Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals: a Mendelian randomization study Abstract Short telomeres might lead to increased risk of Alzheimer’s disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer’s disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer’s disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer’s Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer’s disease was 1.02 (95% CI 1.00–1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0–1 alleles (p = 5 × 10−105). Genetically, odds ratio for Alzheimer’s disease was 1.08 (1.01–1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer’s disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer’s disease.

Healthy lifestyle and the risk of pancreatic cancer in the EPIC study Abstract Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants’ shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e−09) and 0.77 (0.72, 0.82; ptrend = 1.7e−15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e−04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence.

On the relationship of machine learning with causal inference

Statin use, hyperlipidemia, and risk of glioma Abstract Background Statins have previously been shown to have protective effects for other cancers, but no prospective studies of statin use and glioma have been conducted. Methods We evaluated the association between statin use and risk of glioma in the female Nurses’ Health Study (NHS, n = 114,419) and Nurses’ Health Study II (NHSII, n = 115,813) and the male Health Professionals Follow-up Study (HPFS, n = 50,223). Glioma cases were confirmed by medical record review. Age and multivariable-adjusted hazard ratios of glioma by statin use were estimated using Cox proportional hazards models. Results In 4,430,700 person-years of follow-up, we confirmed 483 incident cases of glioma. Compared with never-users, ever statin use was associated with borderline increased risk of glioma in the combined cohorts (age-adjusted HR = 1.23, 95% CI 0.99–1.54), as was longer duration of statin use (HR = 1.48, 95% CI 1.08–2.03 comparing > 8 years of use to never use, p-trend = 0.01). We also observed a significant inverse association between hyperlipidemia and glioma in multivariable models (HR = 0.74, 95% CI 0.59–0.93 in combined cohorts), which was attenuated in lagged analyses. Compared to never use, in multivariable-adjusted models, ever statin use (HR = 1.43, 95% CI 1.10–1.86) and statin use duration (HR = 1.72, 95% CI 1.21–2.45, for > 8 years of use, p-trend = 0.003) were each significantly associated with increased glioma risk. Conclusion In contrast to case–control studies reporting inverse associations, we found borderline increased risk of glioma with statin use. Results were strengthened after adjustment for cardiovascular risk factors due to an unexpected inverse association between hyperlipidemia and glioma risk. Further studies of statin use, hyperlipidemia, and glioma risk are warranted.

Prevalence, incidence and future projection of diabetic eye disease in Europe: a systematic review and meta-analysis Abstract To examine the prevalence and incidence of diabetic eye disease (DED) among individuals with diabetes in Europe, a systematic review to identify all published European prevalence and incidence studies of DED in individuals with diabetes managed in primary health care was performed according to the MOOSE and PRISMA guidelines. The databases Medline, Embase and Web of Science were searched to 2 September 2017. Meta-analyses and meta-regressions were performed. The pooled prevalence estimates were applied to diabetes prevalence rates provided by the International Diabetes Foundation atlas and Eurostat population data, and extrapolated to the year 2050. Data of 35 prevalence and four incidence studies were meta-analyzed. Any diabetic retinopathy (DR) and diabetic macular edema (DME) were prevalent in 25.7% (95% CI 22.8–28.8%) and 3.7% (95% CI 2.2–6.2%), respectively. In meta-regression, the prevalence of DR in persons with type 1 diabetes was significantly higher compared to persons with type 2 diabetes (54.4% vs. 25.0%). The pooled mean annual incidence of any DR and DME in in persons with type 2 diabetes was 4.6% (95% CI 2.3–8.8%) and 0.4% (95% CI 0.5–1.4%), respectively. We estimated that persons with diabetes affected by any DED in Europe will increase from 6.4 million today to 8.6 million in 2050, of whom 30% require close monitoring and/or treatment. DED is estimated to be present in more than a quarter of persons with type 2 diabetes and half of persons with type 1 diabetes underlining the importance of regular monitoring. Future health services need to be planned accordingly.

A meta-analysis of cohort studies including dose-response relationship between shift work and the risk of diabetes mellitus Abstract Previous reviews have suggested that shift work is associated with an increased risk of diabetes mellitus (DM); however, the results should be interpreted with caution due to differences in study designs and non-comprehensive literature searches. In addition, the quantitative dose-response relationship between years of shift work and DM risk is still unknown. We aimed to conduct an updated meta-analysis with cohort studies and to evaluate the relationship between the duration of shift work and the risk of DM in a dose-dependent manner. The PubMed and Web of Science databases were searched through 15 August 2019, and multivariate-adjusted relative risks (RRs) were pooled using random-effects models. Restricted cubic spline analysis with three knots was used to explore the relationship of years of shift work and risk of DM. Twelve cohort studies with 28 independent reports involving 244,266 participants and 15,906 DM cases were included. The summarized adjusted RR for the relationship between shift work and DM risk was 1.14 (95% CI 1.10 to 1.19; I2 = 38.9%, P = 0.028). The summary RR of a 5-year increase in shift work was 1.07 (95% CI 1.04 to 1.09), without heterogeneity (I2= 0.0%, P = 0.829) for the female population. Shift work is associated with an increased risk of DM, and a strong and highly significant linear dose-response relationship between the duration of shift work and the risk of DM in women was observed. Further studies are needed to confirm the results, establish causality and elucidate the underlying mechanisms.

Asthma, asthma control and risk of acute myocardial infarction: HUNT study Abstract Asthma, a chronic inflammatory airway disease, shares several common pathophysiological mechanisms with acute myocardial infarction (AMI). Our aim was to assess the prospective associations between asthma, levels of asthma control and risk of AMI. We followed 57,104 adults without previous history of AMI at baseline from Nord-Trøndelag health study (HUNT) in Norway. Self-reported asthma was categorised as active asthma (i.e., using asthma medication) and non-active asthma (i.e., not using asthma medication). Levels of asthma control were defined as controlled, partly controlled, and uncontrolled based on the Global Initiative for Asthma guidelines. AMI was ascertained by linking HUNT data with hospital records. A total of 2868 AMI events (5.0%) occurred during a mean (SD) follow-up of 17.2 (5.4) years. Adults with active asthma had an estimated 29% higher risk of developing AMI [adjusted hazard ratio (HR) 1.29, 95% CI 1.08–1.54] compared with adults without asthma. There was a significant dose–response association between asthma control and AMI risk, with highest risk in adults with uncontrolled asthma (adjusted HR 1.73, 95% CI 1.13–2.66) compared to adults with controlled asthma (p for trend < 0.05). The associations were not explained by smoking status, physical activity and C-reactive protein levels. Our study suggests that active asthma and poor asthma control are associated with moderately increased risk of AMI. Further studies are needed to evaluate causal relationship and the underlying mechanisms and to clarify the role of asthma medications in the risk of AMI.

Body fatness, diabetes, physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies

Validated inference of smoking habits from blood with a finite DNA methylation marker set Abstract Inferring a person’s smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

Mediterranean diet adherence and risk of colorectal cancer: the prospective Netherlands Cohort Study Abstract Mediterranean diet (MD) adherence has been associated with a large variety of health benefits. However, prospective studies investigating the relation between MD adherence and colorectal cancer risk had inconsistent results. In this analysis of the Netherlands Cohort Study (NLCS), we evaluated sex- and subsite-specific associations of MD adherence with colorectal cancer risk. In 1986, 120,852 subjects filled out the NLCS baseline questionnaire, which incorporated a 150-item food frequency questionnaire. MD adherence was estimated through alternate Mediterranean diet scores including and excluding alcohol (aMED and aMEDr, respectively). Using 20.3 year follow-up data, 1993 male and 1574 female colorectal cancer cases could be included in multivariable case-cohort analyses. aMEDr was not significantly associated with colorectal cancer risk, regardless of sex. Hazard ratios (95% confidence intervals) per two-point increment were 1.04 (0.95–1.13) for men and 0.97 (0.88–1.07) for women. Additionally, there was no evidence of an inverse association with any of the colorectal cancer subsites (colon, proximal colon, distal colon, and rectum). In women, the association between aMEDr and colorectal cancer risk was significantly modified by smoking status (Pinteraction = 0.015). Comparable results were obtained for the original aMED including alcohol. In conclusion, higher MD adherence was not associated with a reduced risk of colorectal cancer or anatomical subsites in the context of a Dutch population.