Our three winners share details of their award-winning dissertations:
Meta-analysis to determine effective interventions for post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) is a common mental disease, but access to face-to-face psychological service is limited. Online interventions thus provide alternative mental health services for PTSD patients.
My dissertation was a meta-analysis review of 46 randomized controlled trials published in English or Chinese on Internet-based treatment for post-traumatic stress since 2000. Seven classes of online interventions, including cognitive behaviour therapy (CBT), expressive writing, Interapy, cognitive performance tasks, psychosocial interventions, psychoeducation and mindfulness were analysed. Four primary outcomes were examined: PTSD summary score, intrusion, avoidance and hyperarousal. Special groups of patients such as parents and cancer patients were also included. Separate meta-analyses were conducted for trials involving active and passive controls.
The results show that CBT and Interapy are most effective compared to passive controls (PTSD sum and subscale score: Hedges’ g = 0.60 to 0.94, all p < 0.001), followed by psychosocial interventions and expressive writing (PTSD sum score: Hedges’ g = 0.45 to 0.53, all p < 0.05). Online interventions are better than passive controls but not superior to active controls. The dropout rates indicate that online interventions for PTSD are well accepted. Subgroup analyses show that differences between CBT for subgroup population are not significant (Cancer vs. non-cancer: p = 0.960; Parental vs. non-parental: p = 0.867). The results for online interventions for post-traumatic stress are promising, but subgroup analyses could only be done for parents and cancer patients because of limited number of trials in other subgroups.
Further investigations into the effects of widening and bridging different therapeutic modes for different patients, as well as the effect of online interventions on negative cognitions after PTSD and post-traumatic growth are necessary. In the long run, it would be best to develop individualized online interventions according to trauma type and personality.
Comparison of home and clinic blood pressure readings in pregnancy – a secondary analysis of the BUMP trials
Blood pressure monitoring is an important part of the routine screening program during pregnancy. The traditional modality for blood pressure measurement is a clinic blood pressure performed by the clinician or midwife. Self-monitoring of blood pressure at home is becoming more popular and makes frequent measurements possible in a well-known environment. It is debated whether home and clinic blood pressure measurements in pregnancy are equivalent measures. The International Society for the Study of Hypertension in Pregnancy (ISSHP) consider home blood pressure readings to be 5 mmHg lower than clinical readings and recommend a threshold for hypertension at ≥135/85 mmHg for home readings based on expert opinion. However, the evidence base to guide such recommendations is sparse.
It is well known that some people have white coat hypertension (WCH) defined by an elevated blood pressure in the clinic and normal values at home readings. Masked hypertension (MHT) denotes the opposite situation with only elevated blood pressures at home readings. It has been suggested that WCH and MHT increases the risk of adverse pregnancy outcomes, but the evidence is limited.
The dissertation aimed to compare the self-monitored blood pressure readings at home with the clinical readings and explore any difference between the two modalities. Furthermore, to evaluate the risk of adverse outcomes in women with WCH and MHT during pregnancy.
The dissertation was based on a secondary analysis of the BUMP 1 and 2 trials (Blood Pressure Monitoring in High Risk Pregnancy to Improve the Detection and Monitoring of Hypertension) which comprised a large cohort of around 1.200 pregnant women randomised to self-monitoring of blood pressure at home alongside usual antenatal care including clinic blood pressure measurements.
This secondary analysis of the BUMP trials is the largest study to date comparing clinic and home blood pressure readings. The risk of adverse outcome (e.g. preeclampsia and a lower birth weight) was increased in pregnancies with WCH and MHT.
No clinically significant difference was found between clinic and home blood pressure readings in normotensive higher risk pregnancies from gestational week 20 until 40. Based on these results, clinic and home blood pressure readings should be considered equal during pregnancy in normotensive women. Accordingly, the results suggest that the threshold for hypertension should be the same for both modalities.
Kasper would like to thank his supervisor, Katherine Tucker, for support and valuable advice, as well as Professor Richard McManus for sharing data from the BUMP trials.
Leveraging genetic data to investigate the effect of Tumour Necrosis Factor Receptor 1 inhibition on cardiovascular disease: A cis-Mendelian randomization study
Cardiovascular disease is the leading cause of death worldwide and so there is a need to develop new and effective treatments for coronary artery disease, ischaemic stroke, atrial fibrillation, and heart failure. Inflammation is increasingly recognised as a process that drives the development of cardiovascular disease. Developing drugs that block inflammatory proteins may therefore be effective in treating cardiovascular disease.
One such inflammatory protein is tumour necrosis factor receptor 1, or ‘TNFR1’. Previous research in animals and observational data in humans suggests that drugs designed to block TNFR1 may be effective. However, animal models of disease are often not representative of disease in humans and observational data often confuse correlation with causation. Indeed, these limitations reflect a broader problem in drug development wherein most newly developed drugs ultimately fail to become approved for use in clinical practice, primarily because they aren’t truly effective when eventually tested in large numbers of humans.
Novel approaches such as ‘Mendelian randomization’ (MR) and ‘colocalization’ overcome many of the limitations inherent to animal research and observational data and as a result are better able to distinguish causation from correlation. MR uses large-scale genetic data from humans to mimic and anticipate the effect of giving a drug on the disease of interest. An increasing amount of evidence shows that such methods are adept at predicting which drugs are likely to be truly effective and which drugs are not.
In this study, MR was used to mimic the effect of blocking TNFR1 to estimate its efficacy in the treatment of coronary artery disease, ischaemic stroke, atrial fibrillation, or heart failure.
The results do not support the proposition that blocking TNFR1 is likely to be an effective treatment for any of these four cardiovascular diseases.
Conducting large-scale RCTs of new drugs is extremely resource-intensive in terms of time, personnel, and financial investment. Prioritising the most promising novel drug targets is necessary to maximise the efficient use of such resources and to produce new treatments for clinical practice as quickly as is feasible. It follows that resources would be better spent on a more promising novel drug target for which the genetic evidence of a causal role in cardiovascular disease is stronger.
Skanda would like to thank his supervisors, Dipender Gill and David Nunan, for their generous guidance and feedback, and Annette Plὕddeman, for supporting his aspiration to undertake such an ambitious project in the first place. He would also like to thank his parents, who have always nurtured and supported his academic interests.