Multiple Sensitivity Analyses Research Articles

Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE

AbstractThe ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19–related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

Simultaneous evaluation of the imprecision and inconsistency domains of GRADE can be performed using prediction intervals

ObjectivesTo explore the use of prediction interval (PI) for the simultaneous evaluation of the imprecision and inconsistency domains of Grading of Recommendations, Assessment, and Evaluation using stakeholder-provided decision thresholds. Study Design and SettingWe propose transforming the PI of a meta-analysis from a relative risk scale to an absolute risk difference using an appropriate baseline risk. The transformed PI is compared to stakeholder-provided thresholds on an absolute scale. We applied this approach to a large convenience sample of meta-analyses extracted from the Cochrane Database of Systematic Reviews and compared it against the traditional approach of rating imprecision and inconsistency separately using confidence intervals and statistical measures of heterogeneity, respectively. We used empirically derived thresholds following Grading of Recommendations, Assessment, and Evaluation guidance. ResultsThe convenience sample consisted of 2516 meta-analyses (median of 7 studies per meta-analysis; interquartile range: 5–11). The main analysis showed the percentage of meta-analyses in which both approaches had the same number of certainty levels rated down was 59%. The PI approach led to more levels of rating down (lower certainty) in 27% and to fewer levels of rating down (higher certainty) in 14%. Multiple sensitivity analyses using different thresholds showed similar results, but the PI approach had particularly increased width with a larger number of included studies and higher I2 values. ConclusionUsing the PI for simultaneous evaluation of imprecision and inconsistency seems feasible and logical but can lead to lower certainty ratings. The PI-based approach requires further testing in future systematic reviews and guidelines using context-specific thresholds and evidence-to-decision criteria. Plain Language SummaryThe prediction interval (PI) addresses both the imprecision and inconsistency domains of certainty. In this study, we applied this PI approach to simultaneously judge both domains and compared this to the traditional approach of making these separate judgments. The 2 approaches had moderate agreement. The PI-based approach requires further testing in future systematic reviews and guidelines using context-specific thresholds and evidence-to-decision criteria.

Gluteal tendinitis and primary coxarthrosis may lead to iliotibial band syndrome: a Mendelian randomization study

To analyze the causal relationship of gluteal tendinitis and primary coxarthrosis with the occurrence of iliotibial band syndrome using Mendelian randomization. The GWAS data of gluteal tendinitis, primary coxarthrosis and iliotibial band syndrome were screened for high correlation single-nucleotide polymorphisms (SNPs). Mendelian randomization analysis was performed using random-effects inverse variance weighting (IVW), MR-Egger regression, and weighted median method to determine whether gluteal tendinitis and primary coxarthrosis were causally related with iliotibial band syndrome. Heterogeneity test, multiple validity test and sensitivity analysis, and clinical data analysis were used to verify the reliability of the results. Both gluteal tendinitis [IVW: OR(95% CI)=1.32 (1.03-1.68), P=0.026] and primary coxarthrosis [IVW: OR (95% CI)=1.40 (1.06-1.84), P=0.017] was positively correlated with iliotibial band syndrome. Gluteal tendinitis and primary coxarthrosis may increase the risk of iliotibial band syndrome.

Overcoming times of crisis: unveiling coping strategies and mental health in a transnational general population sample during and after the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has had an unparalleled impact, precipitating not only direct threats to physical health but also widespread economic and psychological challenges. This study aims to explore the dynamics of coping behaviour and psychological distress (PD) across different phases of the pandemic within an adult general population sample, spanning Austria and Italy.MethodsAn online questionnaire-based panel study was conducted between 2020 and 2023 including three measurements. We collected data on sociodemographic variables, coping responses (Brief COPE), and PD (Brief-Symptom-Checklist). Statistical analyses were conducted within a linear-mixed-model framework. Multiple imputation and sensitivity analysis were applied to validate the results obtained by complete case analysis.ResultsThe study follows 824 participants and reveals a marginal decrease in overall PD from the first to the second follow-up, particularly in clinically relevant phobic anxiety (35.6% and 34.5% to 25.4%). Most coping behaviours exhibited stable mean-levels with intra-individual variability across the study period. Maladaptive coping strategies were consistently linked to increased PD, whereas adaptive strategies were associated with decreased PD.ConclusionOur findings underscore the complex nature of coping behaviours and PD during and after the pandemic, suggesting that while mean-levels of PD and coping responses remained relatively stable, most coping strategies were subject to intra-individual change. Maladaptive strategies were associated with increased PD, pinpointing to the need for interventions that establish the foundation for adaptive coping mechanisms and promote their application. Further research should explore the reciprocal influences of mental health on coping behaviour, incorporating interventional designs to unravel the nuances of these relationships.

Restriction of salt, alcohol and coffee intake and Ménière's disease: insight from Mendelian randomization study.

Restricting salt, caffeine, and alcohol intake is commonly recommended as a first-line treatment for patients with Ménière's disease (MD). However, it remains unclear whether these interventions effectively improve symptoms of MD. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the relationship between these dietary modifications and MD. Summary statistics for salt added to food, alcohol consumption, coffee consumption, and MD were sourced from the United Kingdom Biobank, GSCAN, and the FinnGen study, involving up to 941,280 participants. The main analyses were performed using the random-effects inverse-variance weighted (IVW) approach and were complemented by four additional methods. Multiple sensitivity analyses were performed to validate the findings, and both forward and reverse MR analyses were employed to address potential reverse causality bias. The primary MR results using the IVW method revealed that salt added to food (OR = 0.719, 95% CI: 0.429-1.206; p = 0.211), alcohol consumption (OR = 0.834, 95% CI: 0.427-1.628; p = 0.595), and coffee consumption (OR = 0.852, 95% CI: 0.555-1.306; p = 0.461) were not significantly correlated with MD. In reverse analysis, no evidence of significant effect was found from MD to salt added to food (OR = 1.000, 95% CI: 0.993-1.007; p = 0.957), alcohol consumption (OR = 0.998, 95% CI: 0.987-1.008; p = 0.682), and coffee consumption (OR = 0.998, 95% CI: 0.985-1.011; p = 0.72). This MR analysis did not identify convincing evidence to support the idea that restricting salt, caffeine, and alcohol intake is beneficial for the treatment of MD.

Observational and genetic evidence disagree on the association between loneliness and risk of multiple diseases.

Loneliness-the subjective experience of social disconnection-is now widely regarded as a health risk factor. However, whether the associations between loneliness and multiple diseases are consistent with causal effects remains largely unexplored. Here we combined behavioural, genetic and hospitalization data from the UK Biobank to examine the associations of loneliness with a wide range of non-overlapping diseases. During a median 12.2-year follow-up, loneliness was associated with greater risks in 13 of 14 disease categories and 30 of 56 individual diseases considered. Of the 30 diseases significantly associated with loneliness, 26 had genetic data available for Mendelian randomization (MR) analyses. After Benjamini‒Hochberg correction and multiple sensitivity analyses within the MR framework, non-causal associations were identified between genetic liability to loneliness and 20 out of the 26 specific diseases, including cardiovascular diseases, type 2 diabetes mellitus, obesity, chronic liver diseases, chronic kidney disease, most neurological diseases and the other common diseases. Genetic liability to loneliness was only potentially causally associated with the remaining six diseases. Socioeconomic factors, health behaviours, baseline depressive symptoms and comorbidities largely explained the associations between loneliness and diseases. Overall, our study revealed a dissociation between observational and genetic evidence regarding the associations of loneliness with multiple diseases. These findings suggest that loneliness may serve as a potential surrogate marker rather than a causal risk factor for most diseases tested here.

Causal relationship between neuroticism and bone mineral density: A univariable and multivariable Mendelian randomization study.

Recent observational studies have indicated that psychiatric disorders were associated with risk of bone mineral density (BMD) reduction. But the causal relationship between neuroticism and BMD remained unclear. By using public genome-wide association study data, a 2-sample bidirectional Mendelian randomization (MR) study was performed to investigate the causal relationship between neuroticism and BMD (heel BMD, forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD). Inverse-variance weighted, weighted median, and MR-Egger were used to assess the causal effects. Multiple sensitivity analyses were conducted to assess the potential bias of the causal estimates. Multivariable MR analysis was used to assess the direct causal effects of neuroticism on BMD with adjustment of common risk factors of BMD reduction. Univariable MR analysis indicated that genetically predicted higher neuroticism was significantly associated with an increased risk of heel BMD reduction (inverse-variance weighted β = -0.039; se = 0.01; P = .0001; Bonferroni-corrected P = .0005) but not with other BMD (forearm BMD, femoral neck BMD, lumbar spine BMD, and total body BMD) potentially due to limited statistical power. The causal effects remained significant after accounting for the effects of body mass index, smoking, and drinking. Genetic proxy for higher neuroticism was significantly associated with an increased risk of heel BMD reduction. Further studies were warranted to elucidate the underlying biological mechanisms and explore the potential application in disease early screening and management.

Semi-invasive therapies for pain in knee osteoarthritis: A systematic review and network meta-analysis.

The increasing number of semi-invasive pain therapies in knee osteoarthritis poses challenges in decision-making. This review aimed to simultaneously compare established intra-articular therapies with newer peri-articular therapies and explore effect modifiers. Randomized controlled trials were searched from five electronic databases without date or language restrictions. Study selection and data extraction of reports, retrieved up to May 2024, were performed independently by paired assessors. The primary outcome was 6-month pain score. Nine treatments were included. The effect size (ES) for each treatment, relative to placebo, was estimated using standardized means difference and expressed with 95% confidence intervals (CI). The rigor of results was evaluated with subgroup/sensitivity analyses. A total of 111 studies (14,695 participants) were included, with intra-articular hyaluronic acid having the greatest number of participants. Neuroablation demonstrated the greatest ES (1.08, 95% CI: 0.07, 2.10). While platelet-rich plasma (PRP) ranked second (ES: 0.75, 95% CI: 0.28, 1.22), it was the only intervention demonstrating statistically significant effect at 3, 6, and 12 months. However, this statistical significance was lost in some sensitivity analyses. Larger estimates for biologics and PRP compared with prolotherapy, steroid, and hyaluronic acid injections were consistently observed across different timepoints and in multiple sensitivity analyses. Generally, no statistically significant difference was found between the nine types of therapies. Although there is robust evidence suggesting greater efficacy of PRP, potentially including biologics, over other interventions, future research is needed to identify the phenotype or patient subgroup that would benefit most from PRP.

Association of sleep patterns and disorders with metabolic dysfunction-associated steatotic liver disease and liver fibrosis in contemporary American adults

Introduction and ObjectivesThe impact of sleep on metabolic dysfunction-associated steatotic liver disease (MASLD) in American adults remains unclear. This study aimed to address the relationship of sleep patterns and disorders with MASLD and liver fibrosis comprehensively. Materials and MethodsThis cross-sectional study included adult participants from the National Health and Nutrition Examination Survey 2017-2020. Multivariate adjusted regression analysis were used to examine the association of sleep with MASLD and liver fibrosis. We further addressed these associations using restricted cubic splines, mediation analysis, stratified analysis and multiple sensitivity analysis. ResultsWe enrolled 5368 participants. Certain sleep disorders, sleep duration, high sleep debt and specific sleep-wake time were associated with MASLD. Late workday sleep was a shared risk factor for MASLD and liver fibrosis. Short sleep on workdays and free days favored MASLD, whereas average weekly long sleep protected against MASLD. Workday, free day and average weekly optimal sleep duration was 7.5 h, 8 h and 7.78 h, respectively. Mediation analysis suggested that fasting glucose and high-density lipoprotein cholesterol indirectly mediated the relationship between sleep duration and MASLD, whereas stratified analysis showed that sex influenced the relationship, and that the correlation was only observed in women and specific age groups. ConclusionsSleep duration independently affected MASLD but only in women and specific age groups. Moreover, late sleep on workdays was a shared risk factor for MASLD and liver fibrosis. These results suggest targeting sleep behaviors for MASLD prevention and developing age- and sex-specific strategies.

Sarcopenia as a predictor of nutritional status and comorbidities: a cross-sectional and mendelian randomization study

BackgroundWith the advancement of world population aging, age-related sarcopenia (SP) imposes enormous clinical burden on hospital. Clinical research of SP in non-geriatric wards has not been appreciated, necessitating further investigation. However, observational studies are susceptible to confounders. Mendelian randomization (MR) can effectively mitigate bias to assess causality.ObjectiveTo investigate the correlation between SP and comorbidities in orthopedic wards, and subsequently infer the causality, providing a theoretical basis for developing strategies in SP prevention and treatment.MethodsLogistic regression models were employed to assess the correlation between SP and comorbidities. The MR analysis was mainly conducted with inverse variance weighted, utilizing data extracted from the UK and FinnGen biobank (Round 9).ResultsIn the cross-sectional analysis, SP exhibited significant associations with malnutrition (P = 0.013) and some comorbidities, including osteoporosis (P = 0.014), body mass index (BMI) (P = 0.021), Charlson Comorbidity Index (CCI) (P = 0.006). The MR result also provided supporting evidence for the causality between SP and hypertension, osteoporosis and BMI. These results also withstood multiple sensitivity analyses assessing the validity of MR assumptions.ConclusionThe result indicated a significant association between SP and BMI, CCI, malnutrition, and osteoporosis. We highlighted that SP and comorbidities deserved more attention in non-geriatric wards, urging further comprehensive investigation.

Genetic evidence for the causal association of neuroticism with intracranial aneurysms: A Mendelian randomization study

ObjectiveThe aim of this study was to assess the potential causal relationship between neuroticism and 12 neuroticism items with intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) using a two-sample Mendelian randomization (MR) approach. MethodsStudy data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset, and we extracted summary statistics for neuroticism, 12 neuroticism items, and IAs, which were categorized into ruptured and unruptured aneurysms (IA), aSAH, and unruptured IAs (uIA). Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs) to explore the causal relationship between exposure and outcome using five Mendelian randomization methods, with Inverse variance weighted (IVW) as the primary study method. Horizontal multiple validity tests, sensitivity analyses, and inverse MR ensured the stability of the results. ResultsThe two-sample MR showed a genetically predictive association between neuroticism and IA [odds ratio (OR) = 1.16; 95 % confidence interval (95 % CI): 1.04–1.30; p = 0.009], aSAH (OR = 1.17; 95 % CI: 1.03–1.33; p = 0.013) and uIA (OR = 1.30; 95 % CI: 1.07–1.59; p = 0.009) were all genetically predictive of association. Ivw showed a positive association between 5 neuroticism items and IA risk, 5 neuroticism items and aSAH risk as well as no genetically predictive association between neuroticism items and uIA. Sensitivity analysis and inverse MR confirmed the robustness of the results. ConclusionOur Mendelian randomization analysis demonstrated genetic causality between neuroticism and neuroticism items with intracranial aneurysms, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysms, and further studies are needed to confirm these results and explore potential mechanisms of action.

Causal Effect of Immunocytes, Plasma Metabolites, and Hepatocellular Carcinoma: A Bidirectional Two-Sample Mendelian Randomization Study and Mediation Analysis in East Asian Populations.

Background: Hepatocellular carcinoma (HCC) is a primary malignant liver tumor characterized by a low survival rate and high mortality. This study aimed to investigate the causal effect of immune cell phenotypes, plasma metabolites, and HCC in East Asian populations. Methods: The summary results for 731 immunocytes, 1400 plasma metabolites, and HCCs were acquired from publicly available genome-wide association studies (GWASs). This study utilized two-sample Mendelian randomization (MR) analysis to establish causal relationships, which was achieved by employing various statistical methods including inverse variance-weighted, simple mode, MR-Egger, weighted median, and weighted mode. Multiple sensitivity analyses were conducted to confirm the reliability of the MR data. Ultimately, mediation analysis was employed to ascertain the path that leads from immunocytes to plasma metabolites. Results: Among the 20 immune cells and HCC for East Asians, causal links were found, with one showing an inverse correlation. In addition, 36 metabolites were significantly associated with HCC for East Asians. Through analysis of established causative metabolites, we identified a strong correlation between the glycerophospholipid metabolic pathway and HCC for East Asians. By employing a two-step MR analysis, we identified 11 immunocytes that are causally linked to HCC for East Asians through the mediation of 14 plasma metabolites, with Linolenate [α or γ; (18:3n3 or 6)] levels showing the highest mediation proportion (19.3%). Conclusions: Our findings affirm the causal links among immunocytes, plasma metabolites, and HCC in eastern Asia populations by calculating the percentage of the impact that is influenced by plasma metabolites. This study offers innovative perspectives on the early detection, diagnosis, and therapy of HCC.

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.

Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factorsincluding rare variation and other environmental interactions need to be considered.

Bidirectional Causal Association Between Chronic Obstructive Pulmonary Disease and Cardiovascular Diseases: A Mendelian Randomization Study.

A large number of studies have demonstrated links between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVDs). However, the causal relationship between COPD and CVDs and the reverse causality remains divergent. Exposure and outcome data from the largest available genome-wide association studies were extracted for Mendelian randomization (MR) studies. Univariate MR analysis was performed using IVW as the primary analysis method, and multiple sensitivity analyses were used to enhance the robustness of the results. Furthermore, this was followed by mediation MR analysis of positive results after excluding confounding factors with multivariable MR analysis. The MR estimation based on IVW method indicated a strong association between genetically determined COPD and heart failure (HF) (OR = 1.117, 95% CI: 1.066-1.170, p <0.001), coronary heart disease (CHD) (OR = 1.004, 95% CI: 1.002-1.006, p <0.001), essential hypertension (EH) (OR = 1.009, 95% CI: 1.005-1.013, p <0.001) as well as Stroke (OR = 1.003, 95% CI: 1.001-1.004, p <0.001). The results of multivariable MR analysis revealed that COPD is not significantly associated with CHD after adjusting for IL-6, LDL, or total cholesterol (p>0.05). Our findings indicated that BMI, smoking initiation, smoking status, obesity, and FEV1 played a role in the causal effect of COPD on HF, EH, and Stroke. We found positive causal relationships between COPD and HF, EH, and Stroke essentially unaffected by other confounding factors. The causal relationship exhibited between COPD and CHD was influenced by confounding factors. BMI, obesity, initiation of smoking, smoking status, and FEV1 were the mediators between COPD and CVDs.

Association between immune checkpoint inhibitor and cytomegalovirus infection: A pharmacovigilance study based on the adverse event reporting system.

Immune checkpoint inhibitor (ICI)-induced adverse events due to excessive immune stimulation are problematic in immunotherapy. The activation of viral infection triggered by ICI-induced dysregulated immunity has been proposed; however, this association remains inconsistent. This study investigated the association between ICI administration and cytomegalovirus (CMV) infections, a pathogen linked to immune abnormalities and reactivation, using the Food and Drug Administration Adverse Event Reporting System. We used the crude data set and immunocompromise-free data set from the fourth quarter of 2012 to 2023. The disproportionality between CMV infection and ICI was analyzed using reporting odds ratio (ROR) and information component (IC) methodologies. Disproportionality between ipilimumab and nivolumab combination case and CMV infection was observed in the crude (ROR: 2.83, 95% confidence interval [CI]: 2.32-3.47; IC: 1.48, 95% CI: 1.14-1.73) and immunocompromise-free data set (ROR: 1.76, 95% CI: 1.33-2.33; IC: 0.80, 95% CI: 0.33-1.14), whereas disproportionality between other ICI and CMV infection was not observed in the immunocompromise-free data set. Multiple sensitivity analyses and time-scan analysis also revealed the consistent disproportionality between ipilimumab and nivolumab combination cases and CMV infection, regardless of the host's immune status. While further research is warranted to validate our findings, these results highlight new insights into ICI-induced viral infections and suggest the importance of considering the possibility of CMV infections during ipilimumab and nivolumab combination therapy, regardless of the host's immune status.

Understanding Factors That Cause Benign Paroxysmal Positional Vertigo, Ménière Disease, and Vestibular Neuritis: A Two-Sample Mendelian Randomization Study.

Vertigo is a prevalent clinical symptom, frequently associated with benign paroxysmal positional vertigo (BPPV), Ménière disease (MD), and vestibular neuritis (VN), which are three common peripheral vestibular disorders. However, there is a relative lack of research in epidemiology and etiology, with some existing studies presenting discrepancies in their conclusions. We conducted a two-sample Mendelian randomization (MR) analysis to explore potential risk and protective factors for these three peripheral vestibular disorders. Based on genome-wide association studies, we executed a univariable MR to investigate the potential associations between 38 phenotypes and MD, BPPV, and VN. We used the inverse variance weighted method as the primary MR result and conducted multiple sensitivity analyses. We used false discovery rate (FDR) correction to control for type I errors. For findings that were significant in the univariable MR, a multivariable MR analysis was implemented to ascertain direct effects. In addition, we replicated analyses of significant results from the univariable MR to enhance the robustness of our analyses. For BPPV, both alcohol consumption (odds ratio [OR] = 0.57, 95% confidence interval [CI] = 0.43 to 0.76, FDR Q = 0.004) and educational attainment (OR = 0.77, 95% CI = 0.68 to 0.88, FDR Q = 0.003) were found to decrease the risk. The genetic prediction analysis identified major depression (OR = 1.75, 95% CI = 1.28 to 2.39, FDR Q = 0.008) and anxiety (OR = 5.25, 95% CI = 1.79 to 15.42, FDR Q = 0.036) increased the risk of MD. However, the impact of major depression on MD could be influenced by potential horizontal pleiotropy. Systolic blood pressures (OR = 1.03, 95% CI = 1.02 to 1.04, FDR Q = 4.00 × 10 -7 ) and diastolic blood pressures (OR = 1.05, 95% CI = 1.03 to 1.07, FDR Q = 2.83 × 10 -6 ) were associated with an increased risk of VN, whereas high-density lipoprotein (OR = 0.77, 95% CI = 0.67 to 0.89, FDR Q = 0.009) and urate (OR = 0.75, 95% CI = 0.63 to 0.91, FDR Q = 0.041) reduces the risk of VN. Only the relationship between urate and VN was not replicated in the replication analysis. Multivariable MR showed that the protective effect of education on BPPV was independent of Townsend deprivation index. The protective effect of high-density lipoprotein against VN was independent of triglycerides and apolipoprotein A1. The risk impacts of systolic and diastolic blood pressures on VN exhibited collinearity, but both are independent of chronic kidney disease and estimated glomerular filtration rate. The impacts of anxiety and severe depression on MD demonstrated collinearity. Our study identified the risk association between systolic and diastolic blood pressure with VN and the protective influence of high-density lipoprotein on VN, which may support the vascular hypothesis underlying VN. Furthermore, we observed an elevated risk of MD associated with anxiety. The potential protective effects of education and alcohol consumption on BPPV need further exploration in subsequent studies to elucidate specific mechanistic pathways. In summary, our MR study offers novel insights into the etiology of three peripheral vestibular diseases from a genetic epidemiological standpoint.

Correlation between inflammatory cytokines and the likelihood of developing multiple types of digestive system cancers: A Mendelian randomization study

ObjectiveInflammatory cytokines have been linked to digestive system cancers, yet their exact causal connection remains uncertain. Consequently, we conducted a Mendelian randomization (MR) analysis to gauge how inflammatory cytokines are linked to the risk of five prevalent digestive system cancers (DSCs). MethodsWe collected genetic variation data for 41 inflammatory cytokines from genome-wide association studies (GWAS), and the results data for five common diseases from the Finnish database. Our primary analytical approach involved employing the inverse-variance weighted, residual sum (IVW) method, complemented by the MR-Egger method, the weighted median method, simple mode analysis, and weighted mode analysis as supplementary analytical techniques. Furthermore, we conducted multiple sensitivity analyses. ResultsTumor necrosis factor-related apoptosis-inducing ligand (TRAIL), macrophage colony-stimulating factor (M-CSF), and interleukin (IL)-18 showed a negative association with the risk of hepatocellular carcinoma. Conversely, TRAIL was inversely linked to the risk of gastric cancer, while IL-16 exhibited a positive correlation with gastric cancer risk. Stem cell factor (SCF) acted as a protective factor against pancreatic cancer. For colorectal cancer, IL-7, IL-9, IL-13, and vascular endothelial growth factor (VEGF) were identified as risk factors. Notably, our results did not indicate a significant correlation between inflammatory cytokines and the risk of esophageal cancer. ConclusionOur research unveils potential connections between 41 inflammatory cytokines and the risk of five common DSCs through a MR analysis. These associations offer valuable insights that could aid in the development of diagnostic biomarkers and the identification of novel therapeutic targets for DSCs.

Mendelian randomization implicates causal association between epigenetic age acceleration and age-related eye diseases or glaucoma endophenotypes

BackgroundAge-related eye diseases (AREDs) have become increasingly prevalent with the aging population, serving as the leading causes of visual impairment worldwide. Epigenetic clocks are generated based on DNA methylation (DNAm) levels and are considered one of the most promising predictors of biological age. This study aimed to investigate the bidirectional causal association between epigenetic clocks and common AREDs or glaucoma endophenotypes.MethodsInstrumental variables for epigenetic clocks, AREDs, and glaucoma endophenotypes were obtained from corresponding genome-wide association study data of European descent. Bidirectional two-sample Mendelian randomization (MR) was employed to explore the causal relationship between epigenetic clocks and AREDs or glaucoma endophenotypes. Multivariable MR (MVMR) was used to determine whether glaucoma endophenotypes mediated the association of epigenetic clocks with glaucoma. Multiple sensitivity analyses were conducted to confirm the robustness of MR estimates.ResultsThe results showed that an increased intrinsic epigenetic age acceleration (HorvathAge) was significantly associated with an increased risk of primary open-angle glaucoma (OR = 1.04, 95% CI 1.02 to 1.06, P = 6.1E−04). The epigenetic age acceleration (EEA) of HannumAge was related to a decreased risk of primary angle-closure glaucoma (OR = 0.92, 95% CI 0.86 to 0.99, P = 0.035). Reverse MR analysis showed that age-related cataract was linked to decreased HannumAge (β = −0.190 year, 95% CI −0.374 to −0.008, P = 0.041). The EEA of HannumAge (β = −0.85 μm, 95% CI −1.57 to −0.14, P = 0.019) and HorvathAge (β = −0.63 μm, 95% CI −1.18 to −0.08, P = 0.024) were associated with decreased central corneal thickness (CCT). PhenoAge was related to an increased retinal nerve fiber layer thickness (β = 0.06 μm, 95% CI 0.01 to 0.11, P = 0.027). MVMR analysis found no mediation effect of CCT in the association of HannumAge and HorvathAge with glaucoma. DNAm-based granulocyte proportions were significantly associated with presbyopia, rhegmatogenous retinal detachment, and intraocular pressure (P < 0.05). DNAm-based plasminogen activator inhibitor-1 levels were significantly related to age-related macular degeneration and intraocular pressure (P < 0.05).ConclusionThe present study revealed a causal association between epigenetic clocks and AREDs. More research is warranted to clarify the potential mechanisms of the biological aging process in AREDs.

Circulating pancreatic enzyme levels are a causal biomarker of type 1 diabetes.

Novel biomarkers of type 1 diabetes (T1D) are needed for earlier detection of disease and identifying therapeutic targets. We identified biomarkers of T1D by combining plasma cis and trans protein QTLs (pQTLs) for 2,922 proteins in the UK Biobank with a T1D genome-wide association study (GWAS) in 157k samples. T1D risk variants at over 20% of known loci colocalized with cis or trans pQTLs, and distinct sets of T1D loci colocalized with immune, pancreatic secretion, or gut-related proteins. We identified 23 proteins with evidence for a causal role in using pQTLs as genetic instruments in Mendelian Randomization which included multiple sensitivity analyses. Proteins increasing T1D risk were involved in immune processes (e.g. HLA-DRA) and, more surprisingly, T1D protective proteins were enriched in pancreatic secretions (e.g. CPA1), cholesterol metabolism (e.g. APOA1), and gut homeostasis. Genetic variants associated with plasma levels of T1D-protective pancreatic enzymes such as CPA1 were enriched in cis-regulatory elements in pancreatic exocrine and gut enteroendocrine cells, and the protective effects of CPA1 and other enzymes on T1D were consistent when using instruments specific to acinar cells. Finally, pancreatic enzymes had decreased acinar expression in T1D, including CPA1 which was altered prior to onset. Together, these results reveal causal biomarkers and highlight processes in the exocrine pancreas, immune system, and gut that modulate T1D risk.

Mendelian randomization study reveals causal effects of specific gut microbiota on the risk of interstitial cystitis/bladder pain syndrome (IC/BPS)

Evidence from previous studies have demonstrated that gut microbiota are closely associated with occurrence of interstitial cystitis/bladder pain syndrome (IC/BPS), yet the causal link between the two is not well known. In this study, we performed a two-sample Mendelian randomization (MR) analysis to determine the possible causal association between gut microbiota with IC/BPS. Gut microbiota summary level data were derived from the genome-wide association study (GWAS) conducted by MiBioGen and the IC/BPS GWAS summary level data were obtained from the GWAS Catalog. Next, we performed an MR study to investigate the causal link between gut microbiota and IC/BPS. The primary method for causal analysis was the inverse variance weighted (IVW), and the MR results were validated through multiple sensitivity analyses. A positive association was found between IC/BPS and eight gut microbial taxa, including genus Bacteroides, genus Haemophilus, genus Veillonella, genus Coprococcus1, genus Butyricimonas, family Bacteroidaceae, family Christensenellaceae, and order Lactobacillales. Sensitivity analysis revealed lack of significant pleiotropy or heterogeneity in the obtained results. This MR analysis reveals that a causal association exists between some gut microbiota with IC/BPS. This finding may is expected to guide future research and development of IC/BPS preventions and treatments based on the bladder-gut axis. However, given the clinical complexity and diagnostic challenges of IC/BPS, along with the limitations of using large-scale GWAS summary data for analysis, our MR results require further validation through additional research.