Comparison of caffeine consumption behavior with plasma caffeine levels as exposure measures in drug-target Mendelian randomization.

Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.

Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization.

BACKGROUND: Caffeine is one of the most utilized drugs in the world, yet its clinical effects are not fully understood. Circulating caffeine levels are influenced by the interplay between consumption behaviour and metabolism. This study aimed to investigate the effects of circulating caffeine levels by considering genetically predicted variation in caffeine metabolism. METHODS: Leveraging genetic variants related to caffeine metabolism that affect its circulating levels, we investigated the clinical effects of plasma caffeine in a phenome-wide association study (PheWAS). We validated novel findings using a two-sample Mendelian randomization framework and explored the potential mechanisms underlying these effects in proteome-wide and metabolome-wide Mendelian randomization. RESULTS: Higher levels of genetically predicted circulating caffeine among caffeine consumers were associated with a lower risk of obesity (odds ratio (OR) per standard deviation increase in caffeine = 0.97, 95% confidence interval (CI) CI: 0.95-0.98, p = 2.47 × 10-4), osteoarthrosis (OR = 0.97, 95% CI: 0.96-0.98, P=1.10 × 10-8) and osteoarthritis (OR: 0.97, 95% CI: 0.96 to 0.98, P = 1.09 × 10-6). Approximately one third of the protective effect of plasma caffeine on osteoarthritis risk was estimated to be mediated through lower bodyweight. Proteomic and metabolomic perturbations indicated lower chronic inflammation, improved lipid profiles, and altered protein and glycogen metabolism as potential biological mechanisms underlying these effects. CONCLUSIONS: We report novel evidence suggesting that long-term increases in circulating caffeine may reduce bodyweight and the risk of osteoarthrosis and osteoarthritis. We confirm prior genetic evidence of a protective effect of plasma caffeine on risk of overweight and obesity. Further clinical study is warranted to understand the translational relevance of these findings before clinical practice or lifestyle interventions related to caffeine consumption are introduced.

Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization.

BACKGROUND: Caffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia. METHODS: Summary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study (n = 356,077). Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis. RESULTS: After correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024-1.238, pFDR = 0.039) and a lower odds of bipolar disorder (OR = 0.905, 95% CI = 0.827-0.929, pFDR = 0.041) and MDD (OR = 0.965, 95% CI = 0.937-0.995, pFDR = 0.039). Instrumented plasma caffeine levels were not associated with schizophrenia (OR = 0.986, 95% CI = 0.929-1.047, pFDR = 0.646). CONCLUSIONS: These Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.

Triangulating evidence for the causal impact of single-intervention zinc supplement on glycaemic control for type 2 diabetes: systematic review and meta-analysis of randomised controlled trial and two-sample Mendelian randomisation.

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.

Methods to increase response to postal and electronic questionnaires.

BACKGROUND: Self-administered questionnaires are widely used to collect data in epidemiological research, but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of epidemiological research. OBJECTIVES: To identify effective strategies to increase response to postal and electronic questionnaires. SEARCH METHODS: We searched 14 electronic databases up to December 2021 and manually searched the reference lists of relevant trials and reviews. We contacted the authors of all trials or reviews to ask about unpublished trials; where necessary, we also contacted authors to confirm the methods of allocation used and to clarify results presented. SELECTION CRITERIA: Randomised trials of methods to increase response to postal or electronic questionnaires. We assessed the eligibility of each trial using pre-defined criteria. DATA COLLECTION AND ANALYSIS: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity amongst trial odds ratios using a Chi2 test and quantified the degree of inconsistency between trial results using the I2 statistic. MAIN RESULTS: Postal We found 670 eligible trials that evaluated over 100 different strategies of increasing response to postal questionnaires. We found substantial heterogeneity amongst trial results in half of the strategies. The odds of response almost doubled when: using monetary incentives (odds ratio (OR) 1.86; 95% confidence interval (CI) 1.73 to 1.99; heterogeneity I2 = 85%); using a telephone reminder (OR 1.96; 95% CI 1.03 to 3.74); and when clinical outcome questions were placed last (OR 2.05; 95% CI 1.00 to 4.24). The odds of response increased by about half when: using a shorter questionnaire (OR 1.58; 95% CI 1.40 to 1.78); contacting participants before sending questionnaires (OR 1.36; 95% CI 1.23 to 1.51; I2 = 87%); incentives were given with questionnaires (i.e. unconditional) rather than when given only after participants had returned their questionnaire (i.e. conditional on response) (OR 1.53; 95% CI 1.35 to 1.74); using personalised SMS reminders (OR 1.53; 95% CI 0.97 to 2.42); using a special (recorded) delivery service (OR 1.68; 95% CI 1.36 to 2.08; I2 = 87%); using electronic reminders (OR 1.60; 95% CI 1.10 to 2.33); using intensive follow-up (OR 1.69; 95% CI 0.93 to 3.06); using a more interesting/salient questionnaire (OR 1.73; 95% CI 1.12 to 2.66); and when mentioning an obligation to respond (OR 1.61; 95% CI 1.16 to 2.22). The odds of response also increased with: non-monetary incentives (OR 1.16; 95% CI 1.11 to 1.21; I2 = 80%); a larger monetary incentive (OR 1.24; 95% CI 1.15 to 1.33); a larger non-monetary incentive (OR 1.15; 95% CI 1.00 to 1.33); when a pen was included (OR 1.44; 95% CI 1.38 to 1.50); using personalised materials (OR 1.15; 95% CI 1.09 to 1.21; I2 = 57%); using a single-sided rather than a double-sided questionnaire (OR 1.13; 95% CI 1.02 to 1.25); using stamped return envelopes rather than franked return envelopes (OR 1.23; 95% CI 1.13 to 1.33; I2 = 69%), assuring confidentiality (OR 1.33; 95% CI 1.24 to 1.42); using first-class outward mailing (OR 1.11; 95% CI 1.02 to 1.21); and when questionnaires originated from a university (OR 1.32; 95% CI 1.13 to 1.54). The odds of response were reduced when the questionnaire included questions of a sensitive nature (OR 0.94; 95% CI 0.88 to 1.00). Electronic We found 88 eligible trials that evaluated over 30 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity amongst trial results in half of the strategies. The odds of response tripled when: using a brief letter rather than a detailed letter (OR 3.26; 95% CI 1.79 to 5.94); and when a picture was included in an email (OR 3.05; 95% CI 1.84 to 5.06; I2 = 19%). The odds of response almost doubled when: using monetary incentives (OR 1.88; 95% CI 1.31 to 2.71; I2 = 79%); and using a more interesting topic (OR 1.85; 95% CI 1.52 to 2.26). The odds of response increased by half when: using non-monetary incentives (OR 1.60; 95% CI 1.25 to 2.05); using shorter e-questionnaires (OR 1.51; 95% CI 1.06 to 2.16; I2 = 94%); and using a more interesting e-questionnaire (OR 1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third when: offering survey results as an incentive (OR 1.36; 95% CI 1.16 to 1.59); using a white background (OR 1.31; 95% CI 1.10 to 1.56); and when stressing the benefits to society of response (OR 1.38; 95% CI 1.07 to 1.78; I2 = 41%). The odds of response also increased with: personalised e-questionnaires (OR 1.24; 95% CI 1.17 to 1.32; I2 = 41%); using a simple header (OR 1.23; 95% CI 1.03 to 1.48); giving a deadline (OR 1.18; 95% CI 1.03 to 1.34); and by giving a longer time estimate for completion (OR 1.25; 95% CI 0.96 to 1.64). The odds of response were reduced when: "Survey" was mentioned in the e-mail subject (OR 0.81; 95% CI 0.67 to 0.97); when the email or the e-questionnaire was from a male investigator, or it included a male signature (OR 0.55; 95% CI 0.38 to 0.80); and by using university sponsorship (OR 0.84; 95%CI 0.69 to 1.01). The odds of response using a postal questionnaire were over twice those using an e-questionnaire (OR 2.33; 95% CI 2.25 to 2.42; I2 = 98%). Response also increased when: providing a choice of response mode (electronic or postal) rather than electronic only (OR 1.76 95% CI 1.67 to 1.85; I2 = 97%); and when administering the e-questionnaire by computer rather than by smartphone (OR 1.62 95% CI 1.36 to 1.94). AUTHORS' CONCLUSIONS: Researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this Cochrane review.

Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study.

BACKGROUND: Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm. METHODS: Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10-8) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model. RESULTS: Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91-4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction - 0.27, 95%CI - 0.39 to - 0.15, p = 1.90 × 10-5). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43-0.89, p = 9.33 × 10-3), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76-1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI - 0.04-0.07, p = 0.54). CONCLUSIONS: While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight.

Selective serotonin reuptake inhibitor use and the risk of hepatocellular carcinoma: a systematic review and dose-response analysis of cohort studies with one million participants.

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.

Does pre-notification increase questionnaire response rates: a randomised controlled trial nested within a systematic review.

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/.

Does advance contact with research participants increase response to questionnaires: an updated systematic review and meta-analysis.

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.

Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement.

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.

A comparison of recommendations and received treatment for mood and anxiety disorders in a representative national sample.

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.

MVMRmode: Introducing an R package for plurality valid estimators for multivariable Mendelian randomisation.

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.

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 UK BiLEVE and Mendelian randomisation: using multivariable instrumental variables to address "damned if you, damned if you don't" adjustment problems.

OBJECTIVE: To explore the use of multivariable instrumental variables to resolve the "damned if you do, damned if you don't" adjustment problem created for Mendelian randomisation (MR) analysis using the smoking or lung function related phenotypes in the UK Biobank (UKB). RESULT: "damned if you do, damned if you don't" adjustment problems occur when both adjusting and not-adjusting for a variable will induce bias in an analysis. One instance of this occurs because the genotyping chip of UKB participants differed based on lung function/smoking status. In simulations, we show that multivariable instrumental variables analyses can attenuate potential collider bias introduced by adjusting for a proposed covariate, such as the UKB genotyping chip. We then explore the effect of adjusting for genotyping chip in a multivariable MR model exploring the effect of smoking on seven medical outcomes (lung cancer, emphysema, hypertension, stroke, heart diseases, depression, and disabilities). We additionally compare our results to a traditional univariate MR analysis using genome-wide analyses summary statistics which had and had not adjusted for genotyping chip. This analysis implies that the difference in genotyping chip has introduced only a small amount of bias.

Exploring the Lifetime Effect of Children on Wellbeing Using Two-Sample Mendelian Randomisation.

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 (ß = 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.

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study.

Objective: To investigate the potential causal effects of long term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases. Design: Two sample mendelian randomisation study. Setting: Genome-wide association study summary data for associations of two single nucleotide polymorphisms associated with plasma caffeine at the genome-wide significance threshold (rs2472297 near the CYP1A2 gene and rs4410790 near the AHR gene) and their association with the outcomes. Participants: Primarily individuals of European ancestry participating in cohorts contributing to genome-wide association study consortia. Main outcome measures: Outcomes studied were body mass index, whole body fat mass, whole body fat-free mass, type 2 diabetes, ischaemic heart disease, atrial fibrillation, heart failure, and stroke. Results: Higher genetically predicted plasma caffeine concentrations were associated with lower body mass index (beta -0.08 standard deviation (SD) (95% confidence interval -0.10 to -0.06), where 1 SD equals about 4.8 kg/m2 in body mass index, for every standard deviation increase in plasma caffeine) and whole body fat mass (beta -0.06 SD (-0.08 to -0.04), 1 SD equals about 9.5 kg; P<0.001) but not fat-free mass (beta -0.01 SD (-0.02 to -0.00), 1 SD equals about 11.5 kg; P=0.17). Higher genetically predicted plasma caffeine concentrations were associated with a lower risk of type 2 diabetes in two consortia (FinnGen and DIAMANTE), with a combined odds ratio of 0.81 ((95% confidence interval 0.74 to 0.89); P<0.001). Approximately half (43%; 95% confidence interval 30% to 61%) of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index reduction. No strong associations were reported between genetically predicted plasma caffeine concentrations and a risk of any of the studied cardiovascular diseases. Conclusions: Higher plasma caffeine concentrations might reduce adiposity and risk of type 2 diabetes. Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.

Deriving GWAS summary estimates for paternal smoking in UK biobank: a GWAS by subtraction.

OBJECTIVE: To use genome-wide association study (GWAS) by subtraction, a method for deriving novel GWASs from existing summary statistics, to derive genome-wide summary statistics for paternal smoking. RESULT: A GWAS by subtraction was implemented using a weighted linear model that defined the child-genotype paternal-phenotype association as the child-genotype child-phenotype association minus the child-genotype maternal-phenotype association. We first use the laws of inherence to derive the weighted linear model. We then implemented the linear model to create a GWAS of paternal smoking by subtracting the summary statistics from a GWAS of maternal smoking from the summary statistics of a GWAS of the index individual's smoking. We used a Monte-Carlo simulation to validate the model and showed that this approach performed similarly in terms of bias to performing a traditional GWAS of paternal smoking. Finally, we validated the summary statistics in a Mendelian randomisation analysis by demonstrating an association of genetically predicted paternal smoking with paternal lung cancer and emphysema.

Lipids, Blood Pressure, and Diabetes Mellitus on Risk of Cardiovascular Diseases in East Asians: A Mendelian Randomization Study.

Elevated blood pressure, dyslipidemia, and impaired glycemic control are well-established cardiovascular risk factors in Europeans, but there are comparatively few studies focused on East Asian populations. This study evaluated the potential causal relations between traditional cardiovascular risk factors and disease risk in East Asians through a 2-sample Mendelian randomization approach. We collected summary statistics for blood pressure parameters, lipid subsets, and type 2 diabetes mellitus liability from large genome-wide association study meta-analyses conducted in East Asians and Europeans. These were paired with summary statistics for ischemic heart disease (IHD), ischemic stroke (IS), peripheral vascular disease, heart failure (HF) and atrial fibrillation (AF). We performed univariable Mendelian randomization analyses for each exposure-outcome pair, followed by multivariable analyses for the available lipid subsets. The genetically predicted risk factors associated with IHD and AF were similar between East Asians and Europeans. However, in East Asians only genetically predicted elevated blood pressure was significantly associated with IS (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001) and HF (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001), whereas nearly all genetically predicted risk factors were significantly associated with IS and HF in Europeans. In conclusion, this study provides supportive evidence for similar causal relations between traditional cardiovascular risk factors and IHD and AF in both East Asian and European ancestry populations. However, the identified risk factors for IS and HF differed between East Asians and Europeans, potentially highlighting distinct disease etiologies between these populations.