Evaluating the current state of Mendelian randomization studies: a protocol for a systematic review on methodological and clinical aspects using neurodegenerative disorders as outcome

Mendelian randomization (MR) is fast becoming a popular method to judge causality from routinely conducted observational studies. However, stringent underlying statistical assumptions, missing biological information, and high sample size requirement might make it prone to misuse. Furthermore, rapidly updating methodologies and increasingly available datasets to researchers are making the interpretations of heterogeneous results even more complicated. In this protocol, we provide our design for a multifaceted systematic review on MR studies using neurodegenerative disease as an example outcome. The planned systematic review which has already passed the pilot stage will help to develop an in-depth understanding of how various MR methods have been applied, what has been achieved, and what can be done in future for to arrive at true causal risk factors. During the pilot phase of this systematic review, several versions of questionnaires and frequent consultations between reviewers helped us to finalize a comprehensive list of questions. This will be used to extract information on systematically searched MR articles investigating causality underlying neurodegenerative diseases. A literature search of the electronic databases (Embase, MEDLINE, Web of Science, Scopus, and databases listed in the Cochrane library) will be conducted. The search strategy will include terms related to MR and the spectrum of neurodegenerative diseases. Two independent reviewers will screen the studies, and three will extract the data. The included studies will be further judged by two reviewers for accuracy and completeness of available information. We will perform descriptive and quantitative synthesis using sensitivity analyses of causal association by study design, selection of genetic instrument, validity of MR assumptions, MR method, and sensitivity analysis based on exclusion of potential pleiotropic variants. The quality of conduct as well as quality of reporting in the included studies will be assessed and reported. A meta-analysis will be conducted, if effect estimates on identical genetic instruments are available for both exposure and outcome in the studies using data from participants from ethnically similar populations. This systematic review protocol utilizes a unique comprehensive data abstraction tool based on recent methodological advancements in the field of MR. The planned systematic review will further integrate information on methodological details with clinical f