Evidence For Causal Effect Research Articles

Causality of immune cells on primary sclerosing cholangitis: a bidirectional two-sample Mendelian randomization study.

Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood. A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran's Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy. In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC. Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization

BackgroundsA growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.ObjectivesThis study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.MethodsGenetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.ResultsThere was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10− 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10− 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10− 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10− 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).ConclusionsOur study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

No evidence for a genetic causal effect of breast cancer on venous thromboembolism: a mendelian randomization study.

Active cancer is known to contribute to venous thromboembolism (VTE), but the cause-and-effect association of breast cancer on VTE is not yet clear. In order to investigate the possible causal relationships, we used a Mendelian randomization analysis. Data for generically predicted breast cancer were identified based on the BCAC consortium. A meta-analysis of genome-wide association study (GWAS) comprising 1,500,861 participants for VTE as well as data from the FinnGen study for VTE, DVT and PE was used for the causal-effect estimation. Our primary method was inverse-variance weighted (IVW), and our supplementary methods included weighted median and MR-Egger. We also carried out sensitivity analysis for the study. No evidence of causal-effect was detected of overall breast cancer on VTE in both the GWAS meta-analysis (OR=1.01, 95%CI:0.98-1.04, p = 0.495) and the FinnGen consortium (OR=1.00,95%CI:0.96-1.04, p = 0.945). In addition, the presence of ER-positive or ER-negative disease did not significantly influence the incidence of VTE and its subtypes. In conclusion, no genetic cause-and-effect of breast cancer on VTE risk was detected in the large MR analysis.

A two-sample Mendelian randomization analysis of modifiable risk factors and intracranial aneurysms

We aimed to investigate the causality between potentially modifiable risk factors and the risk of intracranial aneurysm. Genetic instruments for 51 modifiable factors and intracranial aneurysm data were obtained from recently published genome-wide association studies. We applied two-sample Mendelian randomization methods to investigate their causal relationships. Genetically predicted cigarettes per day, smoking initiation, systolic blood pressure, hypertension and body fat percentage were significantly associated with an increased risk of intracranial aneurysm [odds ratios (OR) 2.67, 95% confidence interval (CI) 1.75–4.07, p = 5.36 × 10–6, OR 1.53, 95% CI 1.32–1.77, p = 9.58 × 10–9, OR 1.05, 95% CI 1.02–1.08, p = 1.18 × 10–3, OR 1.65, 95% CI 1.19–2.28, p = 2.56 × 10–3 and OR 1.29, 95% CI 1.11–1.52, p = 1.33 × 10–3, respectively]. Type 2 diabetes mellitus was significantly associated with a decreased risk of intracranial aneurysm (OR 0.89, 95% CI 0.83–0.95, p = 8.54 × 10–4). Body fat percentage was significantly associated with subarachnoid haemorrhage (p = 5.70 × 10–5). This study provided genetic evidence of causal effects of smoking, blood pressure, type 2 diabetes mellitus and obesity on the risk of intracranial aneurysm.

Causal relationship between genetically predicted depression and cancer risk: a two-sample bi-directional mendelian randomization

BackgroundDepression has been reported to be associated with some types of cancer in observational studies. However, the direction and magnitude of the causal relationships between depression and different types of cancer remain unclear.MethodsWe performed the two-sample bi-directional mendelian randomization with the publicly available GWAS summary statistics to investigate the causal relationship between the genetically predicted depression and the risk of multiple types of cancers, including ovarian cancer, breast cancer, lung cancer, glioma, pancreatic cancer, lymphoma, colorectal cancer, thyroid cancer, bladder cancer, and kidney cancer. The total sample size varies from 504,034 to 729,150. Causal estimate was calculated by inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the causal relationship.ResultsAfter correction for heterogeneity and horizontal pleiotropy, we only detected suggestive evidence for the causality of genetically predicted depression on breast cancer (OR = 1.09, 95% CI: 1.03–1.15, P = 0.0022). The causal effect of depression on breast cancer was consistent in direction and magnitude in the sensitivity analysis. No evidence of causal effects of depression on other types of cancer and reverse causality was detected.ConclusionsThe result of this study suggests a causative effect of genetically predicted depression on specific type of cancer. Our findings emphasize the importance of depression in the prevention and treatment of breast cancer.

Effects of increased body mass index on employment status: a Mendelian randomisation study

BackgroundThe obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment.Dataset/methodsWhite UK ethnicity participants of working age (men 40–64 years, women 40–59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes.ResultsRegressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m2 BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results.DiscussionBMI appears to exert a causal effect on employment status, largely by affecting an individual’s health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.

The effect of language on performance: do gendered languages fail women in maths?

Research suggests that gendered languages are associated with gender inequality. However, as languages are embedded in cultures, evidence for causal effects are harder to provide. We contribute to this ongoing debate by exploring the relationship between gendered languages and the gender gap in mathematics achievements. We provide evidence for causality by exploiting the prominent (but not exclusive) practice in gendered languages of using masculine generics to address women. In an experiment on a large representative sample of the Hebrew-speaking adult population in Israel, we show that addressing women in the feminine, compared to addressing them in the masculine, reduces the gender gap in mathematics achievements by a third. These effects are stronger among participants who acquired the Hebrew language early in childhood rather than later in life, suggesting that it is the extent of language proficiency that generates one’s sensitivity to being addressed in the masculine or in the feminine. Moreover, when women are addressed in the masculine, their efforts (in terms of time spent on the maths test) decrease and they report feeling that “science is for men” more than when addressed in the feminine. We supplement the analysis with two experiments that explore the roles of general and task-specific stereotypes in generating these effects.

An investigation of causal relationships between prediabetes and vascular complications

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.

Effects of social network diversity in the disablement process: a comparison of causal inference methods and an outcome-wide approach to the Indonesian Family Life Surveys, 2007\u20132015

BackgroundSocial networks (SN) have been proven to be instrumental for healthy aging and function as important safety nets, particular for older adults in low and middle-income countries (LMICs). Despite the importance of interpreting health outcomes in terms of SN, in many LMICs – including Indonesia – epidemiological studies and policy responses on the health effects of SN for aging populations are still uncommon. Using outcome-wide multi-method approaches to longitudinal panel data, this study aims to outline more clearly the role of SN diversity in the aging process in Indonesia. We explore whether and to what degree there is an association of SN diversity with adult health outcomes and investigate potential gender differences, heterogeneous treatment effects, and effect gradients along disablement processes.MethodsData came from the fourth and fifth waves of the Indonesian Family Life Survey fielded in 2007–08 and 2014–15. The analytic sample consisted of 3060 adults aged 50+ years. The primary exposure variable was the diversity of respondents’ SN at baseline. This was measured through a social network index (SNI), conjoining information about household size together with a range of social ties with whom respondents had active contact across six different types of role relationships. Guided by the disablement process model, a battery of 19 outcomes (8 pathologies, 5 impairments, 4 functional limitations, 2 disabilities) were included into analyses. Evidence for causal effects of SN diversity on health was evaluated using outcome-wide multivariable regression adjustment (RA), propensity score matching (PSM), and instrumental variable (IV) analyses.ResultsAt baseline, 60% of respondents had a low SNI. Results from the RA and PSM models showed greatest concordance and that among women a diverse SN was positively associated with pulmonary outcomes and upper and lower body functions. Both men and women with a high SNI reported less limitations in performing activities of daily living (ADL) and instrumental ADL (IADL) tasks. A high SNI was negatively associated with C-reactive protein levels in women. The IV analyses yielded positive associations with cognitive functions for both men and women.ConclusionsDiverse SN confer a wide range of strong and heterogeneous long-term health effects, particularly for older women. In settings with limited formal welfare protection, intervening in the SN of older adults and safeguarding their access to diverse networks can be an investment in population health, with manifold implications for health and public policy.

Peer effects and educational achievement: evidence of causal effects using age at school entry as exogenous variation for Peer quality

Abstract This paper evaluates the diffusion of peer effects on academic achievement of 4th grade students in the Brazilian public school system. Using data from Prova Brasil 2013, the identification strategy builds on the use of an IV approach, in which the instruments for peers’ performance are the proportions of classmates born in the second semester of the year (and alternatively, in each quarter). The idea behind the instruments is that compulsory school enrolment laws generate variation in the child’s age at school entry, which, in turn, make the date of birth within the year an important determinant of educational achievement and, at the same time, plausibly exogenous to the quality of the student’s peers. The results demonstrate that classrooms with higher proportions of peers born in the 2nd semester (started school at a relatively older age) tend to perform better, on average, than those that concentrate children born in the 1st semester, even after the inclusion of a wide range of control variables. For the math and Portuguese language evaluations, a one standard deviation increase in the classmates’ test scores improves individual achievement by 30% of a SD.

Migration and geopolitical preferences

ABSTRACTThis paper investigates the impact of work experience abroad on migrants’ geopolitical preferences. For this purpose, I analyze representative survey data from Moldova, a country caught in an ideological battle between Russia and the West, with high emigration rates to both destinations. In a first step, I show that return migrants from the West are significantly more likely to support European Union (EU) accession than non-migrants, while return migrants from the East are more likely to support closer ties with Russia, controlling for economic, demographic, and ethnic confounding factors. In a second step, I use district-level variation in migrant networks as an instrument for individual migration. Second-stage regressions show that work experience in the West increases support for EU accession, while no evidence of causal effects is found for work experience in the East. Differences in information exposure and migration policies between the EU and Russia may explain this asymmetry.

Quality press and voter turnout: Evidence for causal effects and its underlying mechanisms

Voting is a central aspect of political participation. Although there seems to be a widespread agreement about the beneficial consequences of reading quality newspapers on turnout, there is a lack of causal evidence. We investigated whether the reading of quality newspapers can increase turnout. In order to develop a more comprehensive understanding, we also investigated whether efficacy, interest, knowledge, and distrust mediate newspapers’ impact on turnout. A panel study with two waves was utilized in the run-up to the 2014 EU parliamentary election. Analyses indicate that exposure to quality newspapers increased turnout and that efficacy and knowledge mediated this effect.

Do Corruption and Social Trust Affect Economic Growth? A Review

Two separate literatures suggest that corruption and social trust, respectively, are related to economic growth, although the strengths of the relationships, and the direction of causality, are still debated. This paper reviews these literatures and evaluates the evidence for causal effects of corruption and trust on economic growth, and discusses how corruption and trust are interrelated. The reviews show that absence of corruption and high levels of social trust foster economic growth. The literatures also indicate that corruption has a causal effect on social trust, while the opposite effect is more uncertain. The conclusion offers the suggestion that fighting corruption may yield a “double dividend”, as reduced corruption is likely to have both direct and indirect effects on growth.

Prenatal substance use, prenatal stress and offspring behavioural outcomes: Considerations for future studies

Background: Numerous studies have been conducted in which the most common forms of maternal substance use during pregnancy (smoking, drinking or using cannabis) and maternal stress during pregnancy and her offspring's developmental or behavioural outcome have been the focus of interest. These studies seem to suggest that any perturbation caused by maternal substance use or maternal stress during fetal development may have (enduring) effects on offspring behaviour. However, recent developments in research methodology used to examine these associations question whether these prenatal influences actually cause altered offspring outcomes. Aims: This review provides a short overview of previous studies in this field of research, some methodological issues particularly involved in studies that focus on the association between maternal substance use or stress during pregnancy and offspring's outcomes. Furthermore, it introduces several new approaches that have been applied recently to test these associations. Results: Studies that applied these designs to disentangle prenatal influences from associated or inherited factors consistently show an effect of prenatal substance use exposure on birth weight, but yield little evidence for causal effects on behaviour. In contrast, prenatal stress may have a causal effect on some aspects of behaviour, although only one study thus far has been able to differentiate heritable factors from environmental factors.

Executive Summary: Healthier Students Are Better Learners

No matter how well teachers are prepared to teach, no matter what accountability measures are put in place, no matter what governing structures are established for schools, educational progress will be profoundly limited if students are not motivated and able to learn. Health-related problems play a major role in limiting the motivation and ability to learn of urban minority youth, and interventions to address those problems can improve educational as well as health outcomes. Healthier students are better learners. Recent research in fields ranging from neurosciences and child development to epidemiology and public health provide compelling evidence for the causal role that educationally relevant health disparities play in the educational achievement gap that plagues urban minority youth. This is why reducing these health disparities must be a fundamental part of school reform. School leaders must prioritize how to use scarce resources to address the critical health problems affecting youth. In the articles presented in this special issue of the Journal of School Health, 3 criteria were used for establishing priorities: prevalence and extent of health disparities negatively affecting urban minority youth; evidence of causal effects on educational outcomes; and feasibility of implementing proven or promising school-based programs and policies to address the health problem. Based on these criteria, 7 educationally relevant health disparities were selected as strategic priorities: (1) vision, (2) asthma, (3) teen pregnancy, (4) aggression and violence, (5) physical activity, (6) breakfast, and (7) inattention and hyperactivity. Many other health problems affecting youth are also important, and the particular health problems deemed most important in a given school or school district will vary. The health factors specified in this essay affect a large proportion of American youth. Visual problems have been estimated to affect 20% of youth.

CAUSAL EFFECTS OF HEALTH SHOCKS ON CONSUMPTION AND DEBT: QUASI-EXPERIMENTAL EVIDENCE FROM BUS ACCIDENT INJURIES.

Endogeneity between health and wealth presents a challenge for estimating causal effects of health shocks. Using a quasi-experimental design, comprising exogenous shocks sustained as bus accident injuries in India, with controls drawn from travelers on the same bus routes one year later, I present new evidence of causal effects on consumption and debt. Using primary household survey data, I find that households faced with shock-related expenditures are able to smooth consumption on food, housing, and festivals, with small reductions in educational spending. Debt was the principal mitigating mechanism households used, leading to significantly larger levels of indebtedness.

Does phonological short-term memory causally determine vocabulary learning? Toward a computational resolution of the debate

The relationship between nonword repetition ability and vocabulary size and vocabulary learning has been a topic of intense research interest and investigation over the last two decades, following the demonstration that nonword repetition accuracy is predictive of vocabulary size (Gathercole & Baddeley, 1989). However, the nature of this relationship is not well understood. One prominent account posits that phonological short-term memory (PSTM) is a causal determinant both of nonword repetition ability and of phonological vocabulary learning, with the observed correlation between the two reflecting the effect of this underlying third variable (e.g., Baddeley, Gathercole, & Papagno, 1998). An alternative account proposes the opposite causality: that it is phonological vocabulary size that causally determines nonword repetition ability (e.g., Snowling, Chiat, & Hulme, 1991). We present a theory of phonological vocabulary learning, instantiated as a computational model. The model offers a precise account of the construct of PSTM, of performance in the nonword repetition task, of novel word form learning, and of the relationship between all of these. We show through simulation not only that PSTM causally affects both nonword repetition accuracy and phonological vocabulary size, but also that phonological vocabulary size causally affects nonword repetition ability. The plausibility of the model is supported by the fact that its nonword repetition accuracy displays effects of phonotactic probability and of nonword length, which have been taken as evidence for causal effects on nonword repetition accuracy of phonological vocabulary knowledge and PSTM, respectively. Thus the model makes explicit how the causal links posited by the two theoretical perspectives are both valid, in the process reconciling the two perspectives, and indicating that an opposition between them is unnecessary.

Psychosocial Factors in Adolescent and Young Adult Self-Reported Depressive Symptoms: Causal or Correlational Associations?

Using a large longitudinal representative community sample, this study identified three groups of subjects who were depressed either in pre-adolescence, late adolescence or early adulthood, and matched by age and gender to controls without depression. The 90th percentile on one or two self-reported symptom scales [i. e. the Center for Epidemilogical Studies Depression Scale (CES-D) or the subscale Anxious / Depressed subscale on either the Youth Self Report (YSR) or the Young Adult Self Report (YASR)] served as the cut-off for the depression groups. Psychosocial variables under study included life events and life events impact, coping, self-related cognitions, perceived parental rearing style, family relations, perceived school environment, and the internalizing (except anxious/depressed) and externalizing problem scale of the YSR/YASR. The study found a large number of time-related correlations between psychosocial factors and depression. Evidence for causal effect (either antecedent or consequent) was obtained only for self-esteem, perceived maternal rejection, and internalizing problems.