Independent Instruments Research Articles

Powerful three-sample genome-wide design and robust statistical inference in summary-data Mendelian randomization.

Summary-data Mendelian randomization (MR) has become a popular research design to estimate the causal effect of risk exposures. With the sample size of GWAS continuing to increase, it is now possible to use genetic instruments that are only weakly associated with the exposure. We propose a three-sample genome-wide design where typically 1000 independent genetic instruments across the whole genome are used. We develop an empirical partially Bayes statistical analysis approach where instruments are weighted according to their strength; thus weak instruments bring less variation to the estimator. The estimator is highly efficient with many weak genetic instruments and is robust to balanced and/or sparse pleiotropy. We apply our method to estimate the causal effect of body mass index (BMI) and major blood lipids on cardiovascular disease outcomes, and obtain substantially shorter confidence intervals (CIs). In particular, the estimated causal odds ratio of BMI on ischaemic stroke is 1.19 (95% CI: 1.07-1.32, P-value <0.001); the estimated causal odds ratio of high-density lipoprotein cholesterol (HDL-C) on coronary artery disease (CAD) is 0.78 (95% CI: 0.73-0.84, P-value <0.001). However, the estimated effect of HDL-C attenuates and become statistically non-significant when we only use strong instruments. A genome-wide design can greatly improve the statistical power of MR studies. Robust statistical methods may alleviate but not solve the problem of horizontal pleiotropy. Our empirical results suggest that the relationship between HDL-C and CAD is heterogeneous, and it may be too soon to completely dismiss the HDL hypothesis.

Association Between Premorbid Body Mass Index and Amyotrophic Lateral Sclerosis: Causal Inference Through Genetic Approaches.

Purpose: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) was implied in observational studies; however, whether this association is causal remains largely unknown.Materials and Methods: We first conducted a meta-analysis to investigate whether there exits an association between premorbid BMI and ALS. We then employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The Mendelian randomization analysis was implemented using summary statistics for independent instruments obtained from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal effect of BMI on ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses.Results: The meta-analysis showed that a unit increase of premorbid BMI can result in about 3.0% (95% CI 2.1–4.5%) risk reduction of ALS. Using 1,031 instruments that were strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97–1.11, p = 0.275) in the European population. This null association between BMI and ALS also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments.Conclusion: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.

Obligación alimentaria internacional en el marco convencional latinoamericano

Las obligaciones alimentarias internacionales esbozan inconvenientes jurídicos de índole práctica, cuyo procedimiento de solución compromete examinarse preferentemente a través de instrumentos jurídicos internacionales; su propósito es establecer una eficaz protección al elemento subjetivo más frágil y propenso a transigir con relación a su crédito. Las derivaciones de tales condiciones han resultado en la necesidad de disponer de instrumentos normativos independientes en el ámbito espacial americano, para examinar las situaciones que se plantean con mayor intensidad en las relaciones privadas internacionales y la importancia de que esos instrumentos no sean representativos, sino que tengan eficacia operativa. El perfeccionamiento metodológico en ese aspecto se debe, fundamentalmente, a las necesidades del tráfico jurídico internacional, al añadir agentes axiológicos en el vínculo o localización de la relación jurídica internacional, y tener en cuenta las políticas gubernamentales regionales y la justicia sustantiva en el caso concreto; o al abandonar la neutralidad típica de las concepciones formalistas. En sentido opuesto, la heterogeneidad de estos instrumentos jurídicos internacionales en el entorno territorial americano y la no coincidencia de sus signatarios en su pluralidad, presenta indudablemente disparidades en el orden empírico.

Assessment of Financial Conditions of South African Municipalities: A Unique Model for KwaZulu-Natal

Most South African municipalities experience significant financial problems. This study investigates the financial conditions of municipalities in the province of KwaZulu-Natal (KZN). It was found that the most important factors which influence their financial position are unobservable municipally unique factors. The ratio of people of non-working age to the total population is also significant in influencing the financial position of municipalities. This article designed a unique financial conditions measurement framework to evaluate the financial status of local governments. Two independent instruments were developed, first to measure the financial quality of a municipality, and secondly, to identify and examine a number of socio-economic factors possibly affecting the financial condition of these municipalities. The study developed a composite financial condition index (CFCI) and a financial conditions management index (FCMI), and then tested the framework on 51 municipalities in the KZN province from 2009 to 2015. The study used a panel data approach with two financial condition indices as indicators. The findings suggest that, in the absence of individual effects, most of the selected socio-economic variables are relevant in terms of explaining some of the variations in municipal financial conditions. Cross-section fixed-effects do, however, significantly improve the overall performance of the model, suggesting that it is rather the unobservable municipally unique factors affecting municipal financial conditions.Â

Autonomous online measurement of β-D-glucuronidase activity in surface water: is it suitable for rapid E. coli monitoring?

Microbiological water quality is traditionally assessed using culture-based enumeration of faecal indicator bacteria such as Escherichia coli. Despite their relative ease of use, these methods require a minimal 18-24 h-incubation step before the results are obtained. This study aimed to assess the suitability of an autonomous online fluorescence-based technology measuring β-glucuronidase (GLUC) activity for rapid near-real time monitoring of E. coli in water. The analytical precision was determined and compared to an automated microbial detection system, two culture-based assays and quantitative real-time PCR (qPCR). Using replicate measurements of grab samples containing E. coli concentrations between 50 and 2330 CFU.100 mL−1, the autonomous GLUC activity measurement technology displayed an average coefficient of variation (CV) of less than 5% that was 4–8-fold lower than other methods tested. Comparable precision was observed during online in situ monitoring of GLUC activity at a drinking water intake using three independent instruments. GLUC activity measurements were not affected by sewage or sediments at concentrations likely to be encountered during long-term monitoring. Furthermore, significant (p < 0.05) correlations were obtained between GLUC activity and the other assays including defined substrate technology (r = 0.77), membrane filtration (r = 0.73), qPCR (r = 0.55) and the automated microbial detection system (r = 0.50). This study is the first to thoroughly compare the analytical performance of rapid automated detection technologies to established culture and molecular-based methods. Results show that further research is required to correlate GLUC activity to the presence of viable E. coli as measured in terms of CFU.100 mL−1. This would allow the use of autonomous online GLUC activity measurements for rapid E. coli monitoring in water supplies used for drinking water production and recreation.

Thermal structure of the mesopause region during the WADIS-2 rocket campaign

Abstract. This paper presents simultaneous temperature measurements by three independent instruments during the WADIS-2 rocket campaign in northern Norway (69∘ N, 14∘ E) on 5 March 2015. Vertical profiles were measured in situ with the CONE instrument. Continuous mobile IAP Fe lidar (Fe lidar) measurements during a period of 24 h, as well as horizontally resolved temperature maps by the Utah State University (USU) Advanced Mesospheric Temperature Mapper (AMTM) in the mesopause region, are analysed. Vertical and horizontal temperature profiles by all three instruments are in good agreement. A harmonic analysis of the Fe lidar measurements shows the presence of waves with periods of 24, 12, 8, and 6 h. Strong waves with amplitudes of up to 10 K at 8 and 6 h are found. The 24 and 12 h components play only a minor role during these observations. In contrast only a few short periodic gravity waves are found. Horizontally resolved temperatures measured with the AMTM in the hydroxyl (OH) layer are used to connect the vertical temperature profiles. In the field of view of 200 km×160 km only small deviations from the horizontal mean of the order of 5 K are found. Therefore only weak gravity wave signatures occurred. This suggests horizontal structures of more than 200 km. A comparison of Fe lidar, rocket-borne measurements, and AMTM temperatures indicates an OH centroid altitude of about 85 km.

Demographic-specific Validity of the Cancer Prevention Study-3 Sedentary Time Survey.

This study examined the 1-yr test-retest reliability and criterion validity of sedentary time survey items in a subset of participants from a large, nationwide prospective cohort. Participants included 423 women and 290 men age 31 to 72 yr in the Cancer Prevention Study-3. Reliability was assessed by computing Spearman correlation coefficients between responses from prestudy and poststudy surveys. Validity was assessed by comparing survey-estimated sedentary time with a latent variable representing true sedentary time estimated from the 7-d diaries, accelerometry, and surveys through the method of triads. Sensitivity analyses were restricted to 566 participants with an average of 14+ h of diary and accelerometer data per day for 7 d per quarter. Reliability estimates for total sitting time were moderate or strong across all demographic strata (Spearman ρ ≥ 0.6), with significant differences by race (P = 0.01). Reliability estimates were strongest for the TV-related sedentary time item (Spearman ρ, 0.74; 95% confidence interval, 0.70-0.77). The overall validity coefficient (VC) for survey-assessed total sedentary time was 0.62 (95% confidence interval, 0.55-0.69), although VC varied by age group and activity level (P < 0.05). However, VC were similar across groups (P < 0.05) when restricting to highly compliant participants in a sensitivity analysis. The Cancer Prevention Study-3 sedentary behavior questionnaire has acceptable reliability and validity for ranking or categorizing participants according to sedentary time. Acceptable reliability and validity estimates persist across various demographic subgroups.

19 - INVESTIGATING CAUSAL RELATIONSHIPS BETWEEN MAJOR DEPRESSIVE DISORDER AND GENETICALLY CORRELATED TRAITS USING MENDELIAN RANDOMISATION

Background Major Depressive Disorder is a common, complex, heterogeneous disorder that has been found to be associated with a wide array of traits and diseases such as coronary heart disease, type 2 diabetes and cancer. Due to the limitations of observational studies, it is not possible to establish whether such associations are causal, due to reverse causality or due to confounding. Mendelian Randomisation (MR) is an analytical technique that uses genetic instruments that are associated with the exposure of interest, to evaluate whether the association between exposure and outcome is causal in observational data. We sought to investigate the causal relationship between MDD and traits showing phenotypic and genetic correlation. Methods We used a novel multi-SNP MR method called Generalised Summary-based Mendelian Randomisation (GSMR) to investigate direction of causality between MDD and 4 traits with high genetic correlation with MDD – years of education (at the genetic level this is a proxy for general intelligence together with other psychosocial factors), body mass index (BMI), schizophrenia and coronary artery disease, for which GWAS summary statistics are publically available. Bi-directional analysis was performed. Sample sizes for risk factors ranged from 150,064 to 405,072, and the number of genome-wide significant SNPs included as independent instruments ranged from 59 to 124. A primary assumption of the MR method is that the genetic instrument does not have pleiotropic effects on the exposure and outcome. The GSMR method filters out SNPs with significant evidence of pleiotropy. Results GSMR analyses provided evidence for a 1.15 fold increase in MDD per standard deviation of BMI (P =2.7×10-7) and a 0.89 fold decrease in MDD per standard deviation of years of education (P=8.8×10-7). There was no evidence of reverse causality of MDD for BMI (P=0.81) or EDY (P =0.28). For BMI there was some evidence of pleiotropy, as eight SNPs were excluded as outliers. For CAD, the MR analyses were not significant when considering MDD as an outcome (P =0.39) or as an exposure (P = 0.13). There was significant evidence of bidirectional causality with a correlation in effect sizes of schizophrenia SNPs in MDD (P = 7.7×10–46) and MDD SNPs in schizophrenia (P = 6.3 × 10–15). Results from other MR methods such as inverse-weighted meta-analysis, weighted median and MR-Egger were similar to those from GSMR Discussion Our results suggest that MDD is not a causal risk factor for decreased years of education and increased BMI. In contrast, our results suggest that decreased years of education and increased BMI could be investigated as causal risk factors for MDD recognising that an alternative explanation is that these factors are correlated with other risk factors for MDD. Evidence from randomised control trials that have shown improved mood in depressed patients who adhere to a weight-loss plan is consistent with our results. Direction of causality could not be established for the association between MDD and CAD, indicating that the association may be due to other confounding factors. Lastly, our results suggest that MDD and schizophrenia have overlapping causal genetic pathways.

Source apportionment using receptor model based on aerosol mass spectra and 1 h resolution chemical dataset in Tianjin, China

Source apportionment studies have been performed on online receptor datasets in recent years (called online source apportionment), including mass spectra and online chemical dataset. Single particle aerosol mass spectrometry (SPAMS), an important online technique, has the ability to analyze mass spectrum (MS) and particular size information of a single particle in real time. Clustering methods have been widely applied to MS dataset to investigate the sources of particles, although the receptor models are the common tools to probe the particle sources based on the receptor dataset. This work developed a new method (SPAMS-RM) that employed the receptor model (RM) on an MS dataset from SPAMS to identify particle sources. Particles were measured by SPAMS from July 14 to August 15, 2015, at an urban site in Tianjin, China. Multilinear Engine-2 (ME2) and adaptive resonance theory-based neural networks-2a (ART-2a) were separately used to analyze the single particle MS dataset. This work also evaluated the performance of SPAMS-RM method. Concentrations of chemical components of PM2.5 (particulate matter with an aerodynamic diameter of less than 2.5 μm) and gaseous pollutants were measured by independent online instruments (1 h resolution). Source apportionment was separately conducted using two receptor models, Positive Matrix Factorization (PMF) and ME2, based on the 1 h resolution chemical dataset. This method was called online chemical source apportionment (OCSA-RM). ART-2a obtained 19 clusters that merged into five major classes: carbon species, rich-K, sea salt, crustal dust, and industrial metals. SPAMS-RM identified eight sources by interpreting the MS characteristic of factors and investigating the relationship of the temporal trends of factor contributions, chemical species, gaseous pollutants, and particle clusters. OCSA-ME2 and OCSA-PMF both identified seven factors. Source apportionment results between SPAMS-RM and OCSA-ME2/PMF were compared. Each method identified coal combustion, biomass burning, sea salt, nitrate source, sulfate source, vehicle emission, and crustal dust. The SPAMS-RM results showed that nitrate source was the most significant contributor (34%) to the PM followed by sulfate source (17%), coal combustion (14%), crustal dust (11%), vehicle emission (10%), biomass burning-OCEC (7%), and industrial activities & sea salt (4%). Some differences between SPAMS-RM and OCSA-ME2/PMF results existed and might be due to chemical analysis methods and sampling methods. ME2 was used for the first time to identify the PM sources based on the MS dataset from SPAMS and demonstrated its capability when coupled with MS dataset from SPAMS to apportion the source of PM.

Solar physics with the Square Kilometre Array

The Square Kilometre Array (SKA) will be the largest radio telescope ever built, aiming to provide collecting area larger than 1 km2. The SKA will have two independent instruments, SKA-LOW comprising of dipoles organized as aperture arrays in Australia and SKA-MID comprising of dishes in South Africa. Currently the phase-1 of SKA, referred to as SKA1, is in its late design stage and construction is expected to start in 2020. Both SKA1-LOW (frequency range of 50–350 MHz) and SKA1-MID Bands 1, 2, and 5 (frequency ranges of 350–1050, 950–1760, and 4600–15,300 MHz, respectively) are important for solar observations. In this paper we present SKA’s unique capabilities in terms of spatial, spectral, and temporal resolution, as well as sensitivity and show that they have the potential to provide major new insights in solar physics topics of capital importance including (i) the structure and evolution of the solar corona, (ii) coronal heating, (iii) solar flare dynamics including particle acceleration and transport, (iv) the dynamics and structure of coronal mass ejections, and (v) the solar aspects of space weather. Observations of the Sun jointly with the new generation of ground-based and space-borne instruments promise unprecedented discoveries.

Are There Any Volatility Spill-Over Effects among Cryptocurrencies and Widely Traded Asset Classes?

In the present paper, we investigate connectedness within cryptocurrency markets as well as across the Bitcoin index (hereafter, BPI) and widely traded asset classes such as traditional currencies, stock market indices and commodities, such as gold and Brent oil. A spill over index approach with the spectral representation of variance decomposition networks, is employed to measure connectedness. Results show no significant spillover effects between the nascent market of cryptocurrencies and other financial markets. We suggest that cryptocurrencies are real independent financial instruments that pose no danger to financial system stability. Concerning the connectedness within the cryptocurrency markets, we report a time–frequency–dynamics connectedness nature. Moreover, the decomposition of the total spill over index is mostly dominated by a short frequency component (2–4 days) leading to the conclusion that this nascent market is highly speculative at present. These findings provide insights for regulators and potential international investors.

Global comparison of benthic nepheloid layers based on 52 years of nephelometer and transmissometer measurements

Global maps of maximum bottom particle concentration, benthic nepheloid layer thickness, and integrated particle mass in benthic nepheloid layers (BNL) based on 2412 global profiles collected using the Lamont Thorndike nephelometer from 1964 to 1984 are compared with maps of those same properties compiled from 6392 global profiles measured by transmissometers from 1979 to 2016. Outputs from both instruments were converted to particulate matter concentration (PM). The purposes of this paper are to compare global differences and similarities in the location and intensity of BNLs measured with these two independent instruments over slightly overlapping decadal time periods, to combine the data sets in order to expand the time scale of global in situ measurements of BNLs, and to gain insight about the factors creating/sustaining BNLs. The similarity between general locations of high and low particle concentration BNLs during the two time periods indicates that the driving forces of erosion and resuspension of bottom sediments are spatially persistent during recent decadal time spans, though in areas of strong BNLs, intensity is highly episodic. Topography and well-developed current systems play a role. These maps will help to understand deep ocean sediment dynamics, linkage with upper ocean dynamics, the potential for scavenging of adsorption-prone elements near the seafloor, and provide a comprehensive comparison of these data sets on a global scale.During both time periods, BNLs are weak or absent in most of the Pacific, Indian, and Atlantic basins away from continental margins. High surface eddy kinetic energy is associated with the Kuroshio Current east of Japan. Both data sets show weak BNLs south of the Kuroshio, but no transmissometer data have been collected beneath the Kuroshio itself. Sparse nephelometer data show moderate BNLs just north of the Kuroshio Extension, but with much lower concentrations than beneath the Gulf Stream. Strong BNLs are found in areas where eddy kinetic energy in overlying waters, mean kinetic energy near bottom, and energy dissipation within the bottom boundary layer are high. Areas of strongest BNLs include the Western North Atlantic, Argentine Basin (South Atlantic), areas around South Africa tied to the Agulhas Current region, and somewhat random locations in the Antarctic Circumpolar Current of the Southern Ocean.

Are EARLINET and AERONET climatologies consistent? The case of Thessaloniki, Greece

Abstract. In this study we investigate the climatological behavior of the aerosol optical properties over Thessaloniki during the years 2003–2017. For this purpose, measurements of two independent instruments, a lidar and a sunphotometer, were used. These two instruments represent two individual networks, the European Lidar Aerosol Network (EARLINET) and the Aerosol Robotic Network (AERONET). They include different measurement schedules. Fourteen years of lidar and sunphotometer measurements were analyzed, independently of each other, in order to obtain the annual cycles and trends of various optical and geometrical aerosol properties in the boundary layer, in the free troposphere, and for the whole atmospheric column. The analysis resulted in consistent statistically significant and decreasing trends of aerosol optical depth (AOD) at 355 nm of −23.2 and −22.3 % per decade in the study period over Thessaloniki for the EARLINET and the AERONET datasets, respectively. Therefore, the analysis indicates that the EARLINET sampling schedule can be quite effective in producing data that can be applied to long-term climatological studies. It is also shown that the observed decreasing trend is mainly attributed to changes in the aerosol load inside the boundary layer. Seasonal profiles of the most dominant aerosol mixture types observed over Thessaloniki have been generated from the lidar data. The higher values of the vertically resolved extinction coefficient at 355 nm appear in summer, while the lower ones appear in winter. The dust component is more dominant in the free troposphere than in the boundary layer during summer. The biomass burning layers tend to arrive in the free troposphere during spring and summer. This kind of information can be quite useful for applications that require a priori aerosol profiles. For instance, they can be utilized in models that require aerosol climatological data as input, in the development of algorithms for satellite products, and also in passive remote-sensing techniques that require knowledge of the aerosol vertical distribution.

Thyroid Stimulating Hormone and Bone Mineral Density: Evidence From a Two-Sample Mendelian Randomization Study and a Candidate Gene Association Study.

With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (expression quantitative trait loci [eQTLs]) are associated with BMD. For both analyses, we used summary-level data of genomewide association studies (GWASs) investigating BMD of the femoral neck (n = 32,735) and the lumbar spine (n = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium. For the MR study, we selected 20 genetic variants that were previously identified for circulating TSH levels in a GWAS meta-analysis (n = 26,420). All independent genetic instruments for TSH were combined in analyses for both femoral neck and lumbar spine BMD. In these studies, we found no evidence that a genetically determined 1-standard deviation (SD) decrease in circulating TSH concentration was associated with femoral neck BMD (0.003 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.053 to 0.048; p = 0.92) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.069 to 0.049; p = 0.73). A total of 706 common genetic variants have been mapped to the TSHR locus and expression loci for TSHR. However, none of these genetic variants were associated with BMD at the femoral neck or lumbar spine. In conclusion, we found no evidence for a causal effect of circulating TSH on BMD, nor did we find any association between genetic variation at the TSHR locus or expression thereof and BMD. © 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc.

A comparison of monetary and fiscal policy interaction under ‘sound’ and ‘functional’ finance regimes

AbstractThe interest rate and the fiscal balance can be thought of as two independent instruments to be assigned to two targets, the path of output and the path of public debt. Under what we term a ‘sound finance rule’ the interest rate targets output while the fiscal balance targets public debt; under a ‘functional finance rule’ the budget balance targets the output gap and the interest rate targets the debt ratio. The same unique combination of interest rate and fiscal balance will be consistent with output at potential and a constant debt‐GDP ratio regardless of which instrument is assigned to which target. The stability characteristics of the two rules differ, however. At low levels of debt, both rules converge to the targets, but there is a threshold debt level above which only the functional finance rule converges. Contrary to conventional wisdom, therefore, the case for countercyclical fiscal policy becomes stronger, not weaker, when the ratio of public debt to GDP is already high. We apply our framework to describe the possibility of policy‐generated cycles in the United States over the past five decades.

Discovery of Galactic O iv and O v X-ray absorption due to transition temperature gas in the PKS 2155-304 spectrum

FUV observations have revealed the transition temperature gas (TTG; $\log{T({\mathrm{K}})}$ ~ 5), located in the lower Galactic halo and in the High Velocity Clouds. However, the corresponding X-ray absorption has so far remained mostly undetected. In order to make an improvement in this respect in Galactic X-ray absorption studies, we accumulated very deep (~3 Ms) spectra of the blazar PKS 2155-304 obtained with the spectrometers RGS1, RGS2, LETG/HRC and LETG/ACIS-S and studied the absorption lines due to the intervening Galactic components. The very high quality of the data and the coverage of important wavelengths with at least two independent instruments allowed us to reliably detect ten Galactic lines with better than 99.95% confidence. We discovered significant absorption from blended OIV transitions 1s-2p $^2$S (22.571 \AA ), 1s-2p $^2$P (22.741 \AA ) and 1s-2p $^2$D (22.777 \AA ), and from the OV transition 1s-2p (22.370 \AA ) from TTG at $\log{T({\mathrm{K}})} \thinspace = \thinspace 5.2\pm0.1$. A joint X-ray and FUV analysis indicated that photoionisation is negligible for this component and that the gas is in a cooling transition phase. However, the temperature is high enough that the column density ratio N(OIV)/N(OV) is not significantly different from that in collisional ionisation equilibrium (CIE). Under CIE we obtained $N_{\mathrm{OIV}}$= 3.6$\pm$2.0 $\times 10^{15}$ cm$^{-2}$, corresponding to $N_{\mathrm{H}}$ = 1.0$\pm$0.5 $\times 10^{19} \frac{Z_{\odot}}{Z_{\mathrm{TTG}}}$ cm$^{-2}$.

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach.

BackgroundThe link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.Methods and FindingsWe conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination.ConclusionsWe present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

Два типа шоков монетарной политики в DSGE-модели, оцененной для России

In the paper DSGE model is estimated with two independent monetary instruments and limited ability to perform intertemporal optimization of households' consumption. The model is estimated on the Russian data of 2001-2014 for revealing two-dimensional monetary policy shocks: foreign exchange rate shocks and interest rate shocks. The estimation takes into account structural break in parameters of monetary policy rules happened at the end of 2008. Decomposing key macroeconomic variables on structural shocks allows to conclude that Bank of Russia had used its discretionary monetary power to struggle inflation and Ruble devaluation at the expense of recession deepening in the period of world financial crises of 2008-2009. Analyzing transmission mechanisms for two monetary policy instruments the conclusion was made that discretionary foreign exchange market interventions should be used in a situation of stagflation caused by strong negative balance of payments shocks.

Are All Biases Bad? Collaborative Grounded Theory in Developmental Evaluation of Education Policy

Background: Using two researchers as independent instruments for interpretation in education policy evaluation, this study applies a collaborative grounded theory approach to qualitative data analysis and theory generation. Purpose: This study argues that varied perspectives should be a critical component in the methodological and analytical choices of education research, especially when the sought after outcome is deeper understanding of the impact, both positive and negative, of an education program or policy. In this study, rather than using one researcher to confirm the reliability of the other, the study explores the outcome of drawing on the positional reflexivity of two researchers, each with a distinct perspective, as a potential strength to co-generate themes and theory in the evaluation of complex policy or programs.Setting: The data for this analysis originated from interviews of education leaders (n = 13) from two states with contrasting approaches to teacher evaluation: Kentucky and California. Intervention: NA Research Design: Qualitative developmental evaluation Data Collection and Analysis: Semi-structured interviews and grounded theory coding Findings: Results suggest that more robust theory and analysis may result from independent thematic development and converged theory generation when working in a research team, as opposed to early application of inter-rater reliability. The reflexivity of different perspectives was, in part, reflexive of the self—their own biased perspective and prior experience. When merged, their joint interpretation may have unearthed greater dimensionality. Findings from this study can inform future strategies for evaluating qualitative research data, especially within a developmental evaluation approach aimed at understanding system complexity in education policy and practice.

Boundary-layer turbulent processes and mesoscale variability represented by numerical weather prediction models during the BLLAST campaign

Abstract. This study evaluates the ability of three operational models, with resolution varying from 2.5 to 16 km, to predict the boundary-layer turbulent processes and mesoscale variability observed during the Boundary Layer Late-Afternoon and Sunset Turbulence (BLLAST) field campaign. We analyse the representation of the vertical profiles of temperature and humidity and the time evolution of near-surface atmospheric variables and the radiative and turbulent fluxes over a total of 12 intensive observing periods (IOPs), each lasting 24 h. Special attention is paid to the evolution of the turbulent kinetic energy (TKE), which was sampled by a combination of independent instruments. For the first time, this variable, a central one in the turbulence scheme used in AROME and ARPEGE, is evaluated with observations.In general, the 24 h forecasts succeed in reproducing the variability from one day to another in terms of cloud cover, temperature and boundary-layer depth. However, they exhibit some systematic biases, in particular a cold bias within the daytime boundary layer for all models. An overestimation of the sensible heat flux is noted for two points in ARPEGE and is found to be partly related to an inaccurate simplification of surface characteristics. AROME shows a moist bias within the daytime boundary layer, which is consistent with overestimated latent heat fluxes. ECMWF presents a dry bias at 2 m above the surface and also overestimates the sensible heat flux. The high-resolution model AROME resolves the vertical structures better, in particular the strong daytime inversion and the thin evening stable boundary layer. This model is also able to capture some specific observed features, such as the orographically driven subsidence and a well-defined maximum that arises during the evening of the water vapour mixing ratio in the upper part of the residual layer due to fine-scale advection. The model reproduces the order of magnitude of spatial variability observed at mesoscale (a few tens of kilometres). AROME provides a good simulation of the diurnal variability of the turbulent kinetic energy, while ARPEGE shows the right order of magnitude.