Improving the measurement and detection of serious adverse drug reactions in databases of stored electronic health records

....................................................................................................................................... 3 1 Background ....................................................................................................................... 15 1.1 Introduction .................................................................................................................. 15 1.2 Adverse drug reactions ............................................................................................... 15 1.2.1 Definition, epidemiology and public health impact .............................................. 15 1.2.2 The genetics of adverse drug reactions .............................................................. 16 1.3 Drug safety, pharmacoepidemiology and databases of stored electronic health records .................................................................................................................................... 16 1.3.1 Detection of adverse drug reactions during drug development .......................... 16 1.3.2 Adverse event reporting and signal detection ..................................................... 17 1.3.3 Pharmacoepidemiological studies of adverse events and databases of stored electronic health records ..................................................................................................... 18 1.3.4 Predictive genetic testing for drug safety ............................................................ 20 1.3.5 Adaptive licensing ............................................................................................... 21 1.4 Serious drug-induced liver injury ................................................................................. 22 1.4.1 Drug-induced cholestatic liver injury ................................................................... 23 1.5 Thesis aim, rationale and objectives ........................................................................... 24 1.5.1 Aim ...................................................................................................................... 24 1.5.2 Rationale ............................................................................................................. 24 1.5.3 Objectives ............................................................................................................ 25 1.5.4 Organisation of the thesis ................................................................................... 25 1.6 Chapter 1 Summary .................................................................................................... 26 2 Systematic review on the identification of individuals with cholestatic liver injury for epidemiological studies utilising databases of stored electronic patient health records 27 2.1 Introduction and Aims ................................................................................................. 27 2.2 Methods ....................................................................................................................... 27 2.2.1 Search strategy ................................................................................................... 27 2.3 Results ........................................................................................................................ 32 2.3.1 Description of studies included in the final review .............................................. 34 2.3.2 Overall approach to identification of individuals with cholestatic liver injury ....... 42