The safety of medicines can be difficult to investigate and often the only possibility is to conduct observational studies to see whether people receiving a drug are more likely to experience a side effect than people who do not receive the drug. Recently more and more of these studies have been done and frequently their results have been of major public health importance (e.g. the lack of association between MMR vaccine and autism). It is important that the results of these studies are reliable, and yet their underpinning methodologies are subject to many possible biases. I plan to investigate some of these methodologies and explore their biases, with the objective of increasing the reliability of drug safety studies. This will be achieved through at least four studies using an electronic database of anonymised patient medical records. The studies will investigate possible links between SSRI antidepressants and cerebral haemorrhage, tiotropium (a treatment for chronic obstructive pulmonary disease) and stroke, ezetimibe (a lipid lowering agent) and cancer and glitazone antidiabetics and myocardial infarction. This programme of research will therefore answer questions directly related to the safety of four drugs/drug classes and will improve methodological approaches to drug safety studies in the future.

Malaria parasites can persist for several months without causing symptoms, infecting mosquitoes and presenting a roadblock to transmission reduction. In in vitro studies, Plasmodium has been observed to increase its investment in parasite multiplication and transmission in the presence of competing strains and other factors affecting its chances of survival. These strategies may be controlled epigenetically and remain to be examined during natural infections. The aim of the proposed project is to bring together genetic, immunologic and microscopy-based assays with a state-of-the-art transcriptomic analysis pipeline to investigate Plasmodium falciparum persistence, virulence, and adaptation over the course of single infections.

Identifying and understanding the causes of death and disease is key to improving health world-wide. But establishing and quantifying cause-effect relationships is difficult. Suppose that a large number of HIV-positive patients are prescribed one of two drugs: a well-established drug, and a new competitor. If more patients on the new drug develop AIDS, can we conclude that it is inferior? What if the new drug was prescribed to more seriously ill patients? Indeed, the decision as to which drug to prescribe is likely to be influenced by a patient‘s CD4 count, a measure of immunity and hence disease severity. But the drugs work precisely by increasing CD4 count. Thus CD4 count affects the choice of drug and vice versa. This so-called causal feedback makes drawing causal inferences even more difficult; but methods have been developed to address this. This Fellowship aims to extend and apply these methods to address three important questions, each affected by causal feedback, in low- and middle-income country settings: (1) what is the causal effect of diarrhoea on stunted growth? (2) among HIV-positive individuals, what is the causal effect of antiretroviral therapy on hospitalisation? (3) what is the causal effect of maternal fertility on child mortality?