Reverse Causality Research Articles

Association of cardiovascular disease and urate levels with aortic aneurysm: a bilateral mendelian randomization study

The aim of this study is to investigate the potential causal relationships between coronary artery disease (CAD), myocardial infarction (MI), urate levels, and aortic aneurysm (AA), abdominal aortic aneurysm (AAA), thoracic aortic aneurysm(TAA), aortic dissection (AD) in individuals of European ancestry. To examine the potential causal relationships between CAD, MI, and urate levels with AA, AAA, TAA, AD, respectively, we performed a two-sample Mendelian randomization (MR) analysis. Genetic instruments that reached genome-wide significance (p < 5 × 10 − 8) for risk factors were obtained from genome-wide association studies(GWASs) conducted on individuals of European origin. On the other hand, genetic instruments of AA, AAA, TAA or AD were chosen from the FinnGen cohort. The primary analysis employed the inverse-variance weighted MR method, while sensitivity analyses were conducted using MR-Egger, weighted median MR, MR pleiotropy residual sum and outlier, and Phenoscanner searching. In addition, we performed the MR-Egger intercept analysis to identify potential pleiotropy and utilized Cochran’s Q statistics to evaluate heterogeneity. Additionally, we conducted bidirectional Mendelian randomization experiments to mitigate the potential influence of reverse causation. According to the results of our study, there were statistically significant higher risks for AA in relation to CAD/MI(odds ratio (OR) with 95% confidence interval (CI): 1.309 (1.150–1.490), and 1.255 (1.147–1.373). Similarly, there were statistically significant higher risks for AAA in relation to CAD and MI (OR with 95% CI: 1.383 (1.189–1.609), and 1.352 (1.178–1.552). The sensitivity analysis demonstrated that the causative effects of CAD/MI, and AA /AAA, were robust. A positive causal link was observed between CAD/MI, and AA/AAA. Nevertheless, no causal link was found between CAD, MI, urate levels, and TAA .

A mendelian randomization analysis of the associations between haptoglobin and multiple sclerosis.

Observational studies have suggested an association between plasma haptoglobin and multiple sclerosis (MS). Haptoglobin plays an important role in the pathogenesis of MS. However, whether it has a causal effect on MS remains unknown. We here used a two-sample bidirectional Mendelian randomization (MR) method to investigate the causality between haptoglobin and MS. Genetic variants associated with plasma haptoglobin from two independent genome wide association studies (GWASs) (used as the discovery and replication datasets, respectively) were applied as the exposure. Their causal effects on summary statistics of GWASs of MS and disease severity were evaluated using the inverse-variance weighted (IVW) approach as the main analysis component. We found in both discovery and replication dataset that plasma haptoglobin was causally positively associated with the risk of MS (discovery: OR: 1.063, 95% CI: 1.022-1.106, P = 0.002; replication: OR: 1.041, 95% CI: 1.005-1.078, P = 0.026), but it was not associated with MS severity (discovery: OR: 1.017, 95% CI: 0.993-1.042, P = 0.168; replication: OR: 1.011, 95% CI: 0.987-1.036, P = 0.373). Besides, we did not detect any significant results in the reverse causation analysis. Our study provides evidence for the causal effects of plasma haptoglobin on the risk of MS.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

Do CEO Connections to the Chinese Politburo Pay Off and How?

ABSTRACTResearch Question/IssueThis study investigates the effect of connections to the Politburo, the top 25 members of the Chinese Communist Party (CCP), on CEO compensation, pay‐for‐performance sensitivity, and turnover decisions using a comprehensive dataset of 3764 Chinese listed firms from 2007 to 2019.Research Findings/InsightsOur findings reveal that CEOs of privately owned listed firms who have connections to the Politburo via shared educational backgrounds receive significantly higher compensation (up to 20% more). However, such connections do not significantly affect CEO compensation in state‐owned enterprises (SOEs). CEOs who have connections to the Politburo also exhibit lower turnover rates, and their compensation is less sensitive to performance outcomes. Our measure of connections excludes reverse causality, as we leverage an exogenous shock—the promotion to the Politburo of an individual with whom the CEO is already connected—to investigate the gain associated with a political connection in the absence of CEO turnover in private firms. This event allows us to observe that CEO pay increases significantly in such cases. We also find that elite connections serve as a mechanism for resource allocation, as politically connected CEOs in private firms benefit from higher subsidies and lower tax rates, and politically connected CEOs in SOEs benefit by being appointed to larger SOEs. Additionally, we find that the positive relationship between CEO pay and elite connections is even stronger when the connection is stronger but is negative when the CEO is a CCP member.Theoretical/Academic ImplicationsThis study enriches the literature on political connections by introducing a novel proxy for elite connections based on past educational ties to members of the political elite. It disentangles the influence of personal educational connections to the political elite from that of a more generic political membership of the CCP, offering a clearer understanding of their distinct impacts.Practitioner/Policy ImplicationsOur study underscores the necessity of differentiating between private and SOEs in China due to their distinct characteristics and goals. Furthermore, it highlights the critical role of elite political connections in emerging economies such as China in resource allocation, labor market dynamics, and corporate governance.

Decoding skin mysteries: Unveiling the link between microbiota and keloid scars through a Mendelian randomization study.

The cause of keloids remains unclear, but studies suggest a link between skin microbiota and keloid formation. However, the causal relationship has not been confirmed. This study utilized Genome-Wide Association Studies (GWAS) data from 2 population-based German cohorts, comprising a total of 1656 skin samples. To bolster the reliability of our results, we incorporated GWAS data from 3 keloid cohorts, encompassing 2555 patients and 870,556 controls (GWAS ID: keloid1, ebi-a-GCST90018874; keloid2, bbj-a-131; keloid3, ebi-a-GCST90018654). Subsequently, we employed bidirectional 2-sample Mendelian randomization (MR) analysis to probe the causal relationship between the variables. The primary method employed was the inverse-variance weighted (IVW) method, supported by heterogeneity analysis, horizontal pleiotropy testing, outlier detection, and "leave-one-out" sensitivity analysis. By synthesizing the results from 3 groups of MR analyses, we discovered a negative causal association between a.ASV063 [Finegoldia (unc.)] located on the volar forearm and keloid disease (IVW (keloid1) odds ratio (OR): 0.939, 95% confidence interval (CI): 0.886-0.994, P = .032; IVW (keloid2) OR: 0.897, 95% CI: 0.813-0.990, P = .031; IVW (keloid3) OR: 0.900, 95% CI: 0.825-0.981, P = .017). Similarly, a negative causal relationship may also exist between the genus: Bacteroides from the antecubital fossa and keloid disease (IVW (keloid1) OR: 0.928, 95% CI: 0.884-0.973, P = .002; IVW (keloid2) OR: 0.891, 95% CI: 0.820-0.968, P = .007; IVW (keloid3) OR: 0.918, 95% CI: 0.849-0.992, P = .030). Additionally, no reverse causation was found, with all analyses showing no signs of horizontal pleiotropy or heterogeneity. This study offers new insights for the prevention and treatment of keloids.

Causal Interpretations of Correlational Evidence Regarding Violence.

Inferring causation from correlation can lead to erroneous explanations of violent behavior and the development and implementation of ineffective or even harmful interventions and policies. This article explores the inferences that violence researchers draw from evidence related to violent offending. We invited authors of articles published in violence journals to complete an online survey in which they were asked to identify a factor that may be a cause of violence, cite a study that demonstrates the factor is associated with violence, and provide their inferences from that study. We read each study and coded its research design (description of a sample [n = 9], cross-sectional/retrospective non-experiment [n = 18], single-wave longitudinal non-experiment [n = 10], multi-wave longitudinal non-experiment [n = 0], or randomized experiment [n = 5]) and the appropriate inferences (inter-rater reliability was adequate; κ = 0.73-1.00). Reassuringly, participants (N = 42; 57.1% in United States; 59.5% women) rarely indicated that their identified study demonstrated that their factor was a cause of violence (0.0%-16.7%) when the study was not a randomized experiment. However, many participants failed to acknowledge any plausible alternate interpretations (e.g., reverse causality, third variable) of the results from non-experimental studies (50.0%-88.9%). Moreover, most participants incorrectly selected a causal implication as following from the results of non-experimental studies (77.8%-100%). Our results suggest that even among authors of articles published in peer-review scientific journals on violence, many appear to infer causation from correlation.

Can depression lead to chronic constipation, or does chronic constipation worsen depression? NHANES 2005–2010 and bidirectional mendelian randomization analyses

BackgroundDepression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation.MethodsThis study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005–2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsIn the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02–1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85–70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03–1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05).ConclusionsDepression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

Macroeconomic Influences on Recycling in Europe: An Econometric Investigation

AbstractWhile the circular economy has garnered significant attention over the last two decades, few studies have explored the relationship between recycling and macroeconomic conditions. This paper aims to elucidate how macroeconomic factors influence and correlate with recycling indicators, focusing on European waste management. First, we analyze how macroeconomic indicators impact key circular economy indicators related to waste management, considering 27 European countries from 2000 to 2019, categorized into Western, Southern, and Eastern Europe. An ordinary least squares model serves as a baseline for comparison with a fixed effects model and a model with regional and time dummies. As a response to Ferrante and Germani's (2020) call for more research on causal studies of this kind, we also address reverse causality both by testing for panel data Granger causality and by applying the dynamic panel data approach developed by Arellano and Bond (1991). Second, we investigate variations in circular economic performance across European regions and countries, both before and after controlling for the macroeconomic context. The empirical analysis reveals a substantial correlation between circular economy indicators and key macroeconomic conditions, but we do not find evidence supporting causal impacts from macroeconomic circumstances in the short run. Regional examinations unveil disparities in circular economic performance, with Western Europe generally surpassing Southern and Eastern Europe. However, these patterns align more closely when considering the macroeconomic context. The methodologies employed in the study may prove valuable for future research on the circular economy and its relation to macroeconomic influences.

Microbe-immune interactions: new perspectives on coagulation deficiencies, purpura, and other hemorrhagic conditions under the regulation of the gut microbiota.

The relationship between gut microbiota and coagulation defects, purpura, and other hemorrhagic conditions (CPH) is currently unclear, with causal links yet to be firmly established. The causal relationships between gut microbiota and CPH, along with the potential mediating role of immune cells, were studied using Mendelian randomization analysis. Data on 412 gut microbiota species, 731 immune cell types, and CPH were methodologically compiled from genome-wide association studies and the FinnGen database. A 2-sample Mendelian randomization approach in 2 stages was used and the causal links between gut microbiota and CPH were statistically analyzed, assessing the potential mediation by immune cells. Sensitivity and reliability were ensured through heterogeneity and pleiotropy tests. The abundance of Alistipes putredinis (odds ratio [OR]=0.77, 95% confidence interval [CI] 0.64-0.93, P=0.006) was negatively correlated with CPH, whereas the abundance of Bacteroides stercoris (OR=1.25, 95%CI 1.09-1.45, P=0.002) was positively correlated with the risk of CPH. There was no evidence of reverse causality or the potential mediating effects of 731 immune cell types. The abundance of Proteobacteria (OR=0.81, 95%CI 0.71-0.92, P=0.001) and Coprococcus sp. ART55/1 (OR=0.87, 95%CI 0.80-0.96, P=0.005) was negatively associated with the risk of CPH, whereas the abundance of Enterobacteriales/Enterobacteriaceae (OR=1.36, 95%CI 1.12-1.64, P=0.002) was positively correlated with the risk of CPH, with no evidence of reverse causality. Furthermore, CD38 levels on CD3-CD19 cells can serve as a mediating factor for the influence of Proteobacteria on the pathogenesis of CPH, with a mediating effect ratio of 7.26%. An increase in Proteobacteria abundance leads to a decrease in CD38 expression on CD3-CD19- cells, thereby reducing the risk of developing CPH. CD3 expression on naive CD4+ in mature T cells serves as a mediating factor for the influence of Enterobacteriales/Enterobacteriaceae on the pathogenesis of CPH, whereas IgD CD38br AC expression on B cells serves as a mediating factor for the influence of Coprococcus sp. ART55/1 on the pathogenesis of CPH. The mediating effect is opposite to the overall trend and has a relatively small impact. No significant heterogeneity or pleiotropy was observed.

The Relationship between Negative Emotions and Atrial Fibrillation: A Mendelian Randomization Study.

The relationship between negative emotions and atrial fibrillation (AF) has garnered significant attention, yet observational studies have yielded contradictory findings regarding the causal associations between the two. Our study sought to provide genetic evidence for a causal relationship between negative emotions and AF through Mendelian randomization (MR) study. Utilizing genetic variations associated with negative emotions and AF as instrumental variables (IVs), a two-sample MR study was implemented. The potential causality between the two was initially assessed by using negative emotions as exposure and AF as outcome. Subsequently, potential reverse causality was evaluated by using AF as exposure and negative emotions as outcome. The inverse variance weighted (IVW) method served as the primary analysis for the two-sample MR, supplemented by weighted median method, MR-Egger regression, Simple mode method, and Weighted mode method. Sensitivity analyses were performed using the MR pleiotropy residual sum and outlier test (MR-PRESSO), Cochran Q test, and leave-one-out analysis to ensure the robustness of the results. The two-sample MR analyses revealed that genetic susceptibility to AF had no potential causal effect on negative emotions (p > 0.05). Conversely, genetic susceptibility to negative emotions was positively correlated with an increased relative risk of AF [odds ratio (OR), 1.173, 95% confidence interval (CI): 1.115-1.235, p = 8.475 × 10-10]. Furthermore, neither horizontal pleiotropy nor heterogeneity was detected in the analysis. Genetic evidence from the study supports a potential causal link between negative emotions and AF. The study suggests that negative emotions may elevate the risk of AF, and the escalation of negative emotions in AF patients is more likely attributable to modifiable factors rather than genetically related factors.

Staff engagement, co‐workers' complementarity and employee retention: evidence from English NHS hospitals

AbstractRetention of skilled workers is essential for labour‐intensive organizations like hospitals, where an excessive turnover of doctors and nurses can reduce the quality and quantity of services provided to patients. Exploiting a unique and rich panel dataset based on employee‐level payroll and staff survey records from the universe of English NHS hospitals, we investigate empirically the role played by two non‐pecuniary job factors, staff engagement and the retention of complementary co‐workers, in affecting employee retention within the public hospital sector. We estimate dynamic panel data models to deal with reverse causality bias, and validate these estimates through unconditional quantile regressions with hospital‐level fixed effects. Our findings show that a one standard deviation increase in nurse engagement is associated with a 16% standard deviation increase in their retention; and also that a 10% increase in nurse retention is associated with a 1.6% increase in doctor retention, with this co‐workers' complementarity spillover effect driven by the retention of more experienced nurses. Nurse and doctor engagement is positively associated with managers who have effective communication, involve staff in the decision‐making process, and act on staff feedback; in particular, older nurse engagement is responsive to managers caring for staff health and wellbeing.

The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Does Coproduction Enhance Quality of Public Infrastructure?

Coproduction is viewed in this paper as joint effort or cooperation between citizens and public infrastructure service providers. There is a paucity of studies on the impact of coproduction on public infrastructure quality or performance. Poor public infrastructure development poses a financial burden to many developing countries. In this paper, we use road maintenance as the example of public infrastructure. Using the Afro-barometer wave-6 dataset on Uganda, we develop the appropriate coproduction indexes as well as the road maintenance performance indexes from the survey data. Our results show that coproduction has significantly positive impacts on public road maintenance performance (RMP), which raises social welfare and economic development. Our results are robust to various model specifications and the conclusions remain valid after controlling for any potential endogenous influence or reverse causality problem that might arise. Our analysis points to the practical importance of cooperation between community and government in transport infrastructure provision such as road maintenance. It also provides practical implications for policy makers on how coproduction between community and government could be arranged.

Systematic evaluation of the correlation between serum metabolites and tinnitus

Objective: We performed a Mendelian randomisation (MR) analysis to explore the relationship between serum metabolites and tinnitus. Methods: In this study, 486 serum metabolites were considered as exposure factors, and single nucleotide polymorphisms (SNP) significantly associated with them were used as instrumental variables (IV). The serum metabolite data were obtained from a public database (http://metabolomips.org/gwas/index.php), while the genome-wide association study (GWAS) summary association statistics for tinnitus were obtained from a Finnish database (https://r10.finngen.fi/pheno/H8_TINNITUS). The inverse variance weighting (IVW) method was employed as the primary determination method for MR analysis, with corrections for multiple comparisons made using the false discovery rate (FDR). Sensitivity tests were conducted using the MR-Egger regression, Mendelian random polymorphism residuals and outliers (MR-PRESSO) methods. The identified serum metabolites were subjected to chained disequilibrium regression analysis (LDSC) and metabolic pathway analysis. Reverse MR analysis was performed to investigate the possibility of reverse causality. Analyses were performed in R software (version 4.3.1). Results: A total of 17 serum metabolites (including 10 known and 7 unknown metabolites) associated with tinnitus were identified. The known metabolites included protective metabolites such as acetylcarnitine, hydroxyisovaleryl carnitine, glycine, monounsaturated glycerol ester, and glycine-L-valine, and hazardous metabolites such as allantoin, glycerylphosphorylcholine 1-eicosatrienoate, myo-inositol, 15-methylpalmitate, and pseudouridine; the strongest causally protective metabolites were acetylcarnitine, the followed by hydroxyisopentanoyl carnitine and glycine; the hazardous metabolite with the strongest causal effect was pseudouridine, followed by inositol and 15-methylpalmitate; and only hydroxyisopentanoyl carnitine (PFDR=0.04) and glycerol monooleate (PFDR=0.04) reached significance values after FDR correction. The findings were free of heterogeneity, pleiotropy and reverse causal associations. The metabolic pathways were mainly enriched in pathways such as ascorbic acid and aldolac metabolism. Conclusions: The study suggests a causal relationship between serum metabolites and tinnitus risk. Serum metabolite levels may influence tinnitus-related metabolic pathways.

Genetic Determinants of Telomere Length and Risk of Aneurysmal Subarachnoid Hemorrhage: A Bidirectional Two-Sample Mendelian Randomization Study

Background Our objective is to investigate the potential causal relationship between telomere length (TL) and aneurysmal subarachnoid hemorrhage (aSAH) and intracranial aneurysms (IAs) by conducting a bidirectional two-sample Mendelian Randomization (MR) study. Methods We utilized publicly available summary data from genome-wide association studies (GWAS) for comprehensive analysis. Telomere length-associated data were sourced from the Epidemiology Unit (IEU) GWAS database (n = 472,174), while data pertaining to intracranial aneurysms were derived from a GWAS meta-analysis conducted by Bakker et al, encompassing aneurysmal subtypes including aSAH (n = 77,074), IAs (n = 79,429), and unruptured intracranial aneurysms (uIA) (n = 74,004), all sampled from European populations. The primary method for MR analysis employed was the Inverse Variance Weighted (IVW) method. Additionally, we conducted various sensitivity analyses to assess the heterogeneity and pleiotropy of study findings. Reverse MR analysis was employed to explore potential reverse causality. Results In the forward MR analysis, the IVW method indicated a negative association between TL and aSAH (OR = 0.636, 95% CI: 0.459–0.883, p = 0.006) as well as IAs (OR = 0.670, 95% CI: 0.499–0.900, p = 0.0079). There was no evidence of heterogeneity or horizontal pleiotropy in the forward MR analysis. Reverse MR analysis did not reveal any causal relationship between aSAH, IAs, uIA and TL. Conclusions In European populations, there exists a causal relationship between longer TL and reduced risks of aSAH and IAs Further research is warranted to elucidate the underlying mechanisms and the potential of TL as an intervention target for lowering the incidence of aSAH and IAs.

The association between BMI and cognition in India: data from the Longitudinal Aging Study in India (LASI)

BackgroundHigh body-mass index (BMI) is an established risk factor for late-life cognitive impairment and dementia, but most evidence comes from high-income contexts. Existing evidence from cross-sectional data in low- and middle-income settings is inconsistent, and many studies do not adequately address potential sources of bias.MethodsWe used data from Wave 1 of the Longitudinal Aging Study in India (LASI) (analytic N = 56,753) to estimate the association between BMI categories and cognitive functioning among older adults aged 45 + years using survey-weighted linear regression models stratified by gender and controlling for potential confounders including demographic factors, socio-economic status (SES) characteristics, and health-related behaviors. To probe potential sources of bias, including residual confounding and reverse causation, we used weighting and trimming methods, sample restriction, and explored effect modification.ResultsIn fully adjusted models, relative to normal BMI underweight BMI was associated with lower cognitive scores (Men: -0.16 SD difference, 95% CI -0.18, -0.13; Women: -0.12 SD, -0.15, -0.10). Overweight and obesity were associated with higher cognitive scores in both men (overweight: 0.09; 0.07, 0.12, obese: 0.10; 0.05, 0.15) and women (overweight: 0.09; 0.07–0.12, obese: 0.12; 0.08–0.15). Estimates were similar after weighting and trimming but were attenuated after excluding those with low cognition (≥1 SD below the mean relative to those with similar demographic characteristics). Positive associations between overweight and obese BMI and cognition were attenuated or null in those living in urban settings and those with higher levels of educational attainment.ConclusionsUnderweight BMI is a risk factor for poor cognitive outcomes in adults 45 years and older and may be indicative of poor nutritional status and life-course disadvantage in India. In tandem with existing literature, supplemental analyses and effect modification results indicate that unmeasured confounding and reverse causation may explain the observed positive associations between overweight and obese BMI and cognitive functioning from cross-sectional studies in low- and middle-income settings. Future data with longitudinal follow-up will be helpful to further disentangle biases.

8473 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City

Abstract Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None. Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population. Presentation: 6/1/2024

9253 Prediabetes As A Risk Factor For All-Cause And Cause-Specific Mortality In 117,227 Diabetes-Free Adults In Mexico City

Abstract Disclosure: C.A. Fermin-Martinez: None. O.Y. Bello-Chavolla: None. N.E. Antonio-Villa: None. D. Ramirez Garcia: None. J.A. Seiglie: None. Background: Prediabetes has been consistently linked to high risk of diabetes progression, cardiovascular disease, and all-cause mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations despite the growing prevalence of this condition in low- and middle-income countries. Methods: We analyzed data from 117,227 adults without diabetes aged ≥35 years who participated in the Mexico City Prospective Study (1998-2004). Individuals with self-reported chronic comorbidities at baseline were excluded to mitigate reverse causation. Participants were followed-up until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c ≥5.7%) and the International Expert Committee (IEC, HbA1c ≥6.0%) definitions. Cox regressions were used to estimate prediabetes-related risk for all-cause and cause-specific mortality, stratified by sex and age-at-risk and adjusted for municipality of residence, education level, physical activity, smoking, alcohol consumption, and adiposity markers. Results: Compared to individuals with normoglycemia, participants with IEC-defined prediabetes had a higher risk of all-cause (HR 1.16, 95%CI 1.05-1.27), cardiac (HR 1.29, 95%CI 1.05-1.59), renal (HR 1.59, 95%CI 1.14-2.23), and acute diabetes-related (HR 2.60, 95%CI 1.52-4.43) mortality at ages 40-74 years compared to normoglycemic participants. HRs were attenuated at older ages. Results were broadly similar irrespective of the definition of prediabetes except for cardiac deaths, in which the risk was non-significant using the ADA cutoff (HR 1.14, 95%CI 0.99-1.31). Long-term effects of prediabetes (IEC-defined) accounted for ∼37% of renal deaths and ∼61% of acute diabetes-related deaths in Mexican adults without diabetes at baseline. Conclusion: Prediabetes is an important risk factor that accounts for a significant fraction of all-cause, cardiac, renal, and acute diabetes-related deaths among Mexican adults, particularly when using the higher threshold of IEC-defined prediabetes. Endpoint-driven definitions of prediabetes should be considered for widespread implementation of screening and preventive strategies that minimize overdiagnosis and improve cardiometabolic outcomes in this population. Presentation: 6/1/2024

The Effects of Social Interaction Intervention on Cognitive Functions Among Older Adults Without Dementia: A Systematic Review and Meta-Analysis

Abstract Background and Objectives Previous systemic reviews, predominantly including observational studies, have shown that participation in social activities is a protective factor against cognitive decline. However, this association is subject to potential reverse causality, creating a knowledge gap in our understanding of the effect of social interaction interventions on cognitive function. Therefore, this study aims to conduct a systematic review and meta-analysis of randomized controlled trials to examine the effects of social interaction interventions on cognitive decline among older adults without dementia. Research Design and Methods This systematic review, registered in PROSPERO (CRD42022367828), systematically searched 6 databases from inception to May 6, 2022, to identify relevant articles on the effects of activities with social interaction components on cognitive function in community-dwelling older adults without dementia aged above 60. Two independent reviewers conducted study selection, data extraction, and bias assessment, with RevMan5.3 used for meta-analysis. Subgroup analysis was conducted to assess variation in intervention effects among subgroups. Results We included 11 studies for qualitative analysis and 8 studies for the meta-analysis. The results showed that social interaction intervention had a significant effect on executive function (standardized mean difference [SMD] = 1.60; 95% CI, 0.50 to 2.70; p = .004), but not attention and memory. The subgroup analysis showed a greater cognitive benefit for healthy older adults, but not those with mild cognitive impairment. Moreover, in-person social interaction positively affected global cognition, whereas online interaction did not. Discussion and Implications Social interaction interventions have a limited impact on cognitive function in older adults without dementia but showed potential effects on executive function. This finding offers insights for implementing social intervention in the community.

Immune cell traits and causal relationships with cholecystitis: a mendelian randomization analysis.

Cholecystitis, characterized by inflammation of the gallbladder, is intricately linked to immune cells and the cytokines they produce. Despite this association, the specific contributions of immune cells to the onset and progression of cholecystitis remain to be fully understood. To delineate this relationship, we utilized the Mendelian randomization (MR) method to scrutinize the causal connections between 731 immune cell phenotypes and cholecystitis. By conducting MR analysis on 731 immune cell markers from public datasets, this study seeks to understand their potential impact on the risk of cholecystitis. It aims to elucidate the interactions between immune phenotypes and the disease, aiming to lay the groundwork for advancing precision medicine and developing effective treatment strategies for cholecystitis. Taking immune cell phenotypes as the exposure factor and cholecystitis as the outcome event, this study used single nucleotide polymorphisms (SNPs) closely associated with both immune cell phenotypes and cholecystitis as genetic instrumental variables. We conducted a two-sample MR analysis on genome-wide association studies (GWAS) data. Our research thoroughly examined 731 immune cell markers, to determine potential causal relationships with susceptibility to cholecystitis. Sensitivity analyses were performed to ensure the robustness of our findings, excluding the potential impacts of heterogeneity and pleiotropy. To avoid reverse causality, we conducted reverse MR analyses with cholecystitis as the exposure factor and immune cell phenotypes as the outcome event. Among the 731 immune phenotypes, our study identified 21 phenotypes with a causal relationship to cholecystitis (P < 0.05). Of these, eight immune phenotypes exhibited a protective effect against cholecystitis (odds ratio (OR) < 1), while the other 13 immune phenotypes were associated with an increased risk of developing cholecystitis (OR > 1). Additionally, employing the false discovery rate (FDR) method at a significance level of 0.2, no significant causal relationship was found between cholecystitis and immune phenotypes. Our research has uncovered a significant causal relationship between immune cell phenotypes and cholecystitis. This discovery not only enhances our understanding of the role of immune cells in the onset and progression of cholecystitis but also establishes a foundation for developing more precise biomarkers and targeted therapeutic strategies. It provides a scientific basis for more effective and personalized treatments in the future. These findings are expected to substantially improve the quality of life for patients with cholecystitis and mitigate the impact of the disease on patients and their families.