Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with 'cigarette smoking initiation' really capturing?

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions.

UK Reproducibility Network open and transparent research practices survey dataset.

Openness and transparency in the research process are a prerequisite to the production of high quality research outputs. Efforts to maximise these features have substantially accelerated in recent years, placing open and transparent research practices at the forefront of funding and related priorities, and encouraging investment in resources and infrastructure to enable such practices. Despite these efforts, there has been no systematic documentation of current practices, infrastructure, or training and resources that support open and transparent research in the UK. To address this gap, we developed and conducted the Open and Transparent Research Practices survey, a large-scale audit study completed by research-active staff in UK research institutions to better understand existing practices, needs, support, and barriers faced when implementing open and transparent research. The data presented here capture responses from over 2,500 research-active staff based at 15 institutions affiliated with the UK Reproducibility Network. The data provide a snapshot of open research practices that can be used to identify barriers, training needs, and areas that require greater investments.

Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability.

Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (rg = 0.53-0.99) and sensation seeking (rg = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

Evaluating the Acceptability of the Drink Less App and the National Health Service Alcohol Advice Web Page: Qualitative Interview Process Evaluation.

BACKGROUND: The extent to which interventions are perceived as acceptable to users impacts engagement and efficacy. OBJECTIVE: In this study, we evaluated the acceptability of (1) the smartphone app Drink Less (intervention) and (2) the National Health Service (NHS) alcohol advice web page (usual digital care and comparator) among adult drinkers in the United Kingdom participating in a randomized controlled trial evaluating the effectiveness of the Drink Less app. METHODS: A subsample of 26 increasing- and higher-risk drinkers (Alcohol Use Disorders Identification Test score≥8) assigned to the intervention group (Drink Less; n=14, 54%; female: n=10, 71%; age: 22-72 years; White: n=9, 64%) or usual digital care group (NHS alcohol advice web page; n=12, 46%; female: n=5, 42%; age: 23-68 years: White: n=9, 75%) took part in semistructured interviews. The interview questions were mapped on to the 7 facets of acceptability according to the Theoretical Framework of Acceptability: affective attitude, burden, perceived effectiveness, ethicality, intervention coherence, opportunity costs, and self-efficacy. Alongside these constructs, we also included a question on perceived personal relevance, which previous research has linked to acceptability and engagement. Framework and thematic analysis of data was undertaken. RESULTS: The Drink Less app was perceived as being ethical, easy, user-friendly, and effective for the period the app was used. Participants reported particularly liking the tracking and feedback sections of the app, which they reported increased personal relevance and which resulted in positive affect when achieving their goals. They reported no opportunity cost. Factors such as negative affect when not meeting goals and boredom led to disengagement in the longer term for some participants. The NHS alcohol advice web page was rated as being easy and user-friendly with no opportunity costs. However, the information presented was not perceived as being personally relevant or effective in changing drinking behavior. Most participants reported neutral or negative affect, most participants thought the alcohol advice web page was accessible, and some participants reported ethical concerns around the availability of suggested resources. Some participants reported that it had acted as a starting point or a signpost to other resources. Participants in both groups discussed motivation to change and contextual factors such as COVID-19 lockdowns, which influenced their perceived self-efficacy regardless of their assigned intervention. CONCLUSIONS: Drink Less appears to be an acceptable digital intervention among the recruited sample. The NHS alcohol advice web page was generally considered unacceptable as a stand-alone intervention among the recruited sample, although it may signpost and help people access other resources and interventions.

Implications of the genomic revolution for education research and policy.

Research at the intersection of social science and genomics, 'sociogenomics', is transforming our understanding of the interplay between genomics, individual outcomes and society. It has interesting and maybe unexpected implications for education research and policy. Here we review the growing sociogenomics literature and discuss its implications for educational researchers and policymakers. We cover key concepts and methods in genomic research into educational outcomes, how genomic data can be used to investigate social or environmental effects, the methodological strengths and limitations of genomic data relative to other observational social data, the role of intergenerational transmission and potential policy implications. The increasing availability of genomic data in studies can produce a wealth of new evidence for education research. This may provide opportunities for disentangling the environmental and genomic factors that influence educational outcomes and identifying potential mechanisms for intervention.

Interventions for smoking cessation in hospitalised patients.

BACKGROUND: In 2020, 32.6% of the world's population used tobacco. Smoking contributes to many illnesses that require hospitalisation. A hospital admission may prompt a quit attempt. Initiating smoking cessation treatment, such as pharmacotherapy and/or counselling, in hospitals may be an effective preventive health strategy. Pharmacotherapies work to reduce withdrawal/craving and counselling provides behavioural skills for quitting smoking. This review updates the evidence on interventions for smoking cessation in hospitalised patients, to understand the most effective smoking cessation treatment methods for hospitalised smokers. OBJECTIVES: To assess the effects of any type of smoking cessation programme for patients admitted to an acute care hospital. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 7 September 2022. SELECTION CRITERIA: We included randomised and quasi-randomised studies of behavioural, pharmacological or multicomponent interventions to help patients admitted to hospital quit. Interventions had to start in the hospital (including at discharge), and people had to have smoked within the last month. We excluded studies in psychiatric, substance and rehabilitation centres, as well as studies that did not measure abstinence at six months or longer. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was abstinence from smoking assessed at least six months after discharge or the start of the intervention. We used the most rigorous definition of abstinence, preferring biochemically-validated rates where reported. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 82 studies (74 RCTs) that included 42,273 participants in the review (71 studies, 37,237 participants included in the meta-analyses); 36 studies are new to this update. We rated 10 studies as being at low risk of bias overall (low risk in all domains assessed), 48 at high risk of bias overall (high risk in at least one domain), and the remaining 24 at unclear risk. Cessation counselling versus no counselling, grouped by intensity of intervention Hospitalised patients who received smoking cessation counselling that began in the hospital and continued for more than a month after discharge had higher quit rates than patients who received no counselling in the hospital or following hospitalisation (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.24 to 1.49; 28 studies, 8234 participants; high-certainty evidence). In absolute terms, this might account for an additional 76 quitters in every 1000 participants (95% CI 51 to 103). The evidence was uncertain (very low-certainty) about the effects of counselling interventions of less intensity or shorter duration (in-hospital only counselling ≤ 15 minutes: RR 1.52, 95% CI 0.80 to 2.89; 2 studies, 1417 participants; and in-hospital contact plus follow-up counselling support for ≤ 1 month: RR 1.04, 95% CI 0.90 to 1.20; 7 studies, 4627 participants) versus no counselling. There was moderate-certainty evidence, limited by imprecision, that smoking cessation counselling for at least 15 minutes in the hospital without post-discharge support led to higher quit rates than no counselling in the hospital (RR 1.27, 95% CI 1.02 to 1.58; 12 studies, 4432 participants). Pharmacotherapy versus placebo or no pharmacotherapy Nicotine replacement therapy helped more patients to quit than placebo or no pharmacotherapy (RR 1.33, 95% CI 1.05 to 1.67; 8 studies, 3838 participants; high-certainty evidence). In absolute terms, this might equate to an additional 62 quitters per 1000 participants (95% CI 9 to 126). There was moderate-certainty evidence, limited by imprecision (as CI encompassed the possibility of no difference), that varenicline helped more hospitalised patients to quit than placebo or no pharmacotherapy (RR 1.29, 95% CI 0.96 to 1.75; 4 studies, 829 participants). Evidence for bupropion was low-certainty; the point estimate indicated a modest benefit at best, but CIs were wide and incorporated clinically significant harm and clinically significant benefit (RR 1.11, 95% CI 0.86 to 1.43, 4 studies, 872 participants). Hospital-only intervention versus intervention that continues after hospital discharge Patients offered both smoking cessation counselling and pharmacotherapy after discharge had higher quit rates than patients offered counselling in hospital but not offered post-discharge support (RR 1.23, 95% CI 1.09 to 1.38; 7 studies, 5610 participants; high-certainty evidence). In absolute terms, this might equate to an additional 34 quitters per 1000 participants (95% CI 13 to 55). Post-discharge interventions offering real-time counselling without pharmacotherapy (RR 1.23, 95% CI 0.95 to 1.60, 8 studies, 2299 participants; low certainty-evidence) and those offering unscheduled counselling without pharmacotherapy (RR 0.97, 95% CI 0.83 to 1.14; 2 studies, 1598 participants; very low-certainty evidence) may have little to no effect on quit rates compared to control. Telephone quitlines versus control To provide post-discharge support, hospitals may refer patients to community-based telephone quitlines. Both comparisons relating to these interventions had wide CIs encompassing both possible harm and possible benefit, and were judged to be of very low certainty due to imprecision, inconsistency, and risk of bias (post-discharge telephone counselling versus quitline referral: RR 1.23, 95% CI 1.00 to 1.51; 3 studies, 3260 participants; quitline referral versus control: RR 1.17, 95% CI 0.70 to 1.96; 2 studies, 1870 participants). AUTHORS' CONCLUSIONS: Offering hospitalised patients smoking cessation counselling beginning in hospital and continuing for over one month after discharge increases quit rates, compared to no hospital intervention. Counselling provided only in hospital, without post-discharge support, may have a modest impact on quit rates, but evidence is less certain. When all patients receive counselling in the hospital, high-certainty evidence indicates that providing both counselling and pharmacotherapy after discharge increases quit rates compared to no post-discharge intervention. Starting nicotine replacement or varenicline in hospitalised patients helps more patients to quit smoking than a placebo or no medication, though evidence for varenicline is only moderate-certainty due to imprecision. There is less evidence of benefit for bupropion in this setting. Some of our evidence was limited by imprecision (bupropion versus placebo and varenicline versus placebo), risk of bias, and inconsistency related to heterogeneity. Future research is needed to identify effective strategies to implement, disseminate, and sustain interventions, and to ensure cessation counselling and pharmacotherapy initiated in the hospital is sustained after discharge.

Exploring the opinions and potential impact of unflavoured e-liquid on smoking cessation among people who smoke and smoking relapse among people who previously smoked and now use e-cigarettes: findings from a UK-based mixed methods study.

BACKGROUND: Although electronic cigarettes (e-cigarettes) appear to be effective in helping people who smoke to stop smoking, concerns about use of e-cigarettes among young people have led to restrictions on non-tobacco flavoured e-liquids in some countries and some US states. These restrictions could reduce the appeal of these products to non-smoking youth but could have negative consequences for people who smoke or use e-cigarettes. METHODS: In this mixed methods study, we recruited UK adults who smoked or used to smoke and subsequently vaped to explore their opinions of unflavoured e-liquids and their beliefs about how they would be impacted by hypothetical e-liquid flavour restrictions. Participants trialled an unflavoured e-liquid instead of their usual nicotine product for four hours and completed a survey and an online interview. RESULTS: Using Interpretive Phenomenological Analysis and graphically presented data, we found differences in participants' opinions of unflavoured e-liquid. If only unflavoured, tobacco flavoured, and menthol flavoured e-liquids remained on the UK market, some people who smoke or vape may be unaffected, but some may relapse to smoking or continue smoking. Despite most wanting to prevent young people from initiating vaping, participants had varying opinions on whether flavour restrictions would be an effective method. CONCLUSIONS: The findings highlight that people who smoke and vape could be impacted by flavour restrictions in a range of ways, some of which could have a potential adverse impact on harm reduction efforts in the UK (e.g., by making smoking more appealing than vaping).

IntEgrating Smoking Cessation treAtment into usual online Psychological care for people with common mEntal illness: Protocol for an online randomised feasibility and pilot study (ESCAPE digital).

BACKGROUND: In the UK, smoking prevalence in people with depression (34%) and anxiety (29%) is more than double that of the general population (13%). People who stop smoking improve their mental health with comparable effect sizes found for antidepressants. In England, online psychological therapy is a standard treatment for depression and anxiety. Online therapy is an acceptable setting for smoking cessation support; however, integrated smoking and mental health support is not available. This novel study aims to assess the acceptability and feasibility of an online smoking cessation intervention, and trial procedures, offered alongside online mental health treatment as it offers increased reach to people with common mental health difficulties who smoke. METHODS: A two-armed; Intervention (Integrated SilverCloud smoking cessation support) and control group (SilverCloud usual care), pragmatic, randomised controlled feasibility trial. We aim to recruit 500 adult smokers eligible for online mental health treatment. Follow-up will be conducted at 3-months and 6-months. We will assess the acceptability and feasibility of the trial procedures (i.e., recruitment, data completeness, self-reported acceptability and satisfaction) and the intervention (i.e., self-reported quit attempt, engagement with the smoking cessation and mental health programs, smoking cessation medicine and e-cigarette use, self-reported acceptability and satisfaction) and pilot clinical outcomes (i.e., biologically validated smoking abstinence, anxiety, depression, quality of health). CONCLUSION: If the Trial is successful, a randomised controlled effectiveness trial will follow to examine whether integrated smoking cessation and mental health treatment increases smoking abstinence and improves depression and anxiety compared to usual care. TRIAL REGISTRATION: ISRCTN10612149 (https://doi.org/10.1186/ISRCTN10612149), 02/02/2023.

The impact of introducing alcohol-free beer options in bars and public houses on alcohol sales and revenue: A randomised crossover field trial.

AIMS: The study aimed to estimate the impact of introducing a draught alcohol-free beer, thereby increasing the relative availability of these products, on alcohol sales and monetary takings in bars and pubs in England. DESIGN: Randomised crossover field trial. SETTING: England. PARTICIPANTS: Fourteen venues that did not previously sell draught alcohol-free beer. INTERVENTION AND COMPARATOR: Venues completed two intervention periods and two control periods in a randomised order over 8 weeks. Intervention periods involved replacing one draught alcoholic beer with an alcohol-free beer. Control periods operated business as usual. MEASUREMENTS: The primary outcome was mean weekly volume (in litres) of draught alcoholic beer sold. The secondary outcome was mean weekly revenue [in GBP (£)] from all drinks. Analyses adjusted for randomised order, special events, season and busyness. FINDINGS: The adjusted mean difference in weekly sales of draught alcoholic beer was -20 L [95% confidence interval (CI) = -41 to +0.4], equivalent to a 4% reduction (95% CI = 8% reduction to 0.1% increase) in the volume of alcoholic draught beer sold when draught alcohol-free beer was available. Excluding venues that failed at least one fidelity check resulted in an adjusted mean difference of -29 L per week (95% CI = -53 to -5), equivalent to a 5% reduction (95% CI = 8% reduction to 0.8% reduction). The adjusted mean difference in weekly revenue was +61 GBP per week (95% CI = -328 to +450), equivalent to a 1% increase (95% CI = 5% decrease to 7% increase) when draught alcohol-free beer was available. CONCLUSIONS: Introducing a draught alcohol-free beer in bars and pubs in England reduced the volume of draught alcoholic beer sold by 4% to 5%, with no evidence of the intervention impacting net revenue.

Do Flavor Descriptions Influence Subjective Ratings of Flavored and Unflavored E-liquids Among Nonsmoking and Non-vaping UK Adolescents?

INTRODUCTION: Youth use of electronic cigarettes (e-cigarettes) is rising globally and is associated with health harms. Flavor descriptions on e-liquid packaging may contribute to the appeal of e-cigarettes among youth. This study compared subjective ratings of e-liquid packaging flavor descriptions among nonsmoking and non-vaping UK adolescents. AIMS AND METHODS: This was an online observational study in a UK sample of nonsmoking and non-vaping adolescents aged 11-17 years. The primary analyses compared flavored versus unflavored descriptions and the secondary analyses compared sweet flavor versus fruit flavor descriptions. Outcomes were packaging appraisal, packaging receptivity, perceived harm, and perceived audience. RESULTS: The survey was completed by 120 participants (74% female). Packaging appraisal ratings were higher for e-liquids with flavored descriptions than unflavored descriptions (mean difference 5.9, 95% CI: 4.2 to 7.6, p < .001). Similarly, packaging receptivity ratings were higher for e-liquids with flavored descriptions than unflavored descriptions (mean difference 4.2, 95% CI: 2.8 to 5.6, p < .001). Participants also perceived e-liquids with flavored (vs. unflavored) descriptions as less "grown-up" (mean difference -5.2, 95% CI: -7.3 to -3.1, p < .001). However, ratings of perceived harm were similar for flavored and unflavored descriptions (mean difference -1.0, 95% CI: -2.6 to .5, p = .189). CONCLUSIONS: Although this study found differences in subjective ratings of e-liquids with flavored and unflavored descriptions, nonsmoking and non-vaping UK adolescents generally had low appraisal and receptivity for e-liquids and they perceived them as being "grown-up" and harmful. IMPLICATIONS: Youth use of electronic cigarettes (e-cigarettes) is increasing globally, leading to concerns about health harms. This study compared adolescents' ratings of e-liquids with flavored versus unflavored descriptions and e-liquids with sweet flavor versus fruit flavor descriptions. This study adds to previous studies that have compared adolescents' ratings of e-liquids with tobacco flavor versus non-tobacco flavor descriptions. Although packaging appraisal and receptivity ratings were higher (more positive) for e-liquids with flavored versus unflavored descriptions, overall, adolescents who do not smoke or vape had low appraisal and receptivity for e-liquids, and they perceived them as being "grown-up" and harmful.

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.

Confirmation of COVID-19 infection status and reporting of Long COVID symptoms in a population-based birth cohort: No evidence of a nocebo effect.

Some patients with COVID-19 develop symptoms after the acute infection, known as 'Long COVID'. We examined whether or not confirmation of COVID-19 infection status could act as a nocebo, using data from questionnaires distributed to the Avon Longitudinal Study of Parents and Children cohort. We examined associations between confirmation of COVID-19 infection status (confirmed by a positive test vs unconfirmed) and reporting of Long COVID symptoms. We explored the roles of sex and anxiety as potential moderators. There was no clear evidence of a strong association between confirmation of COVID-19 infection status and the Long COVID composite score, physical or psychological symptoms or duration of symptoms. There was no clear evidence of moderation by sex or anxiety. We therefore found no evidence of a nocebo effect. Our data suggest that this psychological mechanism does not play a role in the medical symptomatology experienced by patients with Long COVID.

Exploring the dimensions of responsible research systems and cultures: a scoping review.

The responsible conduct of research is foundational to the production of valid and trustworthy research. Despite this, our grasp of what dimensions responsible conduct of research (RCR) might contain-and how it differs across disciplines (i.e. how it is conceptualized and operationalized)-is tenuous. Moreover, many initiatives related to developing and maintaining RCR are developed within disciplinary and institutional silos which naturally limits the benefits that RCR practice can have. To this end, we are working to develop a better understanding of how RCR is conceived and realized, both across disciplines and across institutions in Europe. The first step in doing this is to scope existing knowledge on the topic, of which this scoping review is a part. We searched several electronic databases for relevant published and grey literature. An initial sample of 715 articles was identified, with 75 articles included in the final sample for qualitative analysis. We find several dimensions of RCR that are underemphasized or are excluded from the well-established World Conferences on Research Integrity (WCRI) Singapore Statement on Research Integrity and explore facets of these dimensions that find special relevance in a range of research disciplines.

MRSamePopTest: introducing a simple falsification test for the two-sample mendelian randomisation 'same population' assumption.

Two-sample MR is an increasingly popular method for strengthening causal inference in epidemiological studies. For the effect estimates to be meaningful, variant-exposure and variant-outcome associations must come from comparable populations. A recent systematic review of two-sample MR studies found that, if assessed at all, MR studies evaluated this assumption by checking that the genetic association studies had similar demographics. However, it is unclear if this is sufficient because less easily accessible factors may also be important. Here we propose an easy-to-implement falsification test. Since recent theoretical developments in causal inference suggest that a causal effect estimate can generalise from one study to another if there is exchangeability of effect modifiers, we suggest testing the homogeneity of variant-phenotype associations for a phenotype which has been measured in both genetic association studies as a method of exploring the 'same-population' test. This test could be used to facilitate designing MR studies with diverse populations. We developed a simple R package to facilitate the implementation of our proposed test. We hope that this research note will result in increased attention to the same-population assumption, and the development of better sensitivity analyses.

KEY MESSAGE: • Two-sample Mendelian randomisation (2SMR) can be used to estimate the lifetime effect of a modifiable exposure on an outcome of interest. • 2SMR point estimates are not interpretable if the exposure and outcome GWASs do not come from homogeneous populations, so called 'same population' assumption. However, this assumption is often not validated in applied studies. • We propose and validate a novel sensitivity analysis for this assumption, which checks if SNP effects for the same trait are homogeneous across the two populations.

The potential role of gray matter volume differences in the association between smoking and depression: A narrative review.

Tobacco use and major depression are both leading contributors to the global burden of disease and are also highly comorbid. Previous research indicates bi-directional causality between tobacco use and depression, but the mechanisms that underlie this causality are unclear, especially for the causality from tobacco use to depression. Here we narratively review the available evidence for a potential causal role of gray matter volume in the association. We summarize the findings of large existing neuroimaging meta-analyses, studies in UK Biobank, and the Enhancing NeuroImaging Genetics through MetaAnalysis (ENIGMA) consortium and assess the overlap in implicated brain areas. In addition, we review two types of methods that allow us more insight into the causal nature of associations between brain volume and depression/smoking: longitudinal studies and Mendelian Randomization studies. While the available evidence suggests overlap in the alterations in brain volumes implicated in tobacco use and depression, there is a lack of research examining the underlying pathophysiology. We conclude with recommendations on (genetically-informed) causal inference methods useful for studying these associations.

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes 'on' or 'off' in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother­child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

Reducing bias in secondary data analysis via an Explore and Confirm Analysis Workflow (ECAW): a proposal and survey of observational researchers.

Background. Although preregistration can reduce researcher bias and increase transparency in primary research settings, it is less applicable to secondary data analysis. An alternative method that affords additional protection from researcher bias, which cannot be gained from conventional forms of preregistration alone, is an Explore and Confirm Analysis Workflow (ECAW). In this workflow, a data management organization initially provides access to only a subset of their dataset to researchers who request it. The researchers then prepare an analysis script based on the subset of data, upload the analysis script to a registry, and then receive access to the full dataset. ECAWs aim to achieve similar goals to preregistration, but make access to the full dataset contingent on compliance. The present survey aimed to garner information from the research community where ECAWs could be applied-employing the Avon Longitudinal Study of Parents and Children (ALSPAC) as a case example. Methods. We emailed a Web-based survey to researchers who had previously applied for access to ALSPAC's transgenerational observational dataset. Results. We received 103 responses, for a 9% response rate. The results suggest that-at least among our sample of respondents-ECAWs hold the potential to serve their intended purpose and appear relatively acceptable. For example, only 10% of respondents disagreed that ALSPAC should run a study on ECAWs (versus 55% who agreed). However, as many as 26% of respondents agreed that they would be less willing to use ALSPAC data if they were required to use an ECAW (versus 45% who disagreed). Conclusion. Our data and findings provide information for organizations and individuals interested in implementing ECAWs and related interventions. Preregistration. https://osf.io/g2fw5 Deviations from the preregistration are outlined in electronic supplementary material A.

The providential randomisation of genotypes.

When building causal knowledge in behavioural genetics, the natural randomisation of genotypes at conception (approximately analogous to the artificial randomisation occurring in randomised controlled trials) facilitates the discovery of genetic causes. More importantly, the randomisation of genetic material within families also enables a better identification of (environmental) risk factors and aetiological pathways to diseases and behaviours.

Assessing the effectiveness of online emotion recognition training in healthy volunteers.

Facial emotion recognition (ER) difficulties are associated with mental health and neurodevelopmental conditions, including autism and poorer social functioning. ER interventions may therefore have clinical potential. We investigated the efficacy of ER training (ERT). We conducted three online studies with healthy volunteers completing one ERT session. Studies 1 and 2 included active and control/sham training groups and tested the efficacy of (i) four-emotion ERT (angry, happy, sad and scared) (n = 101), and (ii) six-emotion ERT (adding disgusted and surprised) (n = 109). Study 3 tested generalizability of ERT to non-trained stimuli with groups trained and tested on the same stimuli, or different stimuli (n = 120). Training effects on total correct hits were estimated using linear mixed effects models. We did not observe clear evidence of improvement in study 1 but note the effect was in the direction of improvement (b = 0.02, 95% confidence interval (CI) = -0.02 to 0.07). Study 2 indicated greater total hits following training (b = 0.07, 95% CI = 0.03-0.12). Study 3 demonstrated similar improvement across groups (b = -0.01, 95% CI = -0.05 to 0.02). Our results indicate improved ER (as measured by our task), which generalizes to different facial stimulus sets. Future studies should further explore generalizability, longer-term effects and ERT in populations with known ER difficulties.

Exploring the bidirectional causal pathways between smoking behaviours and headache: A Mendelian randomisation study.

INTRODUCTION: Although observational data suggests a relationship between headache and smoking, there remain questions about causality. Smoking may increase headache risk, individuals may smoke to alleviate headaches, or smoking and headache may share common risk factors. Mendelian randomisation (MR) is a method that uses genetic variants as instruments for making causal inferences about an exposure and an outcome. METHODS: First, we conducted logistic regression of observational data in UK Biobank assessing the association between smoking behaviours (smoking status, cigarettes per day amongst daily smokers and lifetime smoking score) on risk of self-reported headache (in the last month and for more than 3 months). Second, we used genetic instruments for smoking behaviours and headache (identified in independent genome-wide association studies) to perform bidirectional MR analysis. RESULTS: Observationally, there is a weak association between smoking behaviour and experiencing headache, with increased cigarettes per day associated with increased headache risk. In the MR analysis, genetic liability to smoking initiation and lifetime smoking increased odds of headache in the last month but not odds of headaches lasting more than three months. In the opposite direction there was weak evidence for higher genetic liability to headaches decreasing the chance of quitting. CONCLUSION: There was weak evidence for a partially bidirectional causal relationship between smoking behaviours and headache in the last month. Given this relationship is distinct from smoking heaviness, it suggests headache and smoking may share common risk factors such as personality traits. IMPLICATIONS: Using Mendelian Randomisation, this study addresses the uncertainty regarding the observed relationship between headache and smoking. There was evidence for weak causal effects of smoking initiation and lifetime smoking (but not smoking heaviness) on likelihood of experiencing headache in the last month, but not over a prolonged period of more than three months. Those at higher genetic liability for headaches were also less likely to successfully stop smoking. This partially bidirectional causal relationship distinct from smoking heaviness, suggests that observed associations are unlikely due to biological effects of tobacco smoke exposure and may be explained by shared personality traits.