Causal effects of plasma lipids on the risk of atrial fibrillation: A multivariable mendelian randomization study

Background and aimsObservational studies have suggested that plasma lipids contribute substantially to cardiovascular disease, but “cholesterol paradox” in atrial fibrillation (AF) remains. We sought to investigate the causal effects of lipid profiles on the risk of AF.Methods and resultsTwo-sample Mendelian randomization (MR) framework was implemented to examine the causality of association. Summary estimations of genetic variants associated with low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol, triglycerides, lipoprotein-a [Lp(a)], apolipoprotein A1 (ApoA 1), and apolipoprotein B (ApoB) were 81, 99, 96, 61, 30, 10, and 23 single nucleotide polymorphisms, respectively. Genetic association with AF were retrieved from a genome-wide association study that included 1,030,836 individuals. The complications for AF were predefined as cardioembolic stroke (CES) and heart failure (HF). In the multivariable MR, the odds ratios for AF per standard deviation (SD) increase were 1.030 (95% confidence interval (CI) 0.979–1.083; P = 0.257) for LDL-cholesterol, 0.986 (95% CI 0.931–1.044; P = 0.622) for HDL-cholesterol, 0.965 (95% CI 0.896–1.041; P = 0.359) for triglycerides, 1.001 (95% CI 1.000–1.003; P = 0.023) for Lp(a), 1.017 (95% CI 0.966–1.070; P = 0.518) for ApoA1, and 1.002 (95% CI 0.963–1.043; P = 0.923) for ApoB. There was no evidence that other lipid components were causally associated with AF, CES, or HF, other than for a marginal association between triglycerides and HF.ConclusionsThis MR study provides robust evidence that high Lp(a) increases the risk of AF, suggesting that interventions targeting Lp(a) may contribute to the primary prevention of AF.     

Causalidad y responsabilidad en salud laboral

The objective of this work is to review the imperfect relationship between causality and responsibility, from the perspective of occupational health, where this tension occurs so frequently when addressing the prevention of illnesses and occupational injuries. From epidemiology, we are very demanding in our observations, both in terms of internal and external validity, when establishing causal relationships. An essential rigor in the analysis of causality, which does not prevent us from myopia when a purely biomedical vision is adopted, forgetting the causes at different levels and of an economic and political nature. In turn, we need a governance (administrations, companies and governments) that assumes responsibility through the establishment of policies, many of them based on legal norms. Rules resulting from participatory processes, broad in democratic societies, in which conflicting interests intervene, and sometimes extends for years, which can lead to unacceptable situations of unrecognized suffering. So, helping us with some prosthesis, a glasses for science, to provide evidence that explains from macro to micro the process that takes us from health to disease, and a hearing aids for politics, to assume with all consequences their responsibility for taking preventive measures listening to the interests of the most vulnerable people, we could enjoy a long and healthy life.     

Age-related hearing loss and cognitive decline — The potential mechanisms linking the two

The amount of attention to age-related hearing loss (ARHL) has been growing, not only from the perspective of being one of the most common health conditions affecting older adults, but also from the perspective of its relation to cognition. Results from a number of epidemiological and laboratory studies have demonstrated a significant link between ARHL and cognitive decline. The Lancet International Commission on Dementia, Prevention, Intervention, and Care has estimated that mid-life hearing loss, if eliminated, might decrease the risk of dementia by nine percent, since hearing loss is a modifiable age-associated condition linked to dementia. Despite numerous research efforts, elucidation of the underlying causal relationships between auditory and cognitive decline has not yet reached a consensus.In this review article, we focused on the hypotheses of etiological mechanisms between ARHL and cognitive decline: (1) cognitive load hypothesis; (2) common cause hypothesis; (3) cascade hypothesis; and (4) overdiagnosis or harbinger hypothesis. Factual evidence obtained in previous studies was assessed to understand the link between ARHL and cognitive decline or dementia. Additionally, an overview of the conceivable effects of hearing intervention, e.g., hearing aids and cochlear implants, on cognition were presented, and the role of hearing aid use was considered for the relevant hypotheses.We should continue to strive for social enlightenment towards the importance of ‘hearing well’, and cultivate a necessity for hearing screening among patients at risk of cognitive decline.     

Dual-site TMS demonstrates causal functional connectivity between the left and right posterior temporal sulci during facial expression recognition

BackgroundNeuroimaging studies suggest that facial expression recognition is processed in the bilateral posterior superior temporal sulcus (pSTS). Our recent repetitive transcranial magnetic stimulation (rTMS) study demonstrates that the bilateral pSTS is causally involved in expression recognition, although involvement of the right pSTS is greater than involvement of the left pSTS.Objective/Hypothesis: In this study, we used a dual-site TMS to investigate whether the left pSTS is functionally connected to the right pSTS during expression recognition. We predicted that if this connection exists, simultaneous TMS disruption of the bilateral pSTS would impair expression recognition to a greater extent than unilateral stimulation of the right pSTS alone.MethodsParticipants attended two TMS sessions. In Session 1, participants performed an expression recognition task while rTMS was delivered to the face-sensitive right pSTS (experimental site), object-sensitive right lateral occipital complex (control site) or no rTMS was delivered (behavioural control). In Session 2, the same experimental design was used, except that continuous theta-burst stimulation (cTBS) was delivered to the left pSTS immediately before behavioural testing commenced. Session order was counter-balanced across participants.ResultsIn Session 1, rTMS to the rpSTS impaired performance accuracy compared to the control conditions. Crucially in Session 2, the size of this impairment effect doubled after cTBS was delivered to the left pSTS.ConclusionsOur results provide evidence for a causal functional connection between the left and right pSTS during expression recognition. In addition, this study further demonstrates the utility of the dual-site TMS for investigating causal functional links between brain regions.     

Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms

Introduction

We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition.

Dual-centered ANCOVA: Resolving contradictory results from Lord's paradox with implications for reducing bias in longitudinal analyses

IntroductionValid causal inferences are necessary to use developmental research to improve adolescent outcomes. What type of change should be analyzed to approximate causal inferences from longitudinal data? Difference-score and ANCOVA-type analyses often produce contradictory results, a problem known as Lord's paradox. This study investigates 2-group, 2-wave difference-score analyses and ANCOVA, and introduces a method that produces consistent results, namely dual-centered ANCOVA, which is compared to pretest matching.MethodsThese methods are tested first on two datasets simulated to fit each of Lord's contrasting results. The methods are then applied to data investigating the longitudinal associations of parent-adolescent discussions about sexual risks on subsequent unprotected sexual behaviors in 4753 American adolescents (62.2% whites).ResultsThe results replicate Lord's contradictory results for all datasets. Dual-centered ANCOVA and pretest matching both produce consistent results, but dual-centered ANCOVA replicates the original results for difference-score analyses, whereas pretest matching replicates the original ANCOVA results. Thus, the two sets of consistent results differ from each other as much as the original discrepancy rather than reducing bias.ConclusionThe least biased analysis is the one whose null hypothesis best approximates a plausible change pattern to represent a no-treatment effect. When difference-score analyses are thought to approximate valid causal inferences as closely as ANCOVA-type analyses, dual-centered ANCOVA estimates the difference-score effect while retaining the advantages of ANCOVA in statistical power and covariate inclusion. These findings are widely applicable to longitudinal analyses that incorporate one or both of these basic methods to analyze change.     

有向无环图在混杂因素识别与控制中的应用及实例分析

观察性研究是流行病学病因研究常用的研究设计,但应用观察性研究进行因果推断时,常由于未经识别、校正的混杂因素的存在,歪曲暴露因素与研究结局之间的真实因果关系。传统混杂因素判断标准在实际应用中不够直观,且有一定局限性,有时甚至出现混杂因素的误判。有向无环图(DAGs)可以直观识别观察性研究中存在的混杂因素,将复杂的因果关系可视化,判断研究中需要校正的最小校正子集,并可避免传统混杂因素判断标准的局限性,结合DAGs还可以指导混杂因素校正方法的选择,在观察性研究中因果推断具有重要指导价值,DAGs在未来的流行病学研究中将有更多的应用。     

Mechanism of visual network dysfunction in relapsing-remitting multiple sclerosis and its relation to cognition

ObjectiveTo investigate if changes in brain network function and connectivity contribute to the abnormalities in visual event related potentials (ERP) in relapsing-remitting multiple sclerosis (RRMS), and explore their relation to a decrease in cognitive performance.MethodsWe evaluated 72 patients with RRMS and 89 healthy control subjects in a cross-sectional study. Visual ERP were generated using illusory and non-illusory stimuli and recorded using 21 EEG scalp electrodes. The measured activity was modelled using Dynamic Causal Modelling. The model network consisted of 4 symmetric nodes including the primary visual cortex (V1/V2) and the Lateral Occipital Complex. Patients and controls were tested with a neuropsychological test battery consisting of 18 cognitive tests covering six cognitive domains.ResultsWe found reduced cortical connectivity in bottom-up and interhemispheric connections to the right lateral occipital complex in patients (p < 0.001). Furthermore, interhemispherical connections were related to cognitive dysfunction in several domains (attention, executive function, visual perception and organization, processing speed and global cognition) for patients (p < 0.05). No relation was seen between cortical network connectivity and cognitive function in the healthy control subjects.ConclusionChanges in the functional connectivity to higher cortical regions provide a neurobiological explanation for the changes of the visual ERP in RRMS.SignificanceThis study suggests that changes in connectivity to higher cortical regions partly explain visual network dysfunction in RRMS where a lower interhemispheric connectivity may contribute to impaired cognitive function.     

Estimation of treatment effect in a subpopulation: An empirical Bayes approach

It is well recognized that the benefit of a medical intervention may not be distributed evenly in the target population due to patient heterogeneity, and conclusions based on conventional randomized clinical trials may not apply to every person. Given the increasing cost of randomized trials and difficulties in recruiting patients, there is a strong need to develop analytical approaches to estimate treatment effect in subpopulations. In particular, due to limited sample size for subpopulations and the need for multiple comparisons, standard analysis tends to yield wide confidence intervals of the treatment effect that are often noninformative. We propose an empirical Bayes approach to combine both information embedded in a target subpopulation and information from other subjects to construct confidence intervals of the treatment effect. The method is appealing in its simplicity and tangibility in characterizing the uncertainty about the true treatment effect. Simulation studies and a real data analysis are presented.