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Mendelian Randomization


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Table of Contents

I Understanding and Performing Mendelian Randomization1. Introduction and Motivation
2. What is Mendelian Randomization?
3. Assumptions for Causal Inference
4. Estimating a Causal Effect from Individual-level Data
5. Estimating a Causal Effect from Summarized Data
6. Interpretation of Estimates from Mendelian Randomization

II Advanced Methods for Mendelian Randomization7. Robust Methods using Variants from Multiple Gene Regions
8. Other Statistical Issues for Mendelian Randomization
9. Extensions to Mendelian Randomization
10. How to Perform a Mendelian Randomization Investigation

III Prospects for Mendelian Randomization11. Future Directions

About the Author

Dr Stephen Burgess is an MRC Investigator at the MRC Biostatistics Unit in Cambridge, an internationally acclaimed research institute in medical statistics. He holds a Wellcome Trust Sir Henry Dale Fellowship, and leads a research group which aims to develop statistical methods that use genetic variation to answer clinically relevant questions about disease aetiology and prevention. He was previously located at the Cardiovascular Epidemiology Unit in the University of Cambridge, where he held a Sir Henry Wellcome Postdoctoral Fellowship. His main research interests are in causal inference and evidence synthesis.

Professor Simon Thompson was Director of Research in Biostatistics at the Cardiovascular Epidemiology Unit in the University of Cambridge until his retirement in 2018. He is a Fellow of the Academy of Medical Sciences. From 2000-2011, he was Director of the MRC Biostatistics Unit in Cambridge. He held previous academic appointments at the London School of Hygiene and Tropical Medicine, and as the first Professor of Medical Statistics and Epidemiology at Imperial College London. In retirement, he has cut down his research activities substantially, and is not getting involved in new research projects.


Praise for the First Edition"Mendelian randomization (MR) may be regarded as a modern integration of the concepts of instrumental variables from the field of economics with Mendel’s laws of inheritance in the field of genetics. … Stephen Burgess, a mathematician, and Simon Thompson, a biostatistician, present the fundamental ideas and methods behind MR in an easy-to-read book for researchers from different backgrounds such as statistics, genetics, or clinical research. The book is the first and currently only book published on MR, in which the authors not only summarize MR methodology but also share their experience with real data analysis in the field of MR for cardiovascular diseases. … The book has been very well written, and the authors have done an excellent job of bridging the gap between researchers from various backgrounds. … Overall, the book provides the most comprehensive MR resource to date, and it is a valuable resource for researchers even at the graduate level."
—Sandeep Grover, Universität zu Lübeck, in Biometrical Journal, September 2017"… The topic of the book is Mendelian Randomization (MR), a form of instrument variable (IV) analysis using genetic factors as instruments. … I enjoyed reading the book very much. The authors give an excellent overview of the assumptions and statistics underlying MR and the book achieves a good balance between methods and theory, case studies and the discussion of practical issues. … I particularly liked the fact that most if not all of the relevant models, methods and analytical derivations on IV analyses are in a single book. The authors are very precise in their definitions and discuss the issue of when ‘causal’ can be used in the context of inference and, importantly, when not. … In summary, MR analyses have an important role to play in making sense of epidemiological observations and we can expect a plethora of applications in the near future. This book is a thorough practical guide to their assumptions, inference and pitfalls."
—Peter M. Visscher, University of Queensland, in Australian & New Zealand Journal of Statistics, June 2017"The authors have aimed their book at epidemiologists and medical statisticians but anyone with a basic knowledge of regression will understand most of the contents, because the algebra is kept to a minimum and emphasis is on explaining the ideas that underlie MR…will serve as an excellent introduction to Mendelian randomization for anyone who wants to understand the underlying statistical issues…"
—John Thompson, University of Leicester, in Biometrics, March 2017"Mendelian Randomization, by Stephen Burgess and Simon Thompson, represents a compact and accessible resource for Mendelian randomization, providing exactly what one needs to know in a logical, clear, very thorough, and yet pragmatic way. This book will appeal to applied researchers interested in learning more about Mendelian randomization as well as methodological researchers who work in the area. Those new to the field will find that this book covers everything they need to know, from designing the study (e.g., choosing the "instruments" and considering different options for pooling data across multiple studies) to investigating whether the assumptions may hold, analyzing the data, and interpreting the results… Researchers interested in methods for Mendelian randomization will find this book equally useful in bringing together methodological findings published across different disciplines (genetics, epidemiology, statistics, and econometrics), in an articulate and comprehensive way… Being targeted to epidemiologists and medical statisticians with diverse backgrounds, no prior knowledge of genetics is required, and the book explains in very simple terms the basic concepts needed to understand and apply Mendelian randomization… I really enjoyed reading this book and highly recommend it to anyone with an interest in Mendelian randomization."
—Cosetta Minelli, Imperial College London, in The American Statistician, August 2016" . . . the book is well written, in clear language and has many real data analysis examples. This book is an excellent introduction for those who want to learn more about mendelian randomization and a great guide for those who want to perform analysis, including methodological researchers who work in the area. I highly recommend the book to anyone interested in learning more about mendelian randomization."
_Patrícia Soares, ISCB Book Reviews, September 2022"With the rapid advancement in human genetics and the availability of extensive genetic data, this book presents essential concepts for utilizing genetic data to achieve randomization using observational study data. This new edition was needed to address the use of summary statistics data and two-sample Mendelian randomization, which are becoming increasingly popular."— Azeez A Alade, BDS, MS, University of Iowa College of Public Health

"In this regard, Mendelian Randomization by Stephen Burgess and Simon G. Thompson (2021, second edition) is a must-read for anyone interested in MR. This book provides a broad introduction to the field, covering the basics as well as advanced topics in MR methodology, making it an ideal textbook for students and an essential reference for researchers new to the field. In addition to its introductory value, advanced readers can also benefit from this book, as it reviews the state-of-the-art MR methods and lays out the potential future developments of MR."
~Biometrics, Chia-Yen Chen, Biogen

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