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OBJECTIVE: To critically examine the causal association between sleep apnea syndrome and hypertension. METHODS: A retrospective systematic critique of five epidemiologic studies published in the English literature during 1978 to 1989 identified on Medline and manual literature searches. The evidence was evaluated using the standard observational criteria for causation: strength of association, consistency, dose-response relationship, temporal sequence, specificity, and biologic plausibility. RESULTS: We found evidence to support a causal association between sleep apnea syndrome and hypertension in consistency and specificity and some evidence to suggest a dose-response relationship. Review of the data dealing with the mechanisms important in the pathogenesis of sleep apnea and hypertension allowed us to advance several theories to provide support for biologic plausibility. CONCLUSION: We concluded that there is a positive association--relative risk estimate between 1.3 and 40--for sleep apnea syndrome and hypertension, but the risk association is unstable. Thus, we believe that there is insufficient data to justify doing polysomnography as part of the routine diagnostic work-up for patients with hypertension.
Geohelminth infections and allergic disease are major public health problems and there is evidence in developing countries that they are associated. Although there is an extensive literature of the relationship between geohelminth infections and allergy, there is little consensus on whether the association is causal and if so, whether geohelminth infections may increase or decrease the risk of allergy. An explanation for the conflicting findings of epidemiological studies is that geohelminths decrease the risk of allergy in areas of high infection prevalence and increase the risk of allergy in areas of low prevalence. Chronic geohelminth infections are inversely associated with allergy and anthelmintic treatment may increase the prevalence of allergy. In this paper, we review studies that have investigated the relationship between geohelminths and allergy; discuss the relevance of prevalence and timing of geohelminth infections and propose a conceptual model to define relevant scientific questions in future human and animal studies.
The role of asbestos in the etiology of lung cancer and of mesothelioma of the pleura and peritoneum has been well documented. The evidence for a causal association between asbestos and other human cancers is not as extensive but suggests that asbestos may be carcinogenic at several different sites. This paper is concerned specifically with a possible causal association between asbestos and human kidney cancer. A review of the evidence to date indicates that only three human studies have sufficient statistical power to detect an excess mortality from kidney cancer among workers exposed to asbestos. All three were occupational cohort studies, and two of these gave strong direct evidence for such an excess; a study of U.S. insulators (kidney cancer SMR = 2.22, 90% CI 1.44-3.30), and a study of U.S. asbestos products company workers (kidney cancer SMR = 2.76, 90% CI 1.29-5.18). The third study, of Italian shipyard workers, reported excess mortality from "cancers of the kidney, urinary bladder, and other urinary organs" (SMR = 1.98, 90% CI 1.42-2.70). Further support for a causal association includes studies finding asbestos fibers in human kidneys and urine, as well as reports of kidney tumors in two animal bioassays. It is concluded that asbestos should be regarded as a probable cause of human kidney cancer.
Objective: The causality between cardiometabolic disease (CMD) and sepsis has remained largely unknown. To elucidate this, we conducted a Mendelian randomization (MR) and population study. Methods: First, we used univariable and multivariable MR analyses to investigate causal associations between CMD and sepsis-related outcomes. We obtained genome-wide association study summary from both the MRC Integrative Epidemiology Unit and the FinnGen consortium. Subsequently, a two-step mediation MR analysis was performed to explore mediators. Afterward, we conducted an observational study using the Medical Information Mart for Intensive Care IV database, in which multivariable logistic regression models were utilized to examine the relationship between CMD and sepsis-related outcomes. Results: In the MR study, type 2 diabetes mellitus (OR = 1.058, 95% CI = 1.017-1.100, P = 0.005), obesity (OR = 1.113, 95% CI = 1.057-1.172, P < 0.001), and heart failure (HF) (OR = 1.178, 95% CI = 1.063-1.305, P = 0.002) were independently causally related to sepsis. Obesity (OR = 1.215, 95% CI = 1.027-1.437, P = 0.023) and HF (OR = 1.494, 95% CI = 1.080-2.065, P = 0.015) also showed independent causal associations with sepsis critical care admission. Mediation MR analysis identified 23 blood metabolites potentially causally linked to sepsis ( P < 0.05), yet none mediated the relationship between CMD and sepsis. In the observational study, we found associations between sepsis and several conditions including type 2 diabetes mellitus, obesity, hypertension, stroke, HF, and hyperlipidemia after adjusting for confounding factors. Moreover, hypertension, stroke, HF, coronary artery disease, and hyperlipidemia were linked to sepsis critical care admission. Conclusion: This study has, for the first time, revealed indicative evidence of a causal relationship between CMD and sepsis through observational and genetic evidence. Taken together, clinical attention to sepsis may be warranted among patients with CMD.
BACKGROUND: We undertook an epidemiological study to investigate whether measles, mumps, and rubella (MMR) vaccine may be causally associated with autism. METHODS: Children with autism born since 1979 were identified from special needs/disability registers and special schools in eight North Thames health districts, UK. Information from clinical records was linked to immunisation data held on the child health computing system. We looked for evidence of a change in trend in incidence or age at diagnosis associated with the introduction of MMR vaccination to the UK in 1988. Clustering of onsets within defined postvaccination periods was investigated by the case-series method. FINDINGS: We identified 498 cases of autism (261 of core autism, 166 of atypical autism, and 71 of Asperger's syndrome). In 293 cases the diagnosis could be confirmed by the criteria of the International Classification of Diseases, tenth revision (ICD10: 214 [82%] core autism, 52 [31%] atypical autism, 27 [38%] Asperger's syndrome). There was a steady increase in cases by year of birth with no sudden "step-up" or change in the trend line after the introduction of MMR vaccination. There was no difference in age at diagnosis between the cases vaccinated before or after 18 months of age and those never vaccinated. There was no temporal association between onset of autism within 1 or 2 years after vaccination with MMR (relative incidence compared with control period 0.94 [95% CI 0.60-1.47] and 1.09 [0.79-1.52]). Developmental regression was not clustered in the months after vaccination (relative incidence within 2 months and 4 months after MMR vaccination 0.92 [0.38-2.21] and 1.00 [0.52-1.95]). No significant temporal clustering for age at onset of parental concern was seen for cases of core autism or atypical autism with the exception of a single interval within 6 months of MMR vaccination. This appeared to be an artifact related to the difficulty of defining precisely the onset of symptoms in this disorder. INTERPRETATION: Our analyses do not support a causal association between MMR vaccine and autism. If such an association occurs, it is so rare that it could not be identified in this large regional sample.
Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, α-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.
A 24-year-old Japanese male having ulcerative colitis and idiopathic thrombocytopenic purpura is described. When the symptoms of ulcerative colitis were manifest during his clinical course, the platelet life-span was shortened and the platelet associated IgG level was increased. Thus, causal association between the two diseases may be suggested.
This review first considered some general problems in establishing causal links between a virus and a human cancer and offered some guidelines in the pursuit of this objective. Second, it reviewed the current causal associations for several candidate oncogenic viruses in relation to the tumors with which they are associated. These include Epstein-Barr virus in relation to Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's disease, and non-Hodgkin's lymphoma; hepatitis B and C viruses in relation to hepatocellular carcinoma; human T-cell leukemia/lymphoma virus type 1 and atypical leukemia/lymphoma; and human papilloma viruses in relation to cervical carcinoma. For some, the causal relationship is strong: hepatitis B virus with hepatocellular carcinoma, and human T-cell leukemia/lymphoma virus with adult T-cell leukemia/lymphoma. For one, the causal relationship is moderate: Epstein-Barr virus with African Burkitt's lymphoma. For others it is incomplete or inconclusive: Epstein-Barr virus with Hodgkin's disease and non-Hodgkin's lymphoma, and hepatitis C virus with hepatocellular carcinoma. Current techniques do not permit an answer for some: human papilloma virus with cervical carcinoma.
Identification of the cause of the development and progression of periodontitis has received extensive attention, with notable advances over the past decade in clinical, microbiological, immunological, biochemical, and behavioral knowledge. However, it is still largely unknown which factors lead to the conversion of non-destructive forms of periodontal disease into destructive forms and disease progression. Chronic adult periodontitis is believed to be influenced by an interaction of host defense and environmental factors. Although these variables have been studied extensively, no study has employed randomized controlled prospective human or randomized controlled community intervention designs, methodologies necessary to prove a variable to be a cause of periodontitis. Owing to the absence of literature employing rigorous experimental design, this article assesses systematically observational, cross-sectional and longitudinal studies to examine the potential causal association between cigarette smoking and periodontitis. The methodology of Sir Bradford Hill's criteria for causation was used as the framework. Results suggest that cigarette smoking is causally associated with periodontitis. That is, cigarette smoking is consistently associated with an increased prevalence/severity of periodontitis and is suspected on theoretical grounds of playing a causal role. Hill's criteria provide a useful methodology to better understand the pathogenesis of periodontal diseases and may be applied to study the pathogenesis of other dental diseases as well.
BACKGROUND: Sarcoidosis is rarely associated with a distinct disease. One disease infrequently associated with sarcoidosis is psoriasis. CASE PRESENTATION: This case study describes a 38-year-old male, who presented with chest pain, high-grade fever, arthralgias and a skin rash accompanied by bilateral hilar lymphadenopathy on his chest radiograph. Extensive investigations including fiber-optic bronchoscopy with bronchoalveolar lavage and labial and skin biopsies, demonstrated that two distinct clinical entities co-existed in the same patient: pulmonary sarcoidosis and psoriasis vulgaris. Combination therapy for both diseases was applied and the patient was greatly improved. CONCLUSION: This is the first well-documented case of sarcoidosis and psoriasis in the same patient, reported on the basis of safe and widely-used techniques that were not available until fairly recently. These disorders might share common pathogenic mechanisms that could explain their co-existence in the patient.
Prediction error--a mismatch between expected and actual outcome--is critical to associative accounts of inferential learning. However, it has proven difficult to explore the effects of prediction error using functional magnetic resonance imaging (fMRI) while excluding the confounding effects of stimulus novelty and incorrect responses. In this event-related fMRI study we used a three-stage experiment generating preventative- and super-learning conditions. In both cases, it was possible to generate prediction error within a causal associative learning experiment while subtracting the effects of novelty and error. We show that right lateral prefrontal cortex (PFC) activation is sensitive to the magnitude of prediction error. Furthermore, super-learning activation in this region of PFC correlates, across subjects, with the amount learned. We thus provide direct evidence for a brain correlate of the surprise-dependent mechanisms proposed by associative accounts of causal learning. We show that activity in right lateral PFC is sensitive to the magnitude, though not the direction, of the prediction error. Furthermore, its activity is not directly explicable in terms of novelty or response errors and appears directly related to the learning that arises out of prediction error.
The increase in morbidity and mortality attributable to chronic obstructive pulmonary disease (COPD) has focused attention on environmental and host factors causally associated with the clinical entities included under the rubric of this term with a view to early preventive intervention. Despite the biologic plausibility of inhaled agents being causally implicated, only the role of tobacco smoke has been accepted beyond doubt. However, evidence implicating occupational exposures has accumulated, in particular over the last 2 yr, from: (1) community-based studies (in which larger study populations provide greater power than the usually smaller workforce based studies); (2) longitudinal studies of lung function (which enhance the signal of interest, namely the effects of the occupational exposures, and diminish the noise due to between-individual differences); (3) pathology studies (in which the outcome of interest is the quantitative measurement of emphysema), and (4) cohort mortality studies of all or specific causes of death. This evidence, reviewed here according to accepted criteria for establishing causality, leaves little doubt that occupational exposure to dust and/or to dust and fumes may be causally implicated in the genesis of COPD. As with tobacco exposure, both bronchitis (mucus hypersecretion) and airflow limitation are recognized as causally related to exposure, but not necessarily to each other. As with tobacco exposure, though effects are in general dose related to exposure, there is evidence for individual susceptibility. As with tobacco exposure, a possible host factor is the reactivity of airways to inhaled materials.(ABSTRACT TRUNCATED AT 250 WORDS)
Researchers have posited that increased consumption of tea and coffee may be associated with more favorable treatment outcomes in patients with age-related macular degeneration (AMD). However, there is no clear evidence regarding the causal associations. To delve deeper into this potential connection, scientists used a rigorous method known as Mendelian randomization (MR). This technique was used to explore the causal impact of tea and coffee consumption on the development or progression of AMD. With the aim of investigating the cause-and-effect relationship between 16 tea- and coffee-consuming subtypes and 3 AMD, we designed a two-sample MR study using comprehensive data from genome-wide association studies (GWAS). The major approach adopted was inverse variance weighting (IVW). Furthermore, we implemented complementary methods like the weighted median (WM), weighted mode, and MR-Egger to strengthen our findings. Sensitivity analyses, including MR-Egger, MR-PRESSO, leave-one-out, and Cochran's Q tests, were used to validate results, explore heterogeneity and pleiotropy, and pinpoint potential biases. Two hundred and sixty-eight instrumental variables were selected for MR analysis. The results showed that standard tea intake may be a protective factor for wet AMD [odds ratio (OR) = 0.7076, 95% confidence interval (CI) = 0.5776-0.8668, P = 8 × 10-4, PFDR = 0.0402]. Sensitivity analysis suggests that the results are robust. Our findings provide genetic evidence that standard tea intake is a protective factor against wet AMD, providing new insights into early risk stratification and prevention strategies for the disease.NEW & NOTEWORTHY This study investigates the potential causal relationship between tea and coffee consumption and age-related macular degeneration (AMD) using Mendelian randomization. Analyzing data from genome-wide association studies, we focused on 16 beverage subtypes and 3 AMD conditions. Our findings suggest that standard tea consumption may protect against wet AMD, with robust evidence supporting this link. The results offer new insights into risk stratification and prevention strategies for AMD, highlighting the importance of dietary factors in eye health.
Post-traumatic stress disorder (PTSD) is a psychiatric disorder that frequently co-occurs with pain disorders including migraine. There are proposed biological, genetic and environmental factors associated with both PTSD and migraine suggesting shared etiology. Genome-Wide Association Studies (GWAS) have been used to identify genomic risk loci associated with various disorders and to investigate genetic overlap between traits. There is a significant genetic correlation between PTSD and migraine with no evidence of a causal relationship that could be attributed to pleiotropy. Cross-disorder genetic analyses were applied to investigate the genetic overlap and causal associations using GWAS summary statistics of PTSD (n = 214408), migraine (n = 873341) and 23 medication use traits (n = 78808-305913) including anti-depressants, anti-migraine preparations and beta-blocking agents. Across the entire genome, anti-thrombotic agents had a significant and negative genetic correlation with PTSD (rG = -0.2, P FDR = 0.032) and a positive genetic correlation with migraine (rG = 0.26, P FDR = 2.23 x 10-8). PTSD showed significant genetic correlation with 11 other medication use traits including beta blocking agents (rG = -0.11, P FDR = 0.034). Of the 2495 genomic regions tested, PTSD showed significant local genetic correlation with 12 medication use traits at 43 loci; while migraine showed significant genetic correlation with only anti-inflammatory agents and anti-rheumatic products at locus 12:57522282-57607142 (DAB1) (P < 2 x 10-5). The genetic liability to PTSD had a causal effect on increased risk of using pain medication such as opioids (β ivw = 0.59, P = 5.21 x 10-5) while the genetic liability to migraine had a causal effect on the increased risk of using anti-thrombotic agents (β ivw = 0.59, P = 1.69 x 10-7). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy.
INTRODUCTION: In this two-sample, two-step Mendelian randomization (MR) study, we aimed to elucidate the causal associations between sarcopenia-related characteristics and heart failure (HF) risk, and to identify the factors mediating these associations, with a particular focus on the mediating roles of obesity and sedentary habits. METHODS: Genetic instruments for appendicular lean mass (ALM), hand grip strength (HGS), walking pace (WP), and potential mediators were extracted from genome-wide association studies. Inverse-variance weighting (IVW) was used as the primary analytical method, supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses including Cochran's Q test and MR-Egger intercept method were performed to assess heterogeneity and pleiotropy. Bidirectional MR was conducted to exclude reverse causation. RESULTS: IVW revealed that a faster genetically predicted WP was associated with lower HF risk (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.33-0.60, p = 5.806 × 10-7). The mediation analysis indicated that body mass index (BMI) accounted for 32% of this effect, while time spent watching television accounted for 14%. Elevated ALM showed a slight but significant positive association with HF risk (OR 1.06, 95% CI 1.03-1.09, p = 5.437 × 10-4). However, multivariable MR adjusting for BMI completely attenuated this association (p = 0.693), suggesting ALM reflects overall body composition rather than isolated muscle mass. No significant associations were found between HGS and HF. Bidirectional MR showed no robust reverse effects. CONCLUSIONS: These findings suggest that genetically predicted increased WP exerts beneficial effects against HF, partially mediated by obesity and sedentary habits. Targeting weight management and anti-sedentary interventions may mitigate HF risk in individuals with sarcopenia-related characteristics.
There has been a resurgent interest in potential microbial etiologies of inflammatory bowel disease (IBD). Over the past decade there have been both epidemiological and tissue studies exploring the potential role of paramyxoviruses in IBD, particularly Crohn's disease. This article will review the evidence and hence plausibility of a causal association between these viruses and IBD.
Readers of medical literature need to consider two types of validity, internal and external. Internal validity means that the study measured what it set out to; external validity is the ability to generalise from the study to the reader's patients. With respect to internal validity, selection bias, information bias, and confounding are present to some degree in all observational research. Selection bias stems from an absence of comparability between groups being studied. Information bias results from incorrect determination of exposure, outcome, or both. The effect of information bias depends on its type. If information is gathered differently for one group than for another, bias results. By contrast, non-differential misclassification tends to obscure real differences. Confounding is a mixing or blurring of effects: a researcher attempts to relate an exposure to an outcome but actually measures the effect of a third factor (the confounding variable). Confounding can be controlled in several ways: restriction, matching, stratification, and more sophisticated multivariate techniques. If a reader cannot explain away study results on the basis of selection, information, or confounding bias, then chance might be another explanation. Chance should be examined last, however, since these biases can account for highly significant, though bogus results. Differentiation between spurious, indirect, and causal associations can be difficult. Criteria such as temporal sequence, strength and consistency of an association, and evidence of a dose-response effect lend support to a causal link.