A novel and efficient machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition

Mendelian Randomization (MR) enables estimation of causal effects while controlling for unmeasured confounding factors. However, traditional MR's reliance on strong parametric assumptions can introduce bias if these are violated. We introduce a new machine learning MR estimator named Quantile Instrumental Variable (IV) that achieves low estimation error in a wide range of plausible MR scenarios. Quantile IV is distinctive in its ability to estimate nonlinear and heterogeneous causal effects and offers a flexible approach for subgroup analysis. Applying Quantile IV, we investigate the impact of circulating sclerostin levels on heel bone mineral density, osteoporosis, and cardiovascular outcomes in the UK Biobank. Employing various MR estimators and colocalization techniques that allow multiple causal variants, our analysis reveals that a genetically predicted reduction in sclerostin levels significantly increases heel bone mineral density and reduces the risk of osteoporosis, while showing no discernible effect on ischemic cardiovascular diseases. Quantile IV contributes to the advancement of MR methodology, and the case study on the impact of circulating sclerostin modulation contributes to our understanding of the on-target effects of sclerostin inhibition. ### Competing Interest Statement JH is an employee of Recursion during the course of this work and has received optional ownership interest in Recursion. BJA is a consultant for Eli Lilly, Silence Therapeutics, Editas Medicine and Novartis and has received research contracts from Pfizer, Ionis Pharmaceuticals, Eli Lilly and Silence Therapeutics ### Funding Statement MAL is supported by a fellowship from the Canadian Institute of Health Research (CIHR). BJA holds a Senior Scholar Award from the Fonds de recherche du Quebec: Sante. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study only uses publicly available summary statistics or individual-level data from the UK Biobank. The UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this study is from the UK Biobank accessed under application #20168. The access procedure are described on the UK Biobank website at: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access