Trend effects may be adjusted by modeling the expected sequence ratio in the absence of a true association. There is a potential for false positive or negative results and careful consideration should be given to potential sources of bias when interpreting the results of SSA studies.
TL;DR: The Born in Guangzhou Cohort Study is a large-scale prospective observational study investigating the role of social, biological and environmental influences on pregnancy and child health and development in an urban setting in southern China.
Abstract: The Born in Guangzhou Cohort Study (BIGCS) is a large-scale prospective observational study investigating the role of social, biological and environmental influences on pregnancy and child health and development in an urban setting in southern China. Pregnant women who reside in Guangzhou and who attend Guangzhou Women and Children’s Medical Center (GWCMC) for antenatal care in early pregnancy (<20 weeks’ gestation) are eligible for inclusion. Study recruitment commenced in February 2012, with an overall participation rate of 76.3%. Study recruitment will continue until December 2018 to achieve the target sample size of 30,000 mother–child pairs. At 30 April 2016, a total of 75,422 questionnaires have been collected, while 14,696 live births have occurred with planned follow-up of cohort children until age 18 years. During the same period a total of 1,053,000 biological samples have been collected from participants, including maternal, paternal and infant blood, cord blood, placenta, umbilical cord, and maternal and infant stool samples. The dataset has been enhanced by record linkage to routine health and administrative records. We plan future record linkage to school enrolment and national examination records.
TL;DR: Frequent sauna baths may be associated with a reduced risk of acute and chronic respiratory conditions in a middle-aged male Caucasian population.
Abstract: Sauna bathing has been linked with numerous health benefits. Sauna bathing may reduce the risk of respiratory diseases; however, no prospective evidence exists to support this hypothesis. We aimed to assess the association of frequency of sauna bathing with risk of respiratory diseases (defined as chronic obstructive pulmonary disease, asthma, or pneumonia). Baseline sauna bathing habits were assessed in a prospective cohort of 1935 Caucasian men aged 42–61 years. During a median follow-up of 25.6 years, 379 hospital diagnosed incident cases of respiratory diseases were recorded. In adjustment for several major risk factors for respiratory conditions and other potential confounders, the hazard ratios (HRs) 95% confidence intervals (CIs) of respiratory diseases were 0.73 (0.58–0.92) and 0.59 (0.37–0.94) for participants who had 2–3 and ≥4 sauna sessions per week respectively compared with participants who had ≤1 sauna session per week. The multivariate adjusted HR (95% CI) for pneumonia was 0.72 (0.57–0.90) and 0.63 (0.39–1.00) for participants who had 2–3 and ≥4 sauna sessions per week respectively. Frequent sauna baths may be associated with a reduced risk of acute and chronic respiratory conditions in a middle-aged male Caucasian population.
TL;DR: The results suggest that age plays an important role in the relationship between sleep duration and mortality, and the effect of short and long sleep duration on mortality was highest among young individuals and decreased with increasing age.
Abstract: Prior work has shown that both short and long sleep predict mortality. However, sleep duration decreases with age and this may affect the relationship of sleep duration with mortality. The purpose of the present study was to assess whether the association between sleep duration and mortality varies with age. Prospective cohort study. 43,863 individuals (64% women), recruited in September 1997 during the Swedish National March and followed through record-linkages for 13 years. Sleep duration was self-reported and measured using the Karolinska Sleep Questionnaire, and grouped into 4 categories: ≤5, 6, 7 (reference) and ≥8 h. Up to 2010 3548 deaths occurred. Multivariable Cox proportional hazards regression models with attained age as time scale were fitted to estimate mortality rate ratios. Among individuals <65 years, short (≤5 h) and long (≥8 h) sleep duration showed a significant relationship with mortality (HR 1.37, 95% CI 1.09–1.71, and HR 1.27, 95% CI 1.08–1.48). Among individuals 65 years or older, no relationships between sleep duration and mortality were observed. The effect of short and long sleep duration on mortality was highest among young individuals and decreased with increasing age. The results suggest that age plays an important role in the relationship between sleep duration and mortality.
TL;DR: Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.
Abstract: Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.
TL;DR: The possibility of enhancing CRC prognosis by vitamin D supplementation, ideally combined with outdoor physical activity, should be evaluated by randomized controlled trials focusing on patients with vitamin D deficiency.
Abstract: To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels 45.20 nmol/L), those in the lowest 25(OH)D3 quintile (<11.83 nmol/L) had a strongly increased mortality. Adjusted hazard ratios (95% Confidence Interval) were 1.78 (1.39–2.27), 1.65 (1.24–2.21), 1.32 (1.03–1.71) and 1.48 (1.18–1.85) for all-cause mortality, CRC-specific mortality, recurrence-free and disease-free survival, respectively. Subgroup analyses did not show any significant effect modification across strata defined by sex, age, stage, body mass index, or the late entry. Dose–response analyses showed a strong inverse relationship between serum 25(OH)D3 levels and survival endpoints at 25(OH)D3 levels <30 nmol/L, and no association with mortality at higher 25(OH)D3 levels. Vitamin D deficiency is highly prevalent in CRC patients and a strong independent predictor of poor prognosis. The possibility of enhancing CRC prognosis by vitamin D supplementation, ideally combined with outdoor physical activity, should be evaluated by randomized controlled trials focusing on patients with vitamin D deficiency.
TL;DR: It is suggested that occult cancer and shared risk factors of MI and cancer may partly explain the association, and patients with MI had a higher short- and long-term incidence rate of cancer compared to subjects without MI.
Abstract: The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n = 28,763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariable-adjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21–1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29–3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27–2.03) higher HR of future cancer more than 3 years after the event. The increased IRs were higher in women than men. Patients with MI had a higher short- and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.
TL;DR: EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 forPre-di diabetes, incident T 2D and insulin therapy start are identified and various inflammatory markers associated with progression from normoglycemia to pre- diabetics are identified.
Abstract: The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. Main Outcome Measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start.