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Background: Genome-wide association studies have enabled Mendelian randomization analyses to be performed at an industrial scale. Two-sample summary data Mendelian randomization analyses can be performed using publicly available data by anyone who has access to the internet. While this has led to many insightful papers, it has also fuelled an explosion of poor-quality Mendelian randomization publications, which threatens to undermine the credibility of the whole approach. Findings: We detail five pitfalls in conducting a reliable Mendelian randomization investigation: (1) inappropriate research question, (2) inappropriate choice of variants as instruments, (3) insufficient interrogation of findings, (4) inappropriate interpretation of findings, and (5) lack of engagement with previous work. We have provided a brief checklist of key points to consider when performing a Mendelian randomization investigation; this does not replace previous guidance, but highlights critical analysis choices. Journal editors should be able to identify many low-quality submissions and reject papers without requiring peer review. Peer reviewers should focus initially on key indicators of validity; if a paper does not satisfy these, then the paper may be meaningless even if it is technically flawless. Conclusions: Performing an informative Mendelian randomization investigation requires critical thought and collaboration between different specialties and fields of research. [ABSTRACT FROM AUTHOR]

Background: Mendelian randomisation (MR) is the use of genetic variants as instrumental variables. Mode-based estimators (MBE) are one of the most popular types of estimators used in univariable-MR studies and is often used as a sensitivity analysis for pleiotropy. However, because there are no plurality valid regression estimators, modal estimators for multivariable-MR have been under-explored. Methods: We use the residual framework for multivariable-MR to introduce two multivariable modal estimators: multivariable-MBE, which uses IVW to create residuals fed into a traditional plurality valid estimator, and an estimator which instead has the residuals fed into the contamination mixture method (CM), multivariable-CM. We then use Monte-Carlo simulations to explore the performance of these estimators when compared to existing ones and re-analyse the data used by Grant and Burgess (2021) looking at the causal effect of intelligence, education, and household income on Alzheimer's disease as an applied example. Results: In our simulation, we found that multivariable-MBE was generally too variable to be much use. Multivariable-CM produced more precise estimates on the other hand. Multivariable-CM performed better than MR-Egger in almost all settings, and Weighted Median under balanced pleiotropy. However, it underperformed Weighted Median when there was a moderate amount of directional pleiotropy. Our re-analysis supported the conclusion of Grant and Burgess (2021), that intelligence had a protective effect on Alzheimer's disease, while education, and household income do not have a causal effect. Conclusions: Here we introduced two, non-regression-based, plurality valid estimators for multivariable MR. Of these, "multivariable-CM" which uses IVW to create residuals fed into a contamination-mixture model, performed the best. This estimator uses a plurality of variants valid assumption, and appears to provide precise and unbiased estimates in the presence of balanced pleiotropy and small amounts of directional pleiotropy. [ABSTRACT FROM AUTHOR]

Caffeine is a psychoactive substance widely consumed worldwide, mainly via sources such as coffee and tea. The effects of caffeine on kidney function remain unclear. We leveraged the genetic variants in the CYP1A2 and AHR genes via the two-sample Mendelian randomization (MR) framework to estimate the association of genetically predicted plasma caffeine and caffeine intake on kidney traits. Genetic association summary statistics on plasma caffeine levels and caffeine intake were taken from genome-wide association study (GWAS) meta-analyses of 9876 and of >47,000 European ancestry individuals, respectively. Genetically predicted plasma caffeine levels were associated with a decrease in estimated glomerular filtration rate (eGFR) measured using either creatinine or cystatin C. In contrast, genetically predicted caffeine intake was associated with an increase in eGFR and a low risk of chronic kidney disease. The discrepancy is likely attributable to faster metabolizers of caffeine consuming more caffeine-containing beverages to achieve the same pharmacological effect. Further research is needed to distinguish whether the observed effects on kidney function are driven by the harmful effects of higher plasma caffeine levels or the protective effects of greater intake of caffeine-containing beverages, particularly given the widespread use of drinks containing caffeine and the increasing burden of kidney disease. [ABSTRACT FROM AUTHOR]

Although previous studies suggested the protective effect of Zn for type 2 diabetes (T2D), the unitary causal effect remains inconclusive. We investigated the causal effect of Zn as a single intervention on glycaemic control for T2D, using a systematic review of randomised controlled trials and two-sample Mendelian randomisation (MR). Four primary outcomes were identified: fasting blood glucose/fasting glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR) and serum insulin/fasting insulin level. In the systematic review, four databases were searched until June 2021. Studies, in which participants had T2D and intervention did not comprise another co-supplement, were included. Results were synthesised through the random-effects meta-analysis. In the two-sample MR, we used single-nucleotide polymorphisms (SNP) from MR-base, strongly related to Zn supplements, to infer the relationship causally, but not specified T2D. In the systematic review and meta-analysis, fourteen trials were included with overall 897 participants initially. The Zn supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): −26·52 mg/dl, 95 % CI (−35·13, −17·91)), HbA1c (MD: −0·52 %, 95 % CI: (−0·90, −0·13)) and HOMA-IR (MD: −1·65, 95 % CI (−2·62, −0·68)), compared to the control group. In the two-sample MR, Zn supplement with two SNP reduced the fasting glucose (inverse-variance weighted coefficient: −2·04 mmol/l, 95 % CI (−3·26, −0·83)). From the two methods, Zn supplementation alone may causally improve glycaemic control among T2D patients. The findings are limited by power from the small number of studies and SNP included in the systematic review and two-sample MR analysis, respectively. [ABSTRACT FROM AUTHOR]

Background: Observational research implies a negative effect of having children on wellbeing. Objectives: To provide Mendelian randomisation evidence of the effect of having children on parental wellbeing. Design: Two-sample Mendelian randomisation. Setting: Non-clinical European ancestry participants. Participants: We used the UK Biobank (460,654 male and female European ancestry participants) as a source of genotype-exposure associations, the Social Science Genetics Consortia (SSGAC) (298,420 male and female European ancestry participants), and the Within-Family Consortia (effective sample of 22,656 male and female European ancestry participants) as sources of genotype-outcome associations. Interventions: The lifetime effect of an increase in the genetic liability to having children. Primary and secondary outcome measures: The primary analysis was an inverse variance weighed analysis of subjective wellbeing measured in the 2016 SSGAC Genome Wide Association Study (GWAS). Secondary outcomes included pleiotropy robust estimators applied in the SSGAC and an analysis using the Within-Family consortia GWAS. Results: We did not find strong evidence of a negative (standard deviation) change in wellbeing (β = 0.153 (95% CI: −0.210 to 0.516) per child parented. Secondary outcomes were generally slightly deflated (e.g., −0.049 [95% CI: −0.533 to 0.435] for the Within-Family Consortia and 0.090 [95% CI: −0.167 to 0.347] for weighted median), implying the presence of some residual confounding and pleiotropy. Conclusions: Contrary to the existing literature, our results are not compatible with a measurable negative effect of number of children on the average wellbeing of a parent over their life course. However, we were unable to explore non-linearities, interactions, or time-varying effects. [ABSTRACT FROM AUTHOR]

Background Two-sample Mendelian randomization (2SMR) is an increasingly popular epidemiological method that uses genetic variants as instruments for making causal inferences. Clear reporting of methods employed in such studies is important for evaluating their underlying quality. However, the quality of methodological reporting of 2SMR studies is currently unclear. We aimed to assess the reporting quality of studies that used MR-Base, one of the most popular platforms for implementing 2SMR analysis. Methods We created a bespoke reporting checklist to evaluate reporting quality of 2SMR studies. We then searched Web of Science Core Collection, PsycInfo, MEDLINE, EMBASE and Google Scholar citations of the MR-Base descriptor paper to identify published MR studies that used MR-Base for any component of the MR analysis. Study screening and data extraction were performed by at least two independent reviewers. Results In the primary analysis, 87 studies were included. Reporting quality was generally poor across studies, with a mean of 53% (SD = 14%) of items reported in each study. Many items required for evaluating the validity of key assumptions made in MR were poorly reported: only 44% of studies provided sufficient details for assessing if the genetic variant associates with the exposure ('relevance' assumption), 31% for assessing if there are any variant-outcome confounders ('independence' assumption), 89% for the assessing if the variant causes the outcome independently of the exposure ('exclusion restriction' assumption) and 32% for assumptions of falsification tests. We did not find evidence of a change in reporting quality over time or a difference in reporting quality between studies that used MR-Base and a random sample of MR studies that did not use this platform. Conclusions The quality of reporting of two-sample Mendelian randomization studies in our sample was generally poor. Journals and researchers should consider using the STROBE-MR guidelines to improve reporting quality. [ABSTRACT FROM AUTHOR]

Mendelian randomisation (MR) is an increasingly popular method for strengthening causal inference in epidemiological studies. cis-MR in particular uses genetic variants in the gene region of a drug target protein as an instrumental variable to provide quasi-experimental evidence for on-target drug effects. A limitation of this framework is when the genetic variant is correlated to another variant that also effects the outcome of interest (confounding through linkage disequilibrium). Methods for correcting this bias, such as multivariable MR, struggle in a cis setting because of the high correlation among genetic variants. Here, through simulation experiments and an applied example considering the effect of interleukin 6 receptor signaling on coronary artery disease risk, we present an alternative method for attenuating bias that does not suffer from this problem. As our method uses both MR and the product and difference method for mediation analysis, our proposal inherits all assumptions of these methods. We have additionally developed an R package, TwoStepCisMR, to facilitate the implementation of the method. [ABSTRACT FROM AUTHOR]

We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer's disease and Parkinson's disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer's Project, the International Parkinson's Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson's disease in the FinnGen consortium. but not in the International Parkinson's Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer's disease. The association between caffeine and Parkinson's disease requires further study. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies have suggested a lower risk of hepatocellular carcinoma (HCC) in patients receiving selective serotonin reuptake inhibitors (SSRIs). The current study aimed to provide an updated and comprehensive assessment of the association between SSRI use and development of HCC. Methods: This is a systematic review and meta-analysis of all observational studies published until June 2021. We comprehensively searched PubMed/Medline, Web of Science, and Embase to identify studies comparing SSRIs use with control in relation to the risk of HCC. We calculated pooled relative risks (RRs) and 95% confidence intervals (CIs) for the association between SSRI use and incident HCC risk using random-effects meta-analysis. A dose–response analysis was conducted to evaluate the HCC risk according to the defined daily dose (DDD) of SSRI use. Results: Eight observational studies, comprising 1,051,096 participants and 22,316 incidences of HCC, examining the association between SSRIs use and HCC risk, were included in the systematic review (adjusted RR: 0.66; 95% CI: 0.56–0.79; P ≤ 0.001). In subgroup analysis, the magnitude of benefit associated with SSRIs was significantly higher in patients with hepatitis infection (RR: 0.70, 95% CI: 0.51–0.95) than the general population (Pheterogeneity = 0.700). The dose–response analysis indicated strong inverse association between cumulative DDD of SSRI and risk of HCC (coefficient: − 0.0030; P = 0.002; R2 = 0.78). Conclusions: The results of this review show that SSRI use was associated with a 34% lower risk of HCC, which tend to be dose dependent. Further prospective studies are warranted to confirm these observations across the spectrum of chronic liver disease and hepatitis infection. [ABSTRACT FROM AUTHOR]

Background: Missing outcome data can lead to bias in the results of systematic reviews. One way to address missing outcome data is by requesting the data from the trial authors, but non-response is common. One way to potentially improve response rates is by sending study participants advance communication. During the update of a systematic review examining the effect of pre-notification on response rates, study authors needed to be contacted for further information. This study was nested within the systematic review by randomising authors to receive a notification of the upcoming request for information. The objective was to test if pre-notification increased response rates.Methods: The participants were study authors included in the systematic review, whose studies were at unclear risk of bias. The intervention was a pre-notification of the request for further information, sent 1 day before the request. The outcome was defined as the proportion of authors who responded to the request for information. Authors were randomised by simple randomisation. Thirty three authors were randomised to the pre-notification arm, and 42 were randomised to the control arm. Authors were blinded to the possibility of an alternative condition.Results: All authors randomised were analysed. 14/33 (42.4%) authors in the pre-notification arm had returned responses to the questionnaire, and 18/42 (42.9%) in the control arm. There was no evidence of a difference between these groups (absolute difference = - 0.5, 95% CI (- 23.4 to 22.5%), p = 1). We received no complaints about receiving the pre-notification.Conclusions: This study's results do not support the hypothesis that pre-notification increases response from study authors being contacted for a request for more information. However, the study has a low power, and the results may not generalise to other contexts, methods of administering a pre-notification, or study populations.Trial Registration: Registration and protocol: This trial is not registered with any trial registry. However, the protocol was posted in advance on the Open Science Framework website and is available on the Open Science Framework website: DOI: https://doi.org/10.17605/OSF.IO/MSV2W or https://osf.io/msv2w/. [ABSTRACT FROM AUTHOR]

Background: Questionnaires remain one of the most common forms of data collection in epidemiology, psychology and other human-sciences. However, results can be badly affected by non-response. One way to potentially reduce non-response is by sending potential study participants advance communication. The last systematic review to examine the effect of questionnaire pre-notification on response is 10 years old, and lacked a risk of bias assessment.Objectives: Update the section of the Cochrane systematic review, Edwards et al. (2009), on pre-notification to include 1) recently published studies, 2) an assessment of risk of bias, 3) Explore if heterogeneity is reduced by: delay between pre-contact and questionnaire delivery, the method of pre-contact, if pre-contact and questionnaire delivery differ, if the pre-contact includes a foot-in-the-door manipulation, and study's the risk of bias.Methods: Inclusion criteria: population: any population, intervention: comparison of some type of pre-notification, comparison group: no pre-notification, outcome: response rates.Study Design: randomised controlled trails.Exclusion Criteria: NA.Data Sources: Studies which cited or were included in Edwards et al. (2009); We additionally searched: CINAHL, Web of Science, PsycInfo, MEDLINE, EconLit, EMBASE, Cochrane Central, Cochrane CMR, ERIC, and Sociological Abstracts. The searches were implemented in June 2018 and May 2021. Study screening: a single reviewer screened studies, with a random 10% sample independently screened to ascertain accuracy.Data Extraction: data was extracted by a single reviewer twice, with a week between each extraction. Risk of Bias: within studies bias was assessed using the Cochrane Risk of Bias tool (ROB1) by a single unblinded reviewer, across studies bias was assessed using funnel plots. Synthesis Method: study results were meta-analysed with a random effects model using the final response rate as the outcome. Evaluation of Uncertainty: Uncertainty was evaluated using the GRADE approach.Results: One hundred seven trials were included with 211,802 participants. Over-all pre-notification increased response, OR = 1.33 (95% CI: 1.20-1.47). However, there was a large amount of heterogeneity (I2 = 97.1%), which was not explained by the subgroup analyses. In addition, when studies at high or unclear risk of bias were excluded the effect was to reduced OR = 1.09 (95% CI: 0.99-1.20). Because of the large amount of heterogeneity, even after restricting to low risk of bias studies, there is still moderate uncertainty in these results.Conclusions: Using the GRADE evaluation, this review finds moderate evidence that pre-notification may not have an effect on response rates.Funding: Economic and Social Research Council.Preregistration: None. [ABSTRACT FROM AUTHOR]

Importance: Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation.Objective: To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies.Design, Setting, and Participants: The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021.Findings: The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed.Conclusions and Relevance: STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results. [ABSTRACT FROM AUTHOR]

Background: The exact nature of treatment and management recommendations made, and received, for mood and anxiety disorders in a community population is unclear. In addition, there is limited evidence on the impact of recommendations on actual receipt of treatment or implementation of management strategies. We aim to describe the frequency with which specific recommendations were made and implemented; and thus assess the size of any gap between the recommendation and implementation of treatments and management strategies. Methods: We used the Survey 'Living with a Chronic Condition in Canada - Mood and Anxiety Disorders (SLCDC-MA), a unique crossectional survey of a large (N = 3358) and representative sample of Canadians with a diagnosed mood or anxiety disorder, which was conducted by Statistics Canada. The survey collected information on recommendations for medication, counselling, exercise, reduction of alcohol consumption, smoking cessation and reduction of street drug use. We also estimate the frequency that recommendations are made and followed, as well the impact of the prior on the latter. We consulted people with lived experience of the disorders to help interpret our results. Results: The results generally showed that most people would receive recommendations, almost all for antidepressant medications (94.6%), with lower proportions for the other treatment and management strategies (e.g. 62.1 and 66% for counselling and exercise). Most recommendations were implemented and had an impact on behaviour. The exception to this was smoking reduction/cessation, which was often not recommended or followed through. Other than with medication, at least 20% of the population, for each recommendation, would not have their recommendation implemented. A substantive group also exists who access treatments, and employ various management strategies, without a recommendation. Conclusions: The results indicate that there is a gap between recommendations made and the implementation of treatments. However, its size varies substantially across treatments. [ABSTRACT FROM AUTHOR]

Cortisol exerts a broad anti-inflammatory effect on the immune system. Inflammatory cytokines contribute to the molecular signalling pathways implicated in various autoimmune and inflammatory conditions. However, the mechanisms by which cortisol modulates such signalling pathways remain uncertain. Leveraging summary-level data from the CORtisol NETwork (CORNET, n = 25,314) and FINRISK (n = 8293) genome-wide association studies, we used two-sample Mendelian randomisation to investigate the causal effect of genetically proxied morning cortisol levels on 42 circulating cytokines. We found that increased genetically proxied morning cortisol levels were associated with reduced levels of IL-8 and increased levels of MIF. These results provide mechanistic insight into the immunomodulatory effects of endogenous cortisol and the therapeutic effects of exogenous corticosteroids. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play a central pathophysiological role in the onset and progression of disease. [ABSTRACT FROM AUTHOR]