Estimation of causal effects of a time-varying exposure at multiple time points through multivariable mendelian randomization

Mendelian Randomisation (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilising genetic variants as instrumental variables (IVs) for the exposure. The effect estimates obtained from MR studies are often interpreted as the lifetime effect of the exposure in question. However, the causal effects of some exposures are thought to vary throughout an individual’s lifetime with periods during which an exposure has a greater effect on a particular outcome. Multivariable MR (MVMR) is an extension of MR that allows for multiple, potentially highly related, exposures to be included in an MR estimation. MVMR estimates the direct effect of each exposure on the outcome conditional on all the other exposures included in the estimation. We explore the use of MVMR to estimate the direct effect of a single exposure at different time points in an individual’s lifetime on an outcome. We use simulations to illustrate the interpretation of the results from such analyses and the key assumptions required. We show that causal effects at different time periods can be estimated through MVMR when the association between the genetic variants used as instruments and the exposure measured at those time periods varies. However, this estimation will not necessarily identify exact time periods over which an exposure has the most effect on the outcome. Prior knowledge regarding the biological basis of exposure trajectories can help interpretation. We illustrate the method through estimation of the causal effects of childhood and adult BMI on C-Reactive protein and smoking behaviour

Smart homes and their users:a systematic analysis and key challenges

Published research on smart homes and their users is growing exponentially, yet a clear understanding of who these users are and how they might use smart home technologies is missing from a field being overwhelmingly pushed by technology developers. Through a systematic analysis of peer-reviewed literature on smart homes and their users, this paper takes stock of the dominant research themes and the linkages and disconnects between them. Key findings within each of nine themes are analysed, grouped into three: (1) views of the smart home-functional, instrumental, socio-technical; (2) users and the use of the smart home-prospective users, interactions and decisions, using technologies in the home; and (3) challenges for realising the smart home-hardware and software, design, domestication. These themes are integrated into an organising framework for future research that identifies the presence or absence of cross-cutting relationships between different understandings of smart homes and their users. The usefulness of the organising framework is illustrated in relation to two major concerns-privacy and control-that have been narrowly interpreted to date, precluding deeper insights and potential solutions. Future research on smart homes and their users can benefit by exploring and developing cross-cutting relationships between the research themes identified

What Affects Social Attention? Social Presence, Eye Contact and Autistic Traits

Social understanding is facilitated by effectively attending to other people and the subtle social cues they generate. In order to more fully appreciate the nature of social attention and what drives people to attend to social aspects of the world, one must investigate the factors that influence social attention. This is especially important when attempting to create models of disordered social attention, e.g. a model of social attention in autism. Here we analysed participants' viewing behaviour during one-to-one social interactions with an experimenter. Interactions were conducted either live or via video (social presence manipulation). The participant was asked and then required to answer questions. Experimenter eye-contact was either direct or averted. Additionally, the influence of participant self-reported autistic traits was also investigated. We found that regardless of whether the interaction was conducted live or via a video, participants frequently looked at the experimenter's face, and they did this more often when being asked a question than when answering. Critical differences in social attention between the live and video interactions were also observed. Modifications of experimenter eye contact influenced participants' eye movements in the live interaction only; and increased autistic traits were associated with less looking at the experimenter for video interactions only. We conclude that analysing patterns of eye-movements in response to strictly controlled video stimuli and natural real-world stimuli furthers the field's understanding of the factors that influence social attention

Speaking and Listening with the Eyes: Gaze Signaling during Dyadic Interactions

Cognitive scientists have long been interested in the role that eye gaze plays in social interactions. Previous research suggests that gaze acts as a signaling mechanism and can be used to control turn-taking behaviour. However, early research on this topic employed methods of analysis that aggregated gaze information across an entire trial (or trials), which masks any temporal dynamics that may exist in social interactions. More recently, attempts have been made to understand the temporal characteristics of social gaze but little research has been conducted in a natural setting with two interacting participants. The present study combines a temporally sensitive analysis technique with modern eye tracking technology to 1) validate the overall results from earlier aggregated analyses and 2) provide insight into the specific moment-to-moment temporal characteristics of turn-taking behaviour in a natural setting. Dyads played two social guessing games (20 Questions and Heads Up) while their eyes were tracked. Our general results are in line with past aggregated data, and using cross-correlational analysis on the specific gaze and speech signals of both participants we found that 1) speakers end their turn with direct gaze at the listener and 2) the listener in turn begins to speak with averted gaze. Convergent with theoretical models of social interaction, our data suggest that eye gaze can be used to signal both the end and the beginning of a speaking turn during a social interaction. The present study offers insight into the temporal dynamics of live dyadic interactions and also provides a new method of analysis for eye gaze data when temporal relationships are of interest

Separating the effects of early and later life adiposity on colorectal cancer risk:a Mendelian randomization study

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02702-9

Amicus Brief, Lebron v. Gottlieb Memorial Hospital

Illinois Public Act 82-280, § 2-1706.5, as amended by P.A. 94-677, § 330 (eff. Aug. 25, 2005), and as codified as 735 ILCS 5/2-1706.5(a), imposes a $500,000 “cap” on the noneconomic damages that may be awarded in a medical malpractice suit against a physician or other health care professional, and a$1 million “cap” on the noneconomic damages that may be awarded against a hospital, its affiliates, or their employees. This brief will address two of the questions presented for review by the parties: 1. Does the cap violate the Illinois Constitution’s prohibition on “special legislation,” Art. IV, § 3, because it unnecessarily, arbitrarily, and irrationally grants exceptional benefits and privileges exclusively to certain classes of tort defendants. 2. Does the cap violate the Illinois Constitution’s guarantee of “equal protection,” Art. I, § 2, because it unnecessarily, arbitrarily, and irrationally imposes extraordinary burdens uniquely upon certain classes and sub-classes of tort plaintiffs

A cluster randomised controlled trial of the clinical and cost-effectiveness of a 'whole systems' model of self-management support for the management of long- term conditions in primary care: trial protocol

BackgroundPatients with long-term conditions are increasingly the focus of quality improvement activities in health services to reduce the impact of these conditions on quality of life and to reduce the burden on care utilisation. There is significant interest in the potential for self-management support to improve health and reduce utilisation in these patient populations, but little consensus concerning the optimal model that would best provide such support. We describe the implementation and evaluation of self-management support through an evidence-based 'whole systems' model involving patient support, training for primary care teams, and service re-organisation, all integrated into routine delivery within primary care.MethodsThe evaluation involves a large-scale, multi-site study of the implementation, effectiveness, and cost-effectiveness of this model of self-management support using a cluster randomised controlled trial in patients with three long-term conditions of diabetes, chronic obstructive pulmonary disease (COPD), and irritable bowel syndrome (IBS). The outcome measures include healthcare utilisation and quality of life. We describe the methods of the cluster randomised trial.DiscussionIf the 'whole systems' model proves effective and cost-effective, it will provide decision-makers with a model for the delivery of self-management support for populations with long-term conditions that can be implemented widely to maximise 'reach' across the wider patient population.Trial registration numberISRCTN: ISRCTN9094004

Exercise augmentation compared to usual care for Post Traumatic Stress Disorder: A Randomised Controlled Trial (The REAP study: Randomised Exercise Augmentation for PTSD)

<p>Abstract</p> <p>Background</p> <p>The physical wellbeing of people with mental health conditions can often be overlooked in order to treat the primary mental health condition as a priority. Exercise however, can potentially improve both the primary psychiatric condition as well as physical measures that indicate risk of other conditions such as diabetes mellitus and cardiovascular disease. Evidence supports the role of exercise as an important component of treatment for depression and anxiety, yet no randomised controlled trials (RCT's) have been conducted to evaluate the use of exercise in the treatment of people with post traumatic stress disorder (PTSD).</p> <p>This RCT will investigate the effects of structured, progressive exercise on PTSD symptoms, functional ability, body composition, physical activity levels, sleep patterns and medication usage.</p> <p>Methods and design</p> <p>Eighty participants with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of PTSD will be recruited. Participants will have no contraindications to exercise and will be cognitively able to provide consent to participate in the study.</p> <p>The primary outcome measures will be PTSD symptoms, measured through the PTSD Checklist Civilian (PCL-C) scale. Secondary outcome measures will assess depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage. All outcomes will be assessed by a health or exercise professional masked to group allocation at baseline and 12 weeks after randomisation.</p> <p>The intervention will be a 12 week individualised program, primarily involving resistance exercises with the use of exercise bands. A walking component will also be incorporated. Participants will complete one supervised session per week, and will be asked to perform at least two other non-supervised exercise sessions per week. Both intervention and control groups will receive all usual non-exercise interventions including psychotherapy, pharmaceutical interventions and group therapy.</p> <p>Discussion</p> <p>This study will determine the effect of an individualised and progressive exercise intervention on PTSD symptoms, depression and anxiety, mobility and strength, body composition, physical activity levels, sleep patterns and medication usage among people with a DSM-IV diagnosis of PTSD.</p> <p>Trial Registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12605000567628.aspx">ACTRN12610000579099</a></p

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated