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PubMed2025

The causal relationship between steroid hormones and risk of stroke: evidence from a two-sample Mendelian randomization study.

It is unclear how steroid hormones contribute to stroke, and conducting randomized controlled trials to obtain related evidence is challenging. Therefore, Mendelian randomization (MR) technique was employed in this study to examine this association. Through genome-wide association meta-analysis, the genetic variants of steroid hormones, including testosterone/17β-estradiol (T/E2) ratio, aldosterone, androstenedione, progesterone, and hydroxyprogesterone, were acquired as instrumental variables. Analysis was done on the impact of these steroid hormones on the risk of stroke subtypes. The T/E2 ratio was associated to an elevated risk of small vessel stroke (SVS) according to the inverse variance weighted approach which was the main MR analytic technique (OR, 1.23, 95% CI: 1.05-1.44, p = 0.009). These findings were solid since no heterogeneity nor horizontal pleiotropy were found. The causal association between T/E2 and SVS was also confirmed in the replication study (p = 0.009). Nevertheless, there was no proof that other steroid hormones increased the risk of stroke. According to this study, T/E2 ratio and SVS are causally related. However, strong evidence for the impact of other steroid hormones on stroke subtypes is still lacking. These findings may be beneficial for developing stroke prevention strategies from steroid hormones levels.

Mendelian Randomization Analysis↗

PubMed1981

Clinical electroneurography: statistical analysis of controlled measures in twenty-two normal subjects.

Electroneurography, an objective electrophysiologic measurement of a muscle compound action potential, is used to assess the integrity of a peripheral motor nerve. This paper describes how to perform electroneurography with particular attention to control of patient and instrumentation variables. Twenty-two normal adult subjects were tested in a balanced, designed experiment. The resultant average difference between the right and left halves of the face was not significant. The standard deviation of this difference was divided into three components: test-retest daily, and intersubject. The data suggest that the most significant source of error in electroneurography is test-retest variability (p less than 0.05) and that repeated and averaged measures on a given patient will increase the precision of the test. As further understanding and experience are gained, electroneurography measurements should be interpreted in light of clinical findings and more traditional tests.

Action Potentials↗

PubMed2002

Immunophenotypic variability of B-cell non-Hodgkin lymphoma: a retrospective study of cases analyzed by flow cytometry.

Flow cytometric analysis is important in the diagnosis, classification, and follow-up of non-Hodgkin lymphoma. It is assumed that the lymphoma phenotype for each patient remains unchanged over time and is consistent from one specimen to another. To determine the variability in expression of lymphoid antigens, we reviewed 211 flow cytometry specimens of malignant lymphoma from 81 patients. Some antigens showed a stable pattern of expression such as CD5, CD10, CD19, CD20, and HLA-DR. In contrast, CD21, CD22, CD23, and CD25 showed more variability from one specimen to another. We believe several factors affect the stability of antigen expression. True differences in expression most probably are related to the biology and function of the different antigens. For instance, CD19 and CD20 are essential in cell maturation and function and, therefore, are present on the majority of cells. In contrast, CD22 has a role during B-cell activation and, therefore, is more variable. Lack of standardization inflow cytometry procedures also is responsible for some variability. Instrument settings for adequate compensation and the criteria used to determine when an antigen is reported as positive are important considerations when evaluating flow cytometry histograms.

Antibodies, Monoclonal↗

PubMed2002

On the validity of retrospective assessments of pregnancy intention.

Information on pregnancy intention is often gathered retrospectively (after the birth of a child). This article investigates whether the retrospective assessment of pregnancy intention leads to biased estimates of the extent or consequences of unintended fertility. Comparisons are made between pregnancy intentions ascertained during pregnancy and after birth using data from the National Longitudinal Survey of Youth. To address the bias caused by selective recognition or acknowledgment of pregnancy, we used the longitudinal feature of the data to determine actual pregnancy status at the time of interviews, which, in turn, was used as an instrumental variable for the retrospective (versus prospective) reporting of pregnancy intention. After correction for selective pregnancy recognition, we found no evidence that the retrospective assessment of pregnancy intention produces misleading estimates of either the number or the consequences of unintended births. This finding is supported by additional analyses of a small subsample of women for whom information on pregnancy intention was collected both during pregnancy and after birth.

Adolescent↗

PubMed2024

Association of different milk fat content with coronary artery disease and myocardial infarction risk: A Mendelian randomization study.

BACKGROUND: Numerous observational studies have investigated on the correlation of whole, semi-skimmed, and skimmed milk with coronary artery disease (CAD) and myocardial infarction (MI) risk; However, no consensus has been reached and evidence on any causal links between these exposures and outcomes remains unclear. This study aimed to conduct univariate and multivariate Mendelian randomization (MR) analyses, using publicly released genome-wide association study summary statistics (GWAS) from the IEU GWAS database, to ascertain the causal association of milk with various fat content with CAD and MI risk. METHODS: For the exposure data, 29, 15, and 30 single-nucleotide polymorphisms for whole milk, semi-skimmed milk, and skimmed milk, respectively, obtained from 360,806 Europeans, were used as instrumental variables. CAD and MI comprised 141,217 and 395,795 samples, respectively. We used inverse variance weighted (IVW), weighted median, MR-Egger regression, and MR Pleiotropy Residual Sum and Outlier analyses to determine whether pleiotropy and heterogeneity could skew the MR results. Sensitivity tests were conducted to verify the robustness of the results. RESULTS: After adjusting for false discovery rates (FDR), we discovered proof that skimmed milk intake is a genetically predicted risk factor for CAD (odds ratio [OR] = 5.302; 95% confidence interval [CI] 2.261-12.432; P < 0.001; FDR-corrected P < 0.001) and MI (OR = 2.287; 95% CI 1.218-4.300; P = 0.010; FDR-corrected P = 0.009). Most sensitivity assessments yielded valid results. Multivariable MR for CAD and MI produced results consistent with those obtained using the IVW method. There was no causal relationship between whole or semi-skimmed milk, and CAD or MI. CONCLUSION: Our findings indicate that the consumption of skimmed milk may increase the risk of CAD and MI. This evidence may help inform dietary recommendations for preventing cardiovascular disease. Further studies are required to elucidate the underlying mechanisms.

Humans↗

PubMed2024

The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study.

BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while ≥0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Humans↗

PubMed2024

Is there a causal relationship between resistin levels and bone mineral density, fracture occurrence? A mendelian randomization study.

BACKGROUND: In a great many of observational studies, whether there is a relevance of resistin levels on bone mineral density (BMD) and fracture occurrence has been inconsistently reported, and the causality is unclear. METHODS: We aim to assess the resistin levels on BMD and fracture occurrence within a Mendelian randomization (MR) analysis. Exposure and outcome data were derived from the Integrative Epidemiology Unit (IEU) Open genome wide association studies (GWAS) database. Screening of instrumental variables (IVs) was performed subject to conditions of relevance, exclusivity, and independence. Inverse variance weighting (IVW) was our primary method for MR analysis based on harmonized data. Weighted median and MR-Egger were chosen to evaluate the robustness of the results of IVW. Simultaneously, heterogeneity and horizontal pleiotropy were also assessed and the direction of potential causality was detected by MR Steiger. Multivariable MR (MVMR) analysis was used to identify whether confounding factors affected the reliability of the results. RESULTS: After Bonferroni correction, the results showed a suggestively positive causality between resistin levels and total body BMD (TB-BMD) in European populations over the age of 60 [β(95%CI): 0.093(0.021, 0.165), P = 0.011]. The weighted median [β(95%CI): 0.111(0.067, 0.213), P = 0.035] and MR-Egger [β(95%CI): 0.162(0.025, 0.2983), P = 0.040] results demonstrate the robustness of the IVW results. No presence of pleiotropy or heterogeneity was detected between them. MR Steiger supports the causal inference result and MVMR suggests its direct effect. CONCLUSIONS: In European population older than 60 years, genetically predicted higher levels of resistin were associated with higher TB-BMD. A significant causality between resistin levels on BMD at different sites, fracture in certain parts of the body, and BMD in four different age groups between 0-60 years of age was not found in our study.

Bone Density↗

PubMed2024

Multiple sclerosis and abnormal spermatozoa: A bidirectional two-sample mendelian randomization study.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. METHODS: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. RESULTS: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017-1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. CONCLUSION: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians.

Humans↗

PubMed2026

Does Toxoplasma gondii infection have a causal impact on human psychopathology? A Mendelian randomization analysis.

Toxoplasma gondii (T. gondii) is a prevalent zoonotic parasite that has been implicated in influencing human psychiatric disorders and risk-taking behaviors. Using genome-wide association study (GWAS) data, we selected 25 and 76 single-nucleotide polymorphisms as instrumental variables for anti-T. gondii IgG seropositivity and anti-T. gondii IgG levels, respectively, and conducted two-sample Mendelian randomization (MR) analyses across 18 GWAS datasets to investigate potential causal effects on addiction, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and risk-taking behavior in European populations. Contrary to previous epidemiological evidence, our MR analyses do not support a significant causal association between T. gondii infection and any of the studied psychiatric disorders or risk-taking behavior. Collectively, these results establish that any true causal effect of genetic liability to T. gondii infection is likely to be small (OR < 1.18 for schizophrenia, < 1.29 for bipolar disorder) and below the effect sizes typically reported in observational seroepidemiological studies, although small or infection-phase-specific effects cannot be excluded.

Humans↗

PubMedDate not supplied

Measuring patients' trust in physicians when assessing quality of care.

Trust is a fundamentally important aspect of medical treatment relationships. Studies have established that patient trust predicts instrumental variables such as use of preventive services, adherence, and continued enrollment at least as well as satisfaction does, and is more salient for measuring the quality of ongoing relationships. Measuring trust would help to inform public policy deliberations and balance market forces that threaten the doctor-patient relationship. Several validated measures could be easily included in surveys. While further studies to evaluate the cost-effectiveness of measuring trust and test interventions to improve trust are desirable, the action merits serious consideration.

Humans↗

PubMed1995

Comparing MiniWright and spirometer measurements of peak expiratory flow.

The accuracy and instrument variability of the MiniWright (Clement Clarke) peak expiratory flow (PEF) meter was determined with 6 of the 24 American Thoracic Society's (ATS) standard waveforms using a mechanical pump. Both room air and air heated to 37 degrees C and saturated with water vapor were used. In addition, MiniWright-determined PEF measurements were compared with those obtained using a dry rolling-seal spirometer (Ohio No. 822; Ohio Medical Products; Madison, Wis) from 75 subjects on 2 different days. The MiniWright average coefficient of variation within a waveform was found to be 2.8%. Results using heated and humidified air (body temperature, ambient pressure, and saturated with water: body conditions) were 2.5% lower than those obtained using room air. Comparisons with mechanically simulated PEF and with spirometry-determined peak flow in 75 human subjects showed that MiniWright meters over-estimated flows at lower flow rates and slightly under-estimated flows at higher flow rates. These results suggest that the new "mechanical PEF" MiniWright scale should be used instead of the "traditional" MiniWright scale.

Evaluation Studies as Topic↗

PubMed2026

Genome-Wide Association Study of Contrast Media Hypersensitivity in Japanese Patients.

Iodinated contrast media (ICM), commonly used in radiological tests such as coronary angiography, can cause hypersensitivity reactions (HSRs). The mechanism of ICM HSRs is thought to be complex; while IgE-mediated allergic reactions appear to be involved, the details remain unclear. This study aims to elucidate the pathogenesis of ICM HSRs through genetic analysis. To date, a few case-control studies have been conducted exclusively on East Asians, but the results have been inconclusive and have not been replicated.We conducted a multistage GWAS for ICM HSRs in Japanese individuals. The study population comprised 153 cases with ICM HSRs (ranging from mild to severe form), 632 controls with no history of ICM-induced allergies, and < 38,721 individuals from the general population. We identified genome-wide significant association signals in the HLA region and also found that these signals originated from the three HLA alleles-B*52:01, C*12:02, DRB1*15:02-previously reported in a Korean candidate gene study. Using instrumental variable analysis with a polygenic score for pediatric asthma (PGSasthma) as a proxy, we demonstrated that ICM HSRs are associated with the allergic predisposition thought to be shared by asthma and ICM HSRs. There was a significant difference in the distribution of PGSasthma between ICM HSR patients and non-disease controls (per-SD odds ratio: 1.26, P = 0.021).Our genome-wide approach shows that HLA alleles are among the genetic factors underlying ICM HSRs. Furthermore, it provides evidence for the potential usefulness of predicting the risk of developing ICM HSRs based on allergic predisposition.

Allergic predisposition↗

PubMed2004

Uptake of Onchocerca volvulus (Nematoda: Onchocercidae) by Simulium (Diptera: Simuliidae) is not strongly dependent on the density of skin microfilariae in the human host.

The relation between the number of microfilariae (mf) ingested by host-seeking vectors of human onchocerciasis and skin mf load is an important component of the population biology of Onchocerca volvulus, with implications for disease control and evaluation of the risk of transmission recrudescence. The microsimulation model ONCHOSIM has been used to assess such risk in the area of the Onchocerciasis Control Program (OCP) in West Africa, based on a strongly nonlinear relation between vector mf uptake and human mf skin density previously published. However, observed levels of recrudescence have exceeded predictions, warranting a recalibration of the model. To this end, we present the results of a series of fly-feeding experiments carried out in savanna and forest localities of West Africa. Flies belonging to Simulium damnosum s.s., S. sirbanum, S. soubrense, and S. leonense were fed on mf carriers and dissected to assess the number of ingested mf escaping imprisonment by the peritrophic matrix (the number of exo-peritrophic mf), a predictor of infective larval output. The method of instrumental variables was used to obtain (nearly) unbiased estimates of the parameters of interest, taking into account error in the measurement of skin mf density. This error is often neglected in these types of studies, making it difficult to ascertain the degree of density-dependence truly present in the relation between mf uptake and skin load. We conclude that this relation is weakly (yet significantly) nonlinear in savanna settings but indistinguishable from linearity in forest vectors. Exo-peritrophic mf uptake does not account for most of the density dependence in the transmission dynamics of the parasite as previously thought. The number of exo-mf in forest simuliids is at least five times higher than in the savanna vectors. Parasite abundance in human onchocerciasis is regulated by poorly known mechanisms operating mainly on other stages of the lifecycle.

Africa, Western↗

PubMed2006

Complex causal process diagrams for analyzing the health impacts of policy interventions.

Causal diagrams are rigorous tools for controlling confounding. They also can be used to describe complex causal systems, which is done routinely in communicable disease epidemiology. The use of change diagrams has advantages over static diagrams, because change diagrams are more tractable, relate better to interventions, and have clearer interpretations. Causal diagrams are a useful basis for modeling. They make assumptions explicit, provide a framework for analysis, generate testable predictions, explore the effects of interventions, and identify data gaps. Causal diagrams can be used to integrate different types of information and to facilitate communication both among public health experts and between public health experts and experts in other fields. Causal diagrams allow the use of instrumental variables, which can help control confounding and reverse causation.

Audiovisual Aids↗

PubMed1996

The timing of preventive services for women and children: the effect of having a usual source of care.

OBJECTIVES: This study investigated the causal effect of having a usual source of medical care on the timing of preventive services by women and children. METHODS: Data on 17,110 children and 23,488 women from the 1988 and 1990 National Health Interview Surveys were used to estimate ordered probit models of the effect of having a usual source of medical care on the time since the last receipt of each preventive service (routine checkups for children; blood pressure checks, Pap smears, and breast exams for adult women; mammograms for older women). Two-stage instrumental variables methods were used to eliminate simultaneity bias. RESULTS: The existence of a usual source of medical care was strongly correlated with the earlier receipt of preventive services, and the relationship appears to be causal for Pap smears, breast exams, and mammograms. However, there was little evidence that having a regular provider caused an increased rate of routine checkups for children or blood pressure checks for adult women. CONCLUSIONS: Delivery systems that encourage the development of long-term relationships with medical providers may increase cancer screening rates among women.

Adolescent↗

PubMed2004

Native fluorescence flow-through optosensor for the fast determination of diphenhydramine in pharmaceuticals.

A single, rapid flow-through optosensor spectrofluorometric system is proposed for the determination of diphenhydramine in different pharmaceutical preparations. This sensor was developed in conjunction with a monochannel flow-injection analysis system with fluorometric solid-phase transduction. Diphenhydramine was directly injected into a carrier stream of ethanol/water, 50% (v:v), and transitorily retained on a sorption gel Sephadex G-15 placed in the detection area into the cell. The determination was carried out without any derivatization reaction by directly measuring the intrinsic fluorescence of the analyte and using the peak height as an analytical signal. The chemical and instrumental variables were optimized, and the influence of some foreign substances that can be found in typical pharmaceutical samples containing diphenhydramine was also investigated. Diphenhydramine could be determined in the concentration ranges of 0.5 - 8 microg ml(-1) and 0.1 - 1.2 microg ml(-1) with detection limits of 0.088 and 0.019 microg ml(-1) at sampling rates of 30 and 19 h(-1) for 200 and 800 microl of the sample volume, respectively.

Journal Article↗

PubMed2003

Olanzapine versus risperidone in the treatment of schizophrenia : a comparison of costs among Texas Medicaid recipients.

OBJECTIVE: To examine both schizophrenia-related costs and total (schizophrenia plus non-schizophrenia) healthcare costs among Texas Medicaid recipients who had been diagnosed with a schizophrenic disorder and had been initiated on olanzapine or risperidone. METHODS: Cost data for services and prescription use were retrieved for 2,885 patients with schizophrenia who were initiated on olanzapine or risperidone between 1 January 1997 and 31 August 1998. Each patient was followed for 1 year before and 1 year after initiation of therapy. Multivariate analysis was used to control for a wide range of factors (drug choice, patient demographics, pre-utilisation costs, region, health conditions, and treatment patterns) that may influence schizophrenia-related costs and total healthcare costs. Estimation was conducted via a two-stage instrumental variables model. RESULTS: The mean unadjusted total schizophrenia-related cost per patient per year during the observation period was 4,892 US dollars, and the total unadjusted healthcare cost per patient was 7,101 US dollars. Results revealed significant regional variation in schizophrenia-related and total healthcare costs. Significantly higher total healthcare costs were found for patients with other (nonpsychiatric) diagnoses, such as HIV and diabetes mellitus. Although, on average, patients taking olanzapine stayed on therapy longer than those taking risperidone (248.2 days vs 211.1 days; p < 0.0001), multivariate analysis revealed no significant difference in schizophrenia-related costs between patients who received olanzapine and risperidone (123 US dollars lower with olanzapine; p = 0.6439). However, patients who received olanzapine compared with risperidone had significantly lower total medical costs (693 US dollars lower with olanzapine; p = 0.0311). CONCLUSION: This naturalistic study used data from a Texas Medicaid population to examine the schizophrenia-related costs and total healthcare costs for patients who received olanzapine versus risperidone. Multivariate analysis revealed no significant differences in schizophrenia-related costs for patients receiving olanzapine compared with risperidone, although total medical costs were significantly lower for patients initiated on olanzapine.

Adult↗

PubMed2026

Deciphering the Microbiome-Gut-Eye Axis: A Mendelian Randomization Analysis of the Causal Influence of Gut Microbiota on Myopia.

INTRODUCTION: The intricate relationship between the gut microbiome and myopia is increasingly recognized, underscoring the need to explore its causal dynamics. Despite emerging evidence, the influence of Gut Microbiota (GM) on ocular development remains underexplored. METHODS: This study utilized Mendelian Randomization (MR) to investigate the causal impact of GM on the development of myopia. Instrumental variables (IVs) were identified from Genome-Wide Association Studies (GWAS), focusing on genetic variants significantly associated with microbiome composition. A comprehensive array of MR techniques was applied to ensure a robust estimation of causal effects and to adjust for potential confounders and pleiotropy. RESULTS: The Inverse-Variance Weighted (IVW) method was used to identify significant associations between GM and myopia. Increased risk of myopia was linked to the class Betaproteobacteria (OR=1.01, 95% CI 1.004-1.017, P=0.003), the order Burkholderiales (OR=1.009, 95% CI 1.001-1.016, P=0.02), the family Oxalobacteraceae (OR=1.005, 95% CI 1.001-1.01, P=0.023), and several genera including Eubacterium xylanophilum group (OR=1.007, 95% CI 1.001-1.013, P=0.033), and Bifidobacterium (OR=1.005, 95% CI 1-1.01, P=0.038). Protective effects were noted for the order Mollicutes RF9 (OR=0.994, 95% CI 0.99-0.999, P=0.014), the genus Allisonella (OR=0.996, 95% CI 0.993-0.999, P=0.019), the genus Lachnospiraceae UCG001 (OR=0.994, 95% CI 0.989-1, P=0.045), and the family Enterobacteraceae (OR=0.991, 95% CI 0.982-1, P=0.047) and order Enterobacteriales (OR=0.991, 95% CI 0.982-1, P=0.047). Sensitivity analyses further confirmed the robustness of these findings. DISCUSSION: This study provides causal evidence for the "Microbiome-Gut-Eye Axis" in myopia development, identifying specific gut microbiota that influence myopia risk. These findings suggest potential for microbiota-targeted interventions, warranting further research in diverse populations. CONCLUSIONS: The findings support the "Microbiome-Gut-Eye Axis" as a potential factor in myopia pathogenesis and highlight microbiota-targeted interventions as novel therapeutic strategies for managing myopia. This study lays the groundwork for further research on how modifying GM can influence eye health and offers new perspectives on preventive health strategies.

Humans↗