Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality

Love and human flourishing

We present arguments that the promotion of love within society has tremendous underutilized potential to enhance human flourishing. Some indication that this may be so can be found in sweeping claims sometimes made about love within philosophical, theological, psychological, sociological, and even economic, business and management literatures. We review definitional and theoretical considerations concerning love and flourishing. We summarize various streams of empirical evidence for the role of love in the promotion of human flourishing. We then argue that social policy oriented towards promoting love within families, friendships, schools, workplaces, religious communities, medicine, politics and the media could make substantial contributions to advancing societal flourishing

STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.Seaside Therapeutics Inc

Polygenic modelling of treatment effect heterogeneity.

Mendelian randomization is the use of genetic variants to assess the effect of intervening on a risk factor using observational data. We consider the scenario in which there is a pharmacomimetic (i.e., treatment-mimicking) genetic variant that can be used as a proxy for a particular pharmacological treatment that changes the level of the risk factor. If the association of the pharmacomimetic genetic variant with the risk factor is stronger in one subgroup of the population, then we may expect the effect of the treatment to be stronger in that subgroup. We test for gene-gene interactions in the associations of variants with a modifiable risk factor, where one genetic variant is treated as pharmacomimetic and the other as an effect modifier, to find genetic subgroups of the population with different predicted response to treatment. If individual genetic variants that are strong effect modifiers cannot be found, moderating variants can be combined using a random forest of interaction trees method into a polygenic response score, analogous to a polygenic risk score for risk prediction. We illustrate the application of the method to investigate effect heterogeneity in the effect of statins on low-density lipoprotein cholesterol

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

The varieties of vitality: A cross-cultural lexical analysis

Vitality has been underappreciated and underexplored by academia at large. This oversight is potentially explained by the Western-centric nature of most fields, with vitality having been comparatively neglected in the West relative to elsewhere. One explanation for this lacuna is that vitality is not easily pigeonholed within the ontological categories dominant in the West, such as mind and body. This paper therefore aims to learn from cultures that have cultivated a greater understanding of vitality, doing so by engaging with relevant ‘untranslatable’ words (i.e., those without exact equivalent in English), thus enriching our conceptual map of this topic. Over 200 relevant terms were located and analyzed using an adapted form of grounded theory. Three themes were identified, each with four subthemes: spirit (life force, channels, soul, and transcendence); energy (fortitude, channeling, willpower, and recharging); and heart (desire, passion, affection, and satisfaction). The paper thus refines our understanding of this important topic and provides a foundation for future research.

Prospective associations between social connectedness and mental health : evidence from a longitudinal survey and health insurance claims data

Objectives: Evidence on social stimuli associated with mental health is based mostly on self-reported health measures. We aimed to examine prospective associations between social connectedness and clinical diagnosis of depression and of anxiety. Methods: Longitudinal observational data merged with health insurance data comprising medical information on diagnosis of depression and anxiety were used. 1,209 randomly sampled employees of a US employer provided data for the analysis. Robust Poisson regression models were used. Multiple imputation was conducted to handle missing data on covariates. Results: Better social connectedness was associated with lower risks of subsequently diagnosed depression and anxiety, over a one-year follow-up period. Reports of feeling lonely were associated with increased risks of depression and anxiety. Association between community-related social connectedness and subsequent diagnosis of depression, but not of anxiety, was found. The associations were independent of demographics, socioeconomic status, lifestyle, and work characteristics. They were also robust to unmeasured confounding, missing data patterns, and prior health conditions. Conclusion: Social connectedness may be an important factor for reducing risks of depression and anxiety. Loneliness should be perceived as a risk factor for depression and anxiety

Performance of methods to conduct mediation analysis with time-to-event outcomes

Previous studies have discouraged the use of the Cox proportional hazards (PH) model for traditional mediation analysis as it might provide biased results. Accelerated failure time (AFT) models have been proposed as an alternative for Cox PH models. In addition, the use of the potential outcomes framework has been proposed for mediation models with time-to-event outcomes. The aim of this paper is to investigate the performance of traditional mediation analysis and potential outcomes mediation analysis based on both the Cox PH and the AFT model. This is done by means of a Monte Carlo simulation study and the illustration of the methods using an empirical data set. Both the product-of-coefficients method of the traditional mediation analysis and the potential outcomes framework yield unbiased estimates with respect to their own underlying indirect effect value for simple mediation models with a time-to-event outcome and estimated based on Cox PH or AFT