A Mendelian randomization approach to assess the causal relationship of gamma-glutamyl transferase with blood pressure and insulin

Background: Elevated levels of g-glutamyl transferase (GGT) have been associated with subsequent risk of elevated blood pressure (BP), hypertension and diabetes. However, the causality of these relationships has not been addressed. Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. Such allocation is expected to be independent of any behavioural and environmental factors (known or unknown), allowing the analysis of largely unconfounded risk associations that are not due to reverse causation. Methods: We performed a cross-sectional analysis among 4361 participants to the population based CoLaus study. Associations of sex-specific GGT quartiles with systolic BP, diastolic BP and insulin levels were assessed using multivariable linear regression analyses. The rs2017869 GGT1 variant, which explained 1.6% of the variance in GGT levels, was used as an instrument to perform a Mendelian randomization analysis. Results: Median age of the study population was 53 years. After age and sex adjustment, GGT quartiles were strongly associated with systolic and diastolic BP (all p for linear trend <0.0001). After multivariable adjustment, these relationships were significantly attenuated, but remained significant for systolic (b(95%CI)¼1.30 (0.32;2.03), p¼0.007) and diastolic BP (b (95%CI)¼0.57 (0.02;1.13), p¼0.04). Using Mendelian randomization, we observed no positive association of GGT with either systolic BP (b (95%CI)¼-5.68 (-11.51-0.16), p¼0.06) or diastolic BP (b (95%CI)¼ -2.24 (-5.98;1.49) p¼0.24). The association of GGT with insulin was also attenuated after multivariable adjustment. Nevertheless, a strong linear trend persisted in the fully adjusted model (b (95%CI)¼0.07 (0.04;0.09), p<0.0001). Using Mendelian randomization, we observed a similar positive association of GGT with insulin (b (95%CI)¼0.19 (0.01-0.37), p¼0.04). Conclusion: In this study, we found evidence for a direct causal relationship between GGT and insulin, suggesting that oxidative stress may be causally implicated in the pathogenesis of type 2 diabetes mellitus.

Does CRP Play a Causal Role in the Development of Coronary Heart Disease: Results of a Mendelian Randomisation Experiment Involving 128,935 People

Background: C-reactive protein (CRP) is associated with risk of coronary heart disease (CHD). Whether CRP is causally associated with CHD or merely a marker of underlying atherosclerosis is uncertain. Methods: We used a Mendelian randomisation design to investigate the causal relationship of CRP with CHD. We identified three genetic variants in the CRP locus (rs7553007, rs1130864 and rs1205) which influence CRP levels. We tested the three SNPs for association with CHD amongst 28,112 CHD cases and 100,823 controls. We then compared the observed relationship between the SNPs and CHD, with that predicted from the association of SNPs with CRP levels, and of CRP levels with CHD. Results: SNPs in the CRP locus were not associated with CHD: rs7553007, OR 0.98 (95% CI, 0.94-1.01); rs1130864, OR 1.00 (95% CI, 0.86-1.15); rs1205, OR 1.03 (95% CI, 0.99-1.07); combined OR for all three SNPs, 1.00 (95% CI, 0.97-1.02), per 20% lower CRP (figure). In contrast, the predicted OR for CHD from a 20% lower CRP level is 0.94 (95% CI, 0.94- 0.95), based on meta-analysis of observational studies. Conclusions: Though CRP variants are associated with CRP levels, and CRP levels with risk of CHD, we observed that CRP variants are not associated with CHD risk. Our Mendelian randomisation experiment strongly argues against a causal association of CRP with CHD.

Use of a Mendelian randomization approach to assess the causal relation of gamma-Glutamyltransferase with blood pressure and serum insulin levels.

Elevated levels of γ-glutamyltransferase (GGT) have been associated with elevated blood pressure (BP) and diabetes. However, the causality of these relations has not been addressed. The authors performed a cross-sectional analysis (2003-2006) among 4,360 participants from the population-based Cohorte Lausannoise (CoLaus) Study (Lausanne, Switzerland). The rs2017869 variant of the γ-glutamyltransferase 1 (GGT1) gene, which explained 1.6% of the variance in GGT levels, was used as an instrument for Mendelian randomization (MR). Sex-specific GGT quartiles were strongly associated with both systolic and diastolic BP (all P's < 0.0001). After multivariable adjustment, these relations were attenuated but remained significant. Using MR, the authors observed no positive association of GGT with BP (systolic: β -5.68, 95% confidence interval (CI): -11.51, 0.16 (P = 0.06); diastolic: β = -2.24, 95% CI: -5.98, 1.49 (P = 0.24)). The association of GGT with insulin was also attenuated after multivariable adjustment but persisted in the fully adjusted model (β = 0.07, 95% CI: 0.04, 0.09; P < 0.0001). Using MR, the authors also observed a positive association of GGT with insulin (β = 0.19, 95% CI: 0.01, 0.37; P = 0.04). In conclusion, the authors found evidence for a direct causal relation of GGT with fasting insulin but not with BP.

Alcohol and cannabis use as risk factors for injury--a case-crossover analysis in a Swiss hospital emergency department.

BACKGROUND: There is sufficient and consistent evidence that alcohol use is a causal risk factor for injury. For cannabis use, however, there is conflicting evidence; a detrimental dose-response effect of cannabis use on psychomotor and other relevant skills has been found in experimental laboratory studies, while a protective effect of cannabis use has also been found in epidemiological studies. METHODS: Implementation of a case-crossover design study, with a representative sample of injured patients (N = 486; 332 men; 154 women) from the Emergency Department (ED) of the Lausanne University Hospital, which received treatment for different categories of injuries of varying aetiology. RESULTS: Alcohol use in the six hours prior to injury was associated with a relative risk of 3.00 (C.I.: 1.78, 5.04) compared with no alcohol use, a dose-response relationship also was found. Cannabis use was inversely related to risk of injury (RR: 0.33; C.I.: 0.12, 0.92), also in a dose-response like manner. However, the sample size for people who had used cannabis was small. Simultaneous use of alcohol and cannabis did not show significantly elevated risk. CONCLUSION: The most surprising result of our study was the inverse relationship between cannabis use and injury. Possible explanations and underlying mechanisms, such as use in safer environments or more compensatory behavior among cannabis users, were discussed.

The role of causal links in performance measurement models

Abstract Purpose: Several well-known managerial accounting performance measurement models rely on causal assumptions. Whilst users of the models express satisfaction and link them with improved organizational performance, academic research, of the realworld applications, shows few reliable statistical associations. This paper provides a discussion on the"problematic" of causality in a performance measurement setting. Design/methodology/approach: This is a conceptual study based on an analysis and synthesis of the literature from managerial accounting, organizational theory, strategic management and social scientific causal modelling. Findings: The analysis indicates that dynamic, complex and uncertain environments may challenge any reliance upon valid causal models. Due to cognitive limitations and judgmental biases, managers may fail to trace correct cause-and-effect understanding of the value creation in their organizations. However, even lacking this validity, causal models can support strategic learning and perform as organizational guides if they are able to mobilize managerial action. Research limitations/implications: Future research should highlight the characteristics necessary for elaboration of convincing and appealing causal models and the social process of their construction. Practical implications: Managers of organizations using causal models should be clear on the purposes of their particular models and their limitations. In particular, difficulties are observed in specifying detailed cause and effect relations and their potential for communicating and directing attention. They should therefore construct their models to suit the particular purpose envisaged. Originality/value: This paper provides an interdisciplinary and holistic view on the issue of causality in managerial accounting models.

Gene Set Analysis for improving genetic association studies

Introduction. Genetic epidemiology is focused on the study of the genetic causes that determine health and diseases in populations. To achieve this goal a common strategy is to explore differences in genetic variability between diseased and nondiseased individuals. Usual markers of genetic variability are single nucleotide polymorphisms (SNPs) which are changes in just one base in the genome. The usual statistical approach in genetic epidemiology study is a marginal analysis, where each SNP is analyzed separately for association with the phenotype. Motivation. It has been observed, that for common diseases the single-SNP analysis is not very powerful for detecting genetic causing variants. In this work, we consider Gene Set Analysis (GSA) as an alternative to standard marginal association approaches. GSA aims to assess the overall association of a set of genetic variants with a phenotype and has the potential to detect subtle effects of variants in a gene or a pathway that might be missed when assessed individually. Objective. We present a new optimized implementation of a pair of gene set analysis methodologies for analyze the individual evidence of SNPs in biological pathways. We perform a simulation study for exploring the power of the proposed methodologies in a set of scenarios with different number of causal SNPs under different effect sizes. In addition, we compare the results with the usual single-SNP analysis method. Moreover, we show the advantage of using the proposed gene set approaches in the context of an Alzheimer disease case-control study where we explore the Reelin signal pathway.

The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

OBJECTIVE: Studies suggest that smoking may be a risk factor for the development of microvascular complications such as diabetic peripheral neuropathy (DPN). The objective of this study was to assess the relationship between smoking and DPN in persons with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: A systematic review of the PubMed, Embase, and Cochrane clinical trials databases was conducted for the period from January 1966 to November 2014 for cohort, cross-sectional and case-control studies that assessed the relationship between smoking and DPN. Separate meta-analyses for prospective cohort studies and case-control or cross-sectional studies were performed using random effects models. RESULTS: Thirty-eight studies (10 prospective cohort and 28 cross-sectional) were included. The prospective cohort studies included 5558 participants without DPN at baseline. During follow-up ranging from 2 to 10 years, 1550 cases of DPN occurred. The pooled unadjusted odds ratio (OR) of developing DPN associated with smoking was 1.26 (95% CI 0.86-1.85; I(2) = 74%; evidence grade: low strength). Stratified analyses of the prospective studies revealed that studies of higher quality and with better levels of adjustment and longer follow-up showed a significant positive association between smoking and DPN, with less heterogeneity. The cross-sectional studies included 27,594 participants. The pooled OR of DPN associated with smoking was 1.42 (95% CI 1.21-1.65; I(2) = 65%; evidence grade: low strength). There was no evidence of publication bias. CONCLUSIONS: Smoking may be associated with an increased risk of DPN in persons with diabetes. Further studies are needed to test whether this association is causal and whether smoking cessation reduces the risk of DPN in adults with diabetes.

The vertical dimension of social relations and accurate interpersonal perception: A meta-analysis (Publishd online: 24 Oct. 2014)

There is little consensus regarding how verticality (social power, dominance, and status) is related to accurate interpersonal perception. The relation could be either positive or negative, and there could be many causal processes at play. The present article discusses the theoretical possibilities and presents a meta-analysis of this question. In studies using a standard test of interpersonal accuracy, higher socioeconomic status (SES) predicted higher accuracy defined as accurate inference about the meanings of cues; also, higher experimentally manipulated vertical position predicted higher accuracy defined as accurate recall of others' words. In addition, although personality dominance did not predict accurate inference overall, the type of personality dominance did, such that empathic/responsible dominance had a positive relation and egoistic/aggressive dominance had a negative relation to accuracy. In studies involving live interaction, higher experimentally manipulated vertical position produced lower accuracy defined as accurate inference about cues; however, methodological problems place this result in doubt.

Tracing the associations between sex, the atypical and the combined atypical-melancholic depression subtypes: A path analysis.

BACKGROUND: Numerous studies have examined determinants leading to preponderance of women in major depressive disorder (MDD), which is particularly accentuated for the atypical depression subtype. It is thus of interest to explore the specific indirect effects influencing the association between sex and established depression subtypes. METHODS: The data of 1624 subjects with a lifetime diagnosis of MDD derived from the population-based PsyCoLaus data were used. An atypical (n=256), a melancholic (n=422), a combined atypical and melancholic features subtype (n=198), and an unspecified MDD group (n=748) were constructed according to the DSM-IV specifiers. Path models with direct and indirect effects were applied to the data. RESULTS: Partial mediation of the female-related atypical and combined atypical-melancholic depression subtypes was found. Early anxiety disorders and high emotion-orientated coping acted as mediating variables between sex and the atypical depression subtype. In contrast, high Body Mass Index (BMI) served as a suppression variable, also concerning the association between sex and the combined atypical-melancholic subtype. The latter association was additionally mediated by an early age of MDD onset and early/late anxiety disorders. LIMITATIONS: The use of cross-sectional data does not allow causal conclusions. CONCLUSIONS: This is the first study that provides evidence for a differentiation of the general mechanisms explaining sex differences of overall MDD by depression subtypes. Determinants affecting the pathways begin early in life. Since some of them are primarily of behavioral nature, the present findings could be a valuable target in mental health care.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Analysis of Patterns in Electricity Spot Market Time Series

Due to its non-storability, electricity must be produced at the same time that it is consumed, as a result prices are determined on an hourly basis and thus analysis becomes more challenging. Moreover, the seasonal fluctuations in demand and supply lead to a seasonal behavior of electricity spot prices. The purpose of this thesis is to seek and remove all causal effects from electricity spot prices and remain with pure prices for modeling purposes. To achieve this we use Qlucore Omics Explorer (QOE) for the visualization and the exploration of the data set and Time Series Decomposition method to estimate and extract the deterministic components from the series. To obtain the target series we use regression based on the background variables (water reservoir and temperature). The result obtained is three price series (for Sweden, Norway and System prices) with no apparent pattern.

Images of the future of privacy: A privacy dynamics framework and a causal layered

The future of privacy in the information age is a highly debated topic. In particular, new and emerging technologies such as ICTs and cognitive technologies are seen as threats to privacy. This thesis explores images of the future of privacy among non-experts within the time frame from the present until the year 2050. The aims of the study are to conceptualise privacy as a social and dynamic phenomenon, to understand how privacy is conceptualised among citizens and to analyse ideal-typical images of the future of privacy using the causal layered analysis method. The theoretical background of the thesis combines critical futures studies and critical realism, and the empirical material is drawn from three focus group sessions held in spring 2012 as part of the PRACTIS project. From a critical realist perspective, privacy is conceptualised as a social institution which creates and maintains boundaries between normative circles and preserves the social freedom of individuals. Privacy changes when actors with particular interests engage in technology-enabled practices which challenge current privacy norms. The thesis adopts a position of technological realism as opposed to determinism or neutralism. In the empirical part, the focus group participants are divided into four clusters based on differences in privacy conceptions and perceived threats and solutions. The clusters are fundamentalists, pragmatists, individualists and collectivists. Correspondingly, four ideal-typical images of the future are composed: ‘drift to low privacy’, ‘continuity and benign evolution’, ‘privatised privacy and an uncertain future’, and ‘responsible future or moral decline’. The images are analysed using the four layers of causal layered analysis: litany, system, worldview and myth. Each image has its strengths and weaknesses. The individualistic images tend to be fatalistic in character while the collectivistic images are somewhat utopian. In addition, the images have two common weaknesses: lack of recognition of ongoing developments and simplistic conceptions of privacy based on a dichotomy between the individual and society. The thesis argues for a dialectical understanding of futures as present images of the future and as outcomes of real processes and mechanisms. The first steps in promoting desirable futures are the awareness of privacy as a social institution, the awareness of current images of the future, including their assumptions and weaknesses, and an attitude of responsibility where futures are seen as the consequences of present choices.

Cooperative strategy in emerging markets - analysis of interfirm r&d cooperation and performance in Russian manufacturing companies

Emerging markets have come to play a significant role in the world, not only due to their strong economic growth but because they have been able to foster an increasing number of innovative high technology oriented firms. However, as the markets continue to change and develop, there remain many companies in emerging markets that struggle with their competitiveness and innovativeness. To improve competitive capabilities, many scholars have come to favor interfirm cooperation, which is perceived to help companies access new knowledge and complementary resources and, by so doing, enables them to catch up quickly with Western competitors. Regardless of numerous attempts by strategic management scholars, the research field remains very fragmented and lacks understanding on how and when interfirm cooperation contributes to firm performance and competiveness in emerging markets. Furthermore, the reasons why interfirm R&D sometimes succeeds but fails at other times frequently remain unidentified. This thesis combines the extant literature on competitive and cooperative strategy, dynamic capabilities, and R&D cooperation while studying interfirm R&D relationships in and between Russian manufacturing companies. Employing primary survey data, the thesis presents numerous novel findings regarding the effect of R&D cooperation and different types of R&D partner on firms’ exploration and exploitation performance. Utilizing a competitive strategy framework enables these effects to be explained in more detail, and especially why interfirm cooperation, regardless of its potential, has had a modest effect on the general competitiveness of emerging market firms. This thesis contributes especially to the strategic management literature and presents a more holistic perspective on the usefulness of cooperative strategy in emerging markets. It provides a framework through which it is possible to assess the potential impacts of different R&D cooperation partners and to clarify the causal relationships between cooperation, performance, and long term competitiveness.