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.

In observational epidemiology, mendelian randomisation (MR) studies provide an opportunity to study the causal association between an exposure and an outcome while reducing the risk of certain biases Little consensus exists around the reporting of MR studies, and the quality of reporting of these studies has been inconsistent; many MR study reports do not state or examine the various assumptions of MR and report insufficient details on the data sources STROBE-MR (strengthening the reporting of observational studies in epidemiology using mendelian randomisation), a checklist of 20 reporting items, has been developed for the communication of MR studies This article explains the rationale of these checklist items and provides examples of transparent reporting MR study authors, reviewers, and journal editors are encouraged to use STROBE-MR to improve the reporting of these studies on 3 November 2021 by guest. Protected by copyright.

While the number of studies using Mendelian randomization (MR) methods has grown exponentially in the last decade, the quality of reporting of these studies often has been poor. Similar to other reporting guidelines such as CONSORT (Consolidated Standards of Reporting Trials) for randomised trials and STROBE (STrenghtening the Reporting of Observational studies in Epidemiology) for observational studies in epidemiology, the STROBE-MR working group aims to provide guidance to authors on how to improve reporting of MR studies and help readers, reviewers, and journal editors to evaluate the quality of the presented evidence.Empirical evidence indicates that many reports of MR studies do not clearly state or examine the various assumptions of MR methods and report insufficient details on the data sources, which makes it hard to evaluate the quality and reliability of the results. The STROBE-MR guidance covers both one sample and two sample MR studies. At present, the draft checklist consists of 20 items, organized into the title and abstract, introduction, methods, results and discussion sections of articles.As these guidelines aim to reach the entire MR community, we would like to give everyone the opportunity to contribute their comments. The following draft of the STROBE-MR checklist is open for public discussion and all feedback will be taken into account during its next revision. For feedback, please use the comment section below this post on PeerJ Preprints.We hope the final guidelines will serve the entire community and contribute to improving the reporting of MR studies in the future.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.27857v1 | CC BY 4.0 Open Access | rec

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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.

The effect of intravenous infusions of histamine on gastric secretion has recently been studied quantitatively in the cat (Wood, 1948) and in the dog (Obrink, 1948;Hanson, Grossman, and Ivy, 1948). These authors observed that the effect of the drug increased with the dose, and that by choosing a suitable range of doses it was possible to obtain data which could be used to construct doseresponse curves.Little is known about the effect of histamine infusions on gastric secretion in man. According to McElin and Horton (1946) ng./kg./min. Our aim was to study the secretory behaviour of the human stomach in response to prolonged continuous intravenous infusions of histamine, and to determine the relationship between dose and response. At the same time we attempted to gain further information on the fate of histamine in the body by estimating it in samples of various body fluids, including the gastric juice. This part of the work has been reported elsewhere (Adam, Card, Riddell, Roberts, and Strong, 1954).Our data were obtained from three healthy men designated as W.I.C., J.A.S., and A.A.G., each of whom received a series of intravenous infusions of histamine. Estimates of the rates of acid secretion were plotted against rates of infusion of the drug. Each infusion was thus a self-contained experiment and could be represented by a point on a graph. By applying statistical methods to the results it was possible to fit various parameters of the doseresponse curves. METHODS Intubation of the Stomach and Collection of the Juice. -The subject omitted breakfast. A few drops of local anaesthetic (Amethocaine HCI) were instilled into the nose and a Ryle's.tube was passed by this route into the stomach. The position of the tip was ascertained radioscopically and the tube manipulated until the tip lay on the left border of the vertebral column. The subject then lay on his left side, and the stomach contents were aspirated by syringe. This was sometimes made easier by washing the stomach out with warm water. The Ik yle's tube was then connected to a source of continuous suction not exceeding 40 mm. Hg. The gastric juice flowed into a 50-ml. boiling tube, which was replaced every ten minutes by a clean tube. At slow rates of secretion the juice tended to be thick and mucinous and occasionally blocked the tube. The injection of a small quantity of warm water easily cleared the tube, and a correction was subsequently applied to the volume of the sample. saliva was collected by expectoration. The duodenal juice was not withdrawn.Titrations.-The volume of the sample of gastric juice was measured and the free and total acid were determined by titration against 0.lN-NaOH, using 'I pfer's reagent and phenolphthalein as internal indicators. The concentration of acid was expressed in m.equiv. HCl/l. The product of the concentration of total acid and the volume of the sample in litres gave an estimate of the output of acid in m.equiv. HCI.Infisions.-Histamine acid phosphate was supplied by British Drug Houses Ltd. All the values for histam...

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.

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.