Publications

OBJECTIVE To examine the association between age at menarche and risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS A prospective cohort study of 42,109 eligible pregnancies from 27,482 women in the Nurses’ Health Study II. RESULTS The adjusted risk ratios for GDM across the age at menarche categories (≤11, 12, 13, and ≥14 years) were 1.34 (95% CI 1.14–1.58), 1.13 (0.97–1.31), 1.11 (0.95–1.29), and 1.00 (referent; P for trend = 0.0005), respectively. Analysis of the mediating effect indicated that 42.1% (P = 0.0007) of the association was mediated through prepregnancy BMI. CONCLUSIONS These findings suggested that earlier menarche was significantly associated with an increased risk of GDM. This association was largely mediated through prepregnancy excessive body adiposity.

The aim of this study was to investigate the prevalence of smoking and alcohol use in association with dental caries experience and signs of periodontal disease in a Finnish male group born in the early 1990s. The impacts of health behaviour and socioeconomic factors were included in the analyses.Oral health of 8539 conscripts was screened in a cross-sectional study (DT, DMFT and CPI). They also answered a questionnaire covering their habits of smoking and alcohol use as well as other behaviours and background factors. The bleeding on probing index (BOP) was available on 6529 conscripts. Cross-tabulation together with a chi-squared test and generalized linear mixed models were used in the analyses. A mosaic figure was used to illustrate associations of smoking frequency, use of dental services and toothache.Majority (80.9%) in the study group consumed alcohol at least once a month, and 39.4% were daily smokers. Smoking was statistically significantly associated with high caries experience and high bleeding values of gums. Consumption of alcohol was not associated with dental caries and periodontal disease. The high BOP value had the strongest association with infrequent tooth brushing and smoking. The participant's own education level was the main protective factor of oral health. The smokers used dental services more frequently compared to the non-smokers mostly for acute care.Young men's health behaviour, especially of those with low education, does not promote oral health, which may indicate need for extensive healthcare services in the future. Health promotion should not be neglected.

Rationale: Altered lipid metabolism has been implicated in heart failure (HF) development, but no prospective studies have examined comprehensive lipidomics data and subsequent risk of HF. Objective: We aimed to link single lipid metabolites and lipidomics networks to the risk of developing HF. Methods and Results: Discovery analyses were based on 216 targeted lipids in a case-control study (331 incident HF cases and 507 controls, matched by age, sex, and study center), nested within the PREDIMED (Prevención con Dieta Mediterránea) study. Associations of single lipids were examined in conditional logistic regression models. Furthermore, lipidomics networks were linked to HF risk in a multistep workflow, including machine learning–based identification of the HF-related network clusters, and regression-based discovery of the HF-related lipid patterns within these clusters. If available, significant findings were externally validated in a subsample of the EPIC-Potsdam cohort (2414 at-risk participants, including 87 incident HF cases). After confounder-adjustments, 2 lipids were significantly associated with HF risk in both cohorts: CER (ceramide) 16:0 (relative risk [RR] per SD in PREDIMED, 1.28 [95% CI, 1.13–1.47]) and phosphatidylcholine 32_0 (RR per SD in PREDIMED, 1.23 [95% CI, 1.08–1.41]). Additionally, lipid patterns in several network clusters were associated with HF risk in PREDIMED. Adjusted for standard risk factors, an internally cross-validated score based on the significant HF-related lipids that were identified in the network analysis in PREDIMED was associated with a higher HF risk (20 lipids, RR per SD, 2.33 [95% CI, 1.93%–2.81%). Moreover, a lipid score restricted to the externally available lipids was significantly associated with HF incidence in both cohorts (6 lipids, RRs per SD, 1.30 [95% CI, 1.14–1.47] in PREDIMED, and 1.46 [95% CI, 1.17–1.82] in EPIC-Potsdam). Conclusions: Our study identified and validated 2 lipid metabolites and several lipidomics patterns as potential novel biomarkers of HF risk. Lipid profiling may capture preclinical molecular alterations that predispose for incident HF. Registration: URL: https://www.isrctn.com/ISRCTN35739639 ; Unique identifier: ISRCTN35739639.

ISEE-0294 Background and Objective: It has become commonplace to analyze separately atopic and non-atopic asthma in studies on genetic, environmental, and immunological characteristics of asthma. Atopic asthma is in most studies defined simply based on presence of both asthma and positive skin prick test or specific IgE antibodies. We here illustrate the problems introduced by using atopic and non-atopic asthma as endpoint in analyses exploring characteristics associated with asthma/atopy. Methods: Analyses of the 31 year follow-up of the Northern Finland 1966 birth cohort (n = 5417). Asthma was defined as doctor-diagnosed asthma ever and atopy as any skin prick test reaction >3 mm to common allergens at age 31. Atopic and non-atopic asthma were defined as asthma with and without atopy, respectively. Results: The prevalence of asthma was 7.8% and of atopy 30%. Having a cat in childhood was associated with decreased risk of atopy at age 31 years (OR 0.59, 95% CI 0.52-0.66). This created a spurious protective association with atopic asthma (OR 0.69, 95% CI 0.53-0.88) and an opposite association with non-atopic asthma (OR 1.27, 95% CI 0.93-1.75). There was no association between cat ownership and asthma, when analysis was stratified by atopy or in a multivariate model adjusted for atopy (OR 1.05, 95% CI 0.85-1.29). Similar spurious associations were seen for gender. Findings were confirmed with simulated datasets. Conclusion: If a characteristic is associated with atopy, this will produce a similar association with atopic asthma and a reverse association with non-atopic asthma, even if the characteristic has no association with asthma. Therefore, before better methods become available to define phenotypes of asthma, asthma and atopy should be analyzed as separate end points.

Abstract Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ∼800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ∼11 and ∼14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ∼220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83 , which we demonstrate amplifies signaling of MC3R , a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

A multilayered paper-based platform is used to investigate the interactions between human lung tumor cells and fibroblasts that are isolated from primary patient tumor samples. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)2) with mean relative leukocyte telomere length (LTL) using data gathered on 5,096 participants from Northern Finland Birth Cohort 1966 at age 31 years (1997). 25(OH)D was not associated with LTL in either basic or confounder/mediator-adjusted models. BMI was inversely associated with LTL after adjustment for potential confounding by age, sex, socioeconomic position, physical activity, diet, smoking, alcohol intake, and use of oral contraceptives (per 1-unit increase in BMI, mean difference in LTL = −0.4%, 95% confidence interval: −0.6, −0.2). The BMI-LTL association was also independent of 25(OH)D and was attenuated slightly, but remained, after adjustment for C-reactive protein, a marker of low-grade inflammation (mean difference in LTL = −0.3%, 95% confidence interval −0.6, −0.1). These findings suggest that vitamin D status is unlikely to be an important determinant of LTL, at least by young adulthood. Inflammation may partly mediate associations of adiposity with LTL.

Abstract Systematic nonrandom mating in populations results in genetic stratification and is predominantly caused by geographic separation, providing the opportunity to infer individuals’ birthplace from genetic data. Such inference has been demonstrated for individuals’ country of birth, but here we use data from the Northern Finland Birth Cohort 1966 (NFBC1966) to investigate the characteristics of genetic structure within a population and subsequently develop a method for inferring location to a finer scale. Principal component analysis (PCA) shows that while the first PCs are particularly informative for location, there is also location information in the higher-order PCs, but it cannot be captured by a linear model. We introduce a new method, pcLOCATE, which is able to exploit this information to improve the accuracy of location inference. pcLOCATE uses individuals’ PC values to estimate the probability of birth in each town and then averages over all towns to give an estimated longitude and latitude of birth using a fully Bayesian model. We apply pcLOCATE to the NFBC1966 data to estimate parental birthplace, testing with successively more PCs and finding the model with the top 23 PCs most accurate, with a median distance of 23 km between the estimated and the true location. pcLOCATE predicts the most recent residence of NFBC1966 individuals to a median distance of 47 km. We also apply pcLOCATE to Indian individuals from the London Life Sciences Prospective Population Study (LOLIPOP) data, and find that birthplace is predicated to a median distance of 54 km from the true location. A method with such accuracy is potentially valuable in population genetics and forensics.

Introduction: Current dietary guidelines recommend eating a variety of fruits and vegetables. However, based on nutrient composition, specific fruits and vegetables may be more or less beneficial for weight maintenance. Hypothesis: Fruits and vegetables with a higher fiber content or lower glycemic load are more strongly associated with weight maintenance and even weight loss, in part through mechanisms related to increased satiety. Methods: We examined the association between increased consumption of fruits and vegetables and change in body weight among participants <65 years of age from three large prospective cohort studies: 41,608 women in the Nurses’ Health Study (NHS) I, 20,143 men in the Health Professionals Follow-up Study, and 67,533 women in the NHS II. Beginning in 1986, these associations were examined during 24 years of follow-up within 4-year time intervals, adjusting for simultaneous changes in other lifestyle factors such as diet, smoking, and physical activity. Results: Increased consumption of one serving per day of several types of fruits was inversely associated with weight gain over 4 years, for example -1.11 lbs (95% CI, -1.43 to -0.80 lbs) for berries and -0.96 lbs (95% CI, -1.20 to -0.72 lbs) for apples/pears. Increased consumption of several vegetables was also inversely associated with weight gain, for example -2.15 lbs (95% CI, -2.58 to -1.73 lbs) for tofu/soy and -1.18 lbs (95% CI, -1.73 to -0.64 lbs) for cauliflower. On the other hand, increased consumption of some vegetables was positively associated with weight change, for example corn (1.69 lbs; 95% CI, 0.90 to 2.48 lbs) and peas (0.81 lbs; 95% CI 0.16 to 1.46 lbs). The magnitude of weight change associated with increased consumption of high fiber vegetables (-0.37 lbs; 95% CI -0.48 to -0.27 lbs) was larger than that for low fiber vegetables (-0.13 lbs; 95% CI -0.23 to -0.02 lbs). Increased consumption of low glycemic load vegetables was associated with a greater magnitude of weight change, -0.37 lbs (95% CI, -0.63 to -0.11 lbs), compared to high glycemic load vegetables, -0.01 lbs (95% CI, -0.14 to 0.11 lbs). In contrast, weight change associated with fruit consumption did not vary by fiber content or glycemic load. Conclusions: Increased consumption of total fruits and vegetables was inversely associated with weight change over 4 years, however we found wide-ranging associations for specific foods, partly due to the fiber content and glycemic load of vegetables but not fruits.

Magnetic levitation (MagLev) enables 3D self-assembly of diamagnetic objects with control over many aspects of position and orientation. This work demonstrates the ability of MagLev to position and align components, such as mirrors, filters, lenses, and soft objects, without mechanical support. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

<h3>Background</h3> The EU H2020 funded Ageing Lungs in European Cohorts study (ALEC www.alecstudy.org) is a consortia of population-based birth and adult inception cohorts with repeated measures of spirometry several years apart. Using these data, ALEC aims to identify risk factors for spirometrically defined COPD, and to develop an online risk prediction tool for use by the public/physicians. Our systematic review of available risk prediction tools (Matheson <i>et al</i> IJCOPD 2018;13:1927–35) showed previous attempts had used numerous variables (most commonly smoking, sex and age), but current models could not accurately rule in nor rule out future risk of COPD. <h3>Method</h3> Using Bayesian statistical methods we developed a model to predict a subject's lifetime risk of developing COPD (FEV1/FVC&lt;LLN). This model can use information from all cohorts even when some predictors of interest have not been collected within a cohort. Compared with existing approaches to deal with variables missing across studies, our Bayesian approach performs well and is flexible. Furthermore, it allows inclusion in the model of evidence from elsewhere on the effect of specific predictors if available and appropriate. Using R Shiny, we developed an online prototype interface that implements our prediction model allowing users to answer questions on their physical characteristics and lifestyle to generate a personalised risk of COPD. This prototype online prediction tool was reviewed by a group of researchers and clinicians. <h3>Results</h3> R shiny provides a technically suitable web-based interface for input of personal information and linkage to model outputs. Feedback from potential users was cautiously positive with concerns expressed regarding presentation of risk, provision of information to patients directing them for further health advice, limitation of underlying data to white Caucasian populations, interpretation/management of 'low risk of COPD' in those who smoked, and absence of risk prediction of exacerbations in those with established disease. <h3>Conclusion</h3> Using appropriate statistical methods, it is possible to develop a risk prediction model by combining data across cohorts even when they have not all collected exactly the same information. R Shiny provides a user-friendly means to create online disease risk prediction tools; however many challenges remain regarding full-scale implementation. These are common to many risk prediction tools.

Abstract Mass spectrometry lipidomics is becoming customary to analyse serum/plasma samples in epidemiology. The measurables are molecular constituents of lipoprotein particles, but very little is known on the consequences of adjusting lipidomics data with lipoprotein measures. We studied two population cohorts with 5,657 and 2,036 participants. LC-MS/MS lipidomics was applied to analyse 24 molecular lipid classes and NMR spectroscopy to quantify seven lipoprotein lipids plus apolipoprotein A-I (apoA-I) and B (apoB). The associations of these measures were analysed via partial Spearman’s correlations. The effects of nine different lipoprotein adjustments on these interrelationships were assessed. Multivariable regression modelling with these adjustments was also performed for the associations between the lipidomics data and BMI. These novel large-scale lipidomics data and their associations between the lipoprotein measures were coherent in both population cohorts, confirming the compatibility of the analytical approaches. Simulated data were generated to corroborate the mediation effects. The lipoprotein-related lipid-transport and metabolism inherently mediate the lipidomics associations as evident from the striking effects of the lipoprotein adjustments. These effects and their relevance to the interpretations of lipidomics data are presented and discussed in detail for the first time. The combined lipoprotein lipid adjustments appear prone to overadjustment and arbitrary biases.

Understanding complex neuronal networks requires monitoring long‐term neuronal activity in various regions of the brain. Significant progress has been made in multisite implantations of well‐designed probes, such as multisite implantation of Si‐based and polymer‐based probes. However, these multiprobe strategies are limited by the sizes and weights of interfaces to the multiple probes and the inability to track the activity of the same neurons and changes in neuronal activity over longer time periods. Here, a long single flexible probe that can be implanted by stitching into multiple regions of the mouse brain and subsequently transmit chronically stable neuronal signals from the multiple sites via a single low‐mass interface is reported. The probe at four different sites is implemented using a glass capillary needle or two sites using an ultrathin metal needle. In vitro tests in brain‐mimicking hydrogel show that multisite probe implantations achieve a high connection yield of &gt;86%. In vivo histological images at each site of probes, implanted by stitching using either glass capillary or ultrathin metal insertion needles exhibit seamless tissue–probe interfaces with negligible chronic immune response. In addition, electrophysiology studies demonstrate the ability to track single neuron activities at every injection site with chronic stability over at least one month. Notably, the measured spike amplitudes and signal‐to‐noise ratios at different implantation sites show no statistically significant differences. Multisite stitching implantation of flexible electronics in the brain opens up new opportunities for both fundamental neuroscience research and electrotherapeutic applications.

Abstract Objective: Tissue kallikrein (TK) cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which lower blood pressure and protect the heart, kidneys, and blood vessels. Reduction in TK levels is associated with cardiovascular disease and diabetes in animal models. In this study, we investigated the association of TK levels with event‐free survival over 5 years in Chinese first‐ever stroke patients. Methods: We conducted a case–control study with 1,268 stroke patients (941 cerebral infarction, 327 cerebral hemorrhage) and 1,210 controls. Plasma TK levels were measured with an enzyme‐linked immunosorbent assay. We used logistic regression and Cox proportional hazards models to assess the relationship between TK levels and risk of first‐time or recurrent stroke. Results: Plasma TK levels were significantly lower in stroke patients (0.163 ± 0.064mg/l vs 0.252 ± 0.093mg/l, p &lt; 0.001), especially those with ischemic stroke. After adjustment for traditional risk factors, plasma TK levels were negatively associated with the risk of first‐ever stroke (odds ratio [OR], 0.344; 95% confidence interval [CI], 0.30–0.389; p &lt; 0.001) and stroke recurrence and positively associated with event‐free survival during 5 years of follow‐up (relative risk, 0.82; 95% CI, 0.74–0.90; p &lt; 0.001). Compared with the first quartile of plasma TK levels, the ORs for first‐ever stroke patients were as follows: second quartile, 0.77 (95% CI, 0.56–1.07); third quartile, 0.23 (95% CI, 0.17–0.32); fourth quartile, 0.04 (95% CI, 0.03–0.06). Interpretation: Lower plasma TK levels are independently associated with first‐ever stroke and are an independent predictor of recurrence after an initial stroke. ANN NEUROL 2011;