Association of coffee intake with bone mineral density: a Mendelian randomization study.

Background: In observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two. Methods: Genetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results. Results: After Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent. Conclusion: The results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.

No evidence of a causal relationship between miscarriage and 25-hydroxyvitamin D: a Mendelian randomization study.

STUDY QUESTION: Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage? SUMMARY ANSWER: In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages. WHAT IS KNOWN ALREADY: Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear. STUDY DESIGN SIZE DURATION: The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis. PARTICIPANTS/MATERIALS SETTING METHODS: This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (ß = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (ß = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found. LIMITATIONS REASONS FOR CAUTION: This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Causal effects of dietary habits on COVID-19 susceptibility, hospitalisation and severity: a comprehensive Mendelian randomisation study.

This study aimed to investigate the causal effect of dietary habits on COVID-19 susceptibility, hospitalisation and severity. We used data from a large-scale diet dataset and the COVID-19 Host Genetics Initiative to estimate causal relationships using Mendelian randomisation. The inverse variance weighted (IVW) method was used as the main analysis. For COVID-19 susceptibility, IVW estimates indicated that milk (OR: 0·82; 95 % CI (0·68, 0·98); P = 0·032), unsalted peanut (OR: 0·53; 95 % CI (0·35, 0·82); P = 0·004), beef (OR: 0·59; 95 % CI (0·41, 0·84); P = 0·004), pork (OR: 0·63; 95 % CI (0·42, 0·93); P = 0·022) and processed meat (OR: 0·76; 95 % CI (0·63, 0·92); P = 0·005) were causally associated with reduced COVID-19 susceptibility, while coffee (OR: 1·23; 95 % CI (1·04, 1·45); P = 0·017) and tea (OR: 1·17; 95 % CI (1·05, 1·31); P = 0·006) were causally associated with increased risk. For COVID-19 hospitalisation, beef (OR: 0·51; 95 % CI (0·26, 0·98); P = 0·042) showed negative correlations, while tea (OR: 1·54; 95 % CI (1·16, 2·04); P = 0·003), dried fruit (OR: 2·08; 95 % CI (1·37, 3·15); P = 0·001) and red wine (OR: 2·35; 95 % CI (1·29, 4·27); P = 0·005) showed positive correlations. For COVID-19 severity, coffee (OR: 2·16; 95 % CI (1·25, 3·76); P = 0·006), dried fruit (OR: 1·98; 95 % CI (1·16, 3·37); P = 0·012) and red wine (OR: 2·84; 95 % CI (1·21, 6·68); P = 0·017) showed an increased risk. These findings were confirmed to be robust through sensitivity analyses. Our findings established a causal relationship between dietary habits and COVID-19 susceptibility, hospitalisation and severity.

COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: An increasing number of studies have elucidated a close nexus between COVID-19 phenotypes and neuromyelitis optica spectrum disorder (NMOSD), yet the causality between them remains enigmatic. Methods: In this study, we conducted a Mendelian randomization (MR) analysis employing summary data sourced from genome-wide association studies (GWAS) pertaining to COVID-19 susceptibility, hospitalization, severity, and NMOSD. The primary MR analysis employed the Inverse variance weighted (IVW) approach, which was supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. We implemented various sensitivity analyses including Cochran's Q test, MR-PRESSO method, MR-Egger intercept, leave-one-out analysis, and funnel plot. Results: The MR results demonstrated a nominal association between COVID-19 susceptibility and the risk of AQP4+ NMOSD, as evidenced by the IVW method (OR = 4.958; 95% CI: 1.322-18.585; P = 0.018). Conversely, no causal association was observed between COVID-19 susceptibility, hospitalization, or severity and the increased risk of NMOSD, AQP4-NMOSD, or AQP4+ NMOSD. The comprehensive sensitivity analyses further bolstered the robustness and consistency of the MR estimates. Conclusion: Our findings provide compelling evidence for a causal effect of COVID-19 phenotype on AQP4+ NMOSD, shedding new light on the understanding of the comorbidity between COVID-19 and NMOSD.

Sensitivity of estimands in clinical trials with imperfect compliance.

In clinical trials that are subject to noncompliance, the commonly used intention-to-treat estimand is valid as a causal effect of treatment assignment but is sensitive to the level of compliance. An alternative estimand, the complier average causal effect (CACE), measures the average effect of treatment received in the latent subset of subjects who would comply with either assigned treatment. Because the principal stratum of compliers can vary with the circumstances of the trial, CACE too depends on the compliance fraction. We propose a model in which an underlying latent proto-compliance interacts with trial characteristics to determine a subject's compliance behavior. When the latent compliance is independent of the individual treatment effect, the average causal effect is constant across compliance classes, and CACE is robust across trials and equal to the population average causal effect. We demonstrate the potential degree of sensitivity of CACE in a simulation study, an analysis of data from a trial of vitamin A supplementation in children, and a meta-analysis of trials of epidural analgesia in labor.

Evidence for genetic causal relationships between gut microbiome, metabolites, and myasthenia gravis: a bidirectional Mendelian randomization study.

Background: Myasthenia gravis (MG) is an autoimmune disease observed to have connections with gut microbiome. We aimed to systematically assess the causal relationships between gut microbiome, gut microbiome-derived metabolites, and MG using Mendelian randomization (MR) approach. Methods: Summary-level genetic datasets from large-scale genome-wide association studies regarding 196 gut microbial taxa from the MiBioGen consortium (n=18,340), 72 derived metabolites from the TwinsUK and KORA studies (n=7,824), and antiacetylcholine receptor (AChR) antibody-positive MG (case=1,873, control=36,370) were employed for MR causal estimates. The inverse-variance weighted (IVW) method was utilized as the main analysis with MR-Egger, maximum likelihood, simple mode, and weighted median as complements. The tests of Cochran's Q, MR-Egger intercept, Steiger, MR-PRESSO and leave-one-out were implemented for sensitivity analyses. Results: The forward MR estimates of IVW revealed significant causal associations of the abundance of phylum Actinobacteria, class Gammaproteobacteria, family Defluviitaleac, family Family XIII, and family Peptococcaceae with a reduced risk of MG. Conversely, the abundance of phylum Lentisphaerae, order Mollicutes RF9, order Victivallales, and genus Faecalibacterium was causally associated with an increased risk of MG. The reversed MR analysis proved negative causal correlations between the MG and the abundance of family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum. Regarding the derived metabolites, the IVW estimates revealed that elevated levels of beta-hydroxyisovalerate and methionine were causally associated with a decreased risk of MG, while increased levels of choline and kynurenine were linked to an increased risk of MG. Furthermore, genetically predicted MG was associated with a decreased level of cholesterol. The results obtained from complementary MR methods were similar. These findings remained robust in all sensitivity analyses. Conclusion: Our MR findings support the causal effects of specific gut microbiome taxa and derived metabolites on AChR antibody-positive MG, and vice versa, yielding novel insights into prevention and therapy targets of MG. Future studies may be warranted for validation and pursuing the precise mechanisms.

Causal effect of serum 25-hydroxyvitamin D levels on low back pain: A two-sample mendelian randomization study.

Background: Previous observational studies have suggested the involvement of 25-hydroxyvitamin D [25(OH)D] in chronic pain. However, whether the 25(OH)D is a novel target for management, the causality remains unclear. Methods: A two-sample Mendelian randomization (MR) study was conducted to identify the causal association between 25(OH)D and low back pain (LBP). The primary analysis was revealing causality from serum 25(OH)D level (n = 417,580) on LBP (21,140 cases and 227,388 controls). The replicated analysis was performing MR estimates from circulating 25(OH)D concentration (n = 79,366) on LBP experienced last month (118,471 cases and 343,386 controls). Inverse variance weighted (IVW) was used as the main analysis. In addition, we used weighted median and MR-Egger to enhance the robustness. Sensitivity analysis was conducted to evaluate the robustness of MR results. Results: IVW estimation indicated strong evidence that higher serum 25(OH)D levels exerted a protective effect on LBP (OR = 0.89, 95% CI = 0.83-0.96, p = 0.002). Similar trends were also found in replicate analysis (OR = 0.98, 95% CI = 0.96-1.00, p = 0.07). After meta-analysis combining primary and replicated analysis, the causal effect is significant (p = 0.03). Sensitivity analysis supported that the MR estimates were robust. Conclusion: In our MR study, genetically increased serum 25(OH)D levels were associated with a reduced risk of LBP in the European population. This might have an implication for clinicians that vitamin D supplements might be effective for patients with LBP in clinical practice.

Smoking, alcohol and coffee consumption and risk of low back pain: a Mendelian randomization study.

PURPOSE: Low back pain (LBP) is a common health problem in the global population. This study aims to assess whether smoking initiation, alcohol consumption, and coffee consumption are causally with an increased risk of LBP. METHODS: A two-sample Mendelian Randomization (MR) study was designed, based on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with genome-wide significance level (P < 5.0 × 10-8) were selected as instrumental variables for each exposure. Standard inverse-variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods, which relax some IV assumptions, were used for sensitivity analysis. RESULTS: Genetically predicted smoking initiation was causally associated with higher odds of LBP. The pooled OR of LBP using IVW method was 1.36 (95%CI 1.22 1.52; P = 6.0 × 10-8) for one SD increase in the prevalence of smoking initiation, which was supported by the weighted median method (OR: 1.41, 95%CI 1.22, 1.64; P = 5.7 × 10-6). Sensitivity analysis confirmed the robustness of pooled OR of LBP. There was no evidence to suggest a causal effect of alcohol and coffee consumption on LBP. The pooled ORs of LBP were 1.36 (95%CI 0.94, 1.97; P = 0.10) for alcohol consumption and 1.00 (95%CI 0.99, 1.00; P = 0.17) for coffee consumption, respectively. CONCLUSION: Smoking is casually associated with an increased risk of LBP. Smoking control should be recommended in LBP patients to avoid worsening the disease. The safety of LBP with moderate alcohol and coffee consumption merits more study.

Habitual coffee intake and risk for nonalcoholic fatty liver disease: a two-sample Mendelian randomization study.

PURPOSE: Epidemiological studies support a protective role of habitual coffee and caffeine consumption against the risk of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the causal relationship between coffee intake and the risk of NAFLD. METHODS: We performed a two-sample Mendelian randomization (MR) analysis using SNPs associated with habitual coffee intake in a published genome-wide association study (GWAS) as genetic instruments and summary-level data from a published GWAS of NAFLD (1122 cases and 399,900 healthy controls) in the UK Biobank. The causal relationship was estimated with the inverse weighted method using a 4-SNP and 6-SNP instrument based on the single largest non-UK Biobank GWAS (n = 91,462) and meta-analysis (n = 121,524) of GWAS data on habitual coffee intake, respectively. To maximize power, we also used up to 77 SNPs associated with coffee intake at a liberal significance level (p ≤ 1e-4) as instruments. RESULTS: We observed a non-significant trend towards a causal protective effect of coffee intake on NAFLD based upon either the 4-SNP (OR: 0.76; 95% CI 0.51, 1.14, p = 0.19) or 6-SNP genetic instruments (OR: 0.77; 95% CI 0.48, 1.25, p = 0.29). The result also remains non-significant when using the more liberal 77-SNP instrument. CONCLUSION: Our findings do not support a causal relationship between coffee intake and NAFLD risk. However, despite the largest-to-date sample size, the power of this study may be limited by the non-specificity and moderate effect size of the genetic alleles on coffee intake.

Investigating the causal effect of socioeconomic status on quality of care under a universal health insurance system - a marginal structural model approach.

BACKGROUND: Social disparities in healthcare persist in the US despite the expansion of Medicaid under the Affordable Care Act. We investigated the causal impact of socioeconomic status on the quality of care in a setting with minimal confounding bias from race, insurance type, and access to care. METHODS: We designed a retrospective population-based study with a random 25% sample of adult Taiwan population enrolled in Taiwan's National Health Insurance system from 2000 to 2016. Patient's income levels were categorized into low-income group (<25th percentile) and high-income group (≥25th percentile). We used marginal structural modeling analysis to calculate the odds of hospital admissions for 11 ambulatory care sensitive conditions identified by the Agency for Healthcare Research and Quality and the odds of having an Elixhauser comorbidity index greater than zero for low-income patients. RESULTS: Among 2,844,334 patients, those in lower-income group had 1.28 greater odds (95% CI 1.24-1.33) of experiencing preventable hospitalizations, and 1.04 greater odds (95% CI 1.03-1.05) of having a comorbid condition in comparison to high-income group. CONCLUSIONS: Income was shown to be a causal factor in a patient's health and a determinant of the quality of care received even with equitable access to care under a universal health insurance system. Policies focusing on addressing income as an important upstream causal determinant of health to provide support to patients in lower socioeconomic status will be effective in improving health outcomes for this vulnerable social stratum.

From cumulative cultural transmission to evidence-based medicine: evolution of medicinal plant knowledge in Southern Italy.

In Mediterranean cultures written records of medicinal plant use have a long tradition. This written record contributed to building a consensus about what was perceived to be an efficacious pharmacopeia. Passed down through millennia, these scripts have transmitted knowledge about plant uses, with high fidelity, to scholars and laypersons alike. Herbal medicine's importance and the long-standing written record call for a better understanding of the mechanisms influencing the transmission of contemporary medicinal plant knowledge. Here we contextualize herbal medicine within evolutionary medicine and cultural evolution. Cumulative knowledge transmission is approached by estimating the causal effect of two seminal scripts about materia medica written by Dioscorides and Galen, two classical Greco-Roman physicians, on today's medicinal plant use in the Southern Italian regions of Campania, Sardinia, and Sicily. Plant-use combinations are treated as transmissible cultural traits (or "memes"), which in analogy to the biological evolution of genetic traits, are subjected to mutation and selection. Our results suggest that until today ancient scripts have exerted a strong influence on the use of herbal medicine. We conclude that the repeated empirical testing and scientific study of health care claims is guiding and shaping the selection of efficacious treatments and evidence-based herbal medicine.

Abnormal causal connectivity by structural deficits in first-episode, drug-naive schizophrenia at rest.

Anatomical deficits and resting-state functional connectivity (FC) alterations in prefrontal-thalamic-cerebellar circuit have been implicated in the neurobiology of schizophrenia. However, the effect of structural deficits in schizophrenia on causal connectivity of this circuit remains unclear. This study was conducted to examine the causal connectivity biased by structural deficits in first-episode, drug-naive schizophrenia patients. Structural and resting-state functional magnetic resonance imaging (fMRI) data were obtained from 49 first-episode, drug-naive schizophrenia patients and 50 healthy controls. Data were analyzed by voxel-based morphometry and Granger causality analysis. The causal connectivity of the integrated prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit was partly affected by structural deficits in first-episode, drug-naive schizophrenia as follows: (1) unilateral prefrontal-sensorimotor connectivity abnormalities (increased driving effect from the left medial prefrontal cortex [MPFC] to the sensorimotor regions); (2) bilateral limbic-sensorimotor connectivity abnormalities (increased driving effect from the right anterior cingulate cortex [ACC] to the sensorimotor regions and decreased feedback from the sensorimotor regions to the right ACC); and (3) bilateral increased and decreased causal connectivities among the sensorimotor regions. Some correlations between the gray matter volume of the seeds, along with their causal effects and clinical variables (duration of untreated psychosis and symptom severity), were also observed in the patients. The findings indicated the partial effects of structural deficits in first-episode, drug-naive schizophrenia on the prefrontal-thalamic (limbic)-cerebellar (sensorimotor) circuit. Schizophrenia may reinforce the driving connectivities from the left MPFC or right ACC to the sensorimotor regions and may disrupt bilateral causal connectivities among the sensorimotor regions.