249 research outputs found

    Weak-Instrument and Pleiotropy-Robust Methods for Mendelian randomisation, with Applications to Mental Health

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    This PhD dissertation focused on developing and applying new methods for Mendelian Randomisation (MR), a technique that uses genetic variants as instrumental variables in order to assess causal effects of exposures on health outcomes. The major focus of the applied research is psychiatric research and mental health, with a range of analyses that address the topic of causal risk factors for depression with the use of these genetics-informed methods. The first contribution of this dissertation is the development of new methods for pleiotropy-robust MR by leveraging sex specificity of phenotypes. These methods allow for more accurate and robust estimation of causal effects by cancelling out potential pleiotropic effects of genetic instruments. The second contribution is a new method for appraising high-dimensional correlated variables in multivariable MR. This method allows for the inclusion of multiple correlated variables as exposures in MR analyses, through a transformation to groups of exposures that have attractive statistical properties and biological meaning. Finally, the dissertation provides an applied analysis of how inflammation and BMI affect a range of depression phenotypes with cutting-edge methods. This analysis replicates previous results on the harmful effects of overweight on mood and challenges the independent effect of inflammation as proxied by CRP. The introduction of the dissertation is divided into two parts. The first part provides a walkthrough of the epidemiological concepts of bias, randomisation, and causal inference with observational data. The second part is a specific introduction to MR, including its underlying assumptions and limitations, as well as detailed discussion of developments that make it more robust. Overall, this dissertation contributes new methods and applied analyses to the field of MR, with potential implications for researchers and practitioners

    The use of scRNA-seq to characterise the tumour microenvironment of high grade serous ovarian carincoma (HGSOC)

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    High Grade Serous Ovarian Carcinoma (HGSOC) is the most common type of ovarian cancer. Patients with this disease typically experience relapse in their disease following surgical debulking and initially effective chemotherapy. HGSOC has been intensely studied at the genomic and transcriptomic levels in efforts to advance knowledge of the biological mechanisms that drive the behaviour of this malignancy, and so that new treatment strategies may curb the disease progression relapse. This body of work contributes an optimised protocol for generating robust 10X scRNA-seq libraries from fresh and preserved HGSOC tissue, aiming to dissect the cellular heterogeneity of HGSOC’s Tumour microenvironment (TME). Through unsupervised clustering analysis, it uncovers distinct cellular communities, elucidates transcriptomic signatures across HGSOC tumours, and augments bulk RNA-seq datasets via computational deconvolution, enhancing understanding of HGSOC's cellular complexity across an expanded clinical cohort. The sequencing and analysis of these HGSOC patient tumours revealed 11 distinct cell types, including 2 that are novel in this tumour type; namely ciliated epithelial cells and metallothionein expressing T-cells. These 11 distinct cell types can be broadly categorised into 3 TME components (Tumour, Stroma and Immune) as in other previous tumour scRNA-seq studies. An additional analysis of these components examined the copy number variation (CNV) in the profiled cells and revealed HGSOC tumour cells to be mostly aneuploid while ciliated epithelial cells were diploid. A novel integrative subcluster analysis of HGSOC aneuploid tumour cells identified several apparently tumourigenic gene expression signatures. These include a KRT17+, protease inhibitory signature, an increased cellular metabolism signature, and an immune-reactive signature. Additionally, a ciliated cluster re-emerged within the HGSOC tumour cells, even though the diploid ciliated epithelial cells were not included in the integrative analysis. Finally, the high granularity of HGSOC cellular composition revealed by scRNA-seq is utilised to perform deconvolution analyses to estimate cellular proportions and infer the TME of earlier bulk RNA-seq profiled HGSOC tumour samples. This investigation of earlier sequenced HGSOC samples revealed heterogeneity in the proportions of the TME compartments across the patient cohorts. Survival analysis using these inferred cellular proportions suggest that immune cell presence alone is not associated with survival, but metastatic fibroblast burden in tumour samples is significantly associated with worsen overall survival in HGSOC patients. In conclusion, the laboratory protocol, the scRNA-seq datasets produced, and their analysis and application presented in this work expands the collective knowledge base of HGSOC. Specifically by characterising the cells of the HGSOC tumour microenvironment, and nuances of expression signatures of the malignant cells. The deconvolution approach showcases how scRNA-seq data can expand the clinical utility of earlier RNA-seq HGSOC datasets in a way that is scalable

    COVID-19 Booster Vaccine Acceptance in Ethnic Minority Individuals in the United Kingdom: a mixed-methods study using Protection Motivation Theory

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    Background: Uptake of the COVID-19 booster vaccine among ethnic minority individuals has been lower than in the general population. However, there is little research examining the psychosocial factors that contribute to COVID-19 booster vaccine hesitancy in this population.Aim: Our study aimed to determine which factors predicted COVID-19 vaccination intention in minority ethnic individuals in Middlesbrough, using Protection Motivation Theory (PMT) and COVID-19 conspiracy beliefs, in addition to demographic variables.Method: We used a mixed-methods approach. Quantitative data were collected using an online survey. Qualitative data were collected using semi-structured interviews. 64 minority ethnic individuals (33 females, 31 males; mage = 31.06, SD = 8.36) completed the survey assessing PMT constructs, COVID-19conspiracy beliefs and demographic factors. 42.2% had received the booster vaccine, 57.6% had not. 16 survey respondents were interviewed online to gain further insight into factors affecting booster vaccineacceptance.Results: Multiple regression analysis showed that perceived susceptibility to COVID-19 was a significant predictor of booster vaccination intention, with higher perceived susceptibility being associated with higher intention to get the booster. Additionally, COVID-19 conspiracy beliefs significantly predictedintention to get the booster vaccine, with higher conspiracy beliefs being associated with lower intention to get the booster dose. Thematic analysis of the interview data showed that barriers to COVID-19 booster vaccination included time constraints and a perceived lack of practical support in the event ofexperiencing side effects. Furthermore, there was a lack of confidence in the vaccine, with individuals seeing it as lacking sufficient research. Participants also spoke of medical mistrust due to historical events involving medical experimentation on minority ethnic individuals.Conclusion: PMT and conspiracy beliefs predict COVID-19 booster vaccination in minority ethnic individuals. To help increase vaccine uptake, community leaders need to be involved in addressing people’s concerns, misassumptions, and lack of confidence in COVID-19 vaccination

    Microbial biogeography of 1,000 geothermal springs: spatial, temporal, and allopatric dynamics of extremophiles in the Taupō Volcanic Zone, Aotearoa-New Zealand

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    Geothermal springs are model ecosystems to investigate microbial biogeography as they represent discrete, relatively homogeneous habitats, are distributed across multiple geographical scales, and span broad geochemical gradients. This thesis reports the largest consolidated study of geothermal ecosystems to determine causal factors that influence both spatial and temporal biogeographical patterns of extremophiles. Bacterial and archaeal community composition, 46 physicochemical parameters, and metadata from 925 geothermal spring water columns across the Taupō Volcanic Zone (TVZ), Aotearoa-New Zealand were measured. Standardised methodologies were employed to define microbial diversity via 16S rRNA gene amplicon sequencing, and associated physicochemistry, ensuring confidence in sample comparison. Over an 8,000 km² spatial scale, multivariate statistical analyses determined diversity was primarily influenced by pH at temperatures 70 °C. Further, community dissimilarity increased with increasing geographic distance across the region, highlighting niche selection driving assembly at a local scale. This research also describes the first comprehensive temporal study of geothermal microbial communities in Aotearoa-New Zealand. One hundred and fifteen water column samples from 31 geothermal features were taken over a 34-month period to ascertain microbial community stability, community response to both natural and anthropogenic disturbances in the local environment, and temporal variation in spring diversity across the pH range found in the TVZ. Results indicated temperature and associated groundwater physicochemistry were the most likely parameters to vary stochastically in these geothermal features, with community abundances rather than composition more readily affected by a changing environment. However, variation in pH (pH ±1) had a more significant effect on community structure than temperature (±20 °C), with alpha diversity failing to be an adequate measure of temporal microbial disparity in geothermal features outside of circumneutral conditions. While a substantial physicochemical disturbance was required to shift community structures at the phylum level, geothermal ecosystems were resilient at this broad taxonomic rank and returned to a pre-disturbed state if environmental conditions re-established. The discovery that genus (phylum Aquificota) exhibited the greatest average abundance (11.2 %) and distribution (74.2 %) of all taxa across 925 geothermal ecosystems in the TVZ, and an apparent absence of this taxon in global geothermal systems, led to the hypothesis that allopatric speciation enabled the evolution of an endemic bacterial genus to Aotearoa-New Zealand. Maximal read abundance of occurred in geothermal features with pH 4-6, 50-70 °C, and low oxidation-reduction potentials, highlighting a specific environmental niche that could enhance habitat isolation. Genomic analysis of the only characterised species for the genus, CP.B2ᵀ, confirmed a chemolithoautotrophic metabolism dependent on hydrogen oxidation. While similarity between populations illustrated dispersal was not limited across the TVZ, extensive amplicon, metagenomic, and phylogenomic analyses of local and global microbial communities from DNA sequence databases indicated is geographically restricted to the Aotearoa-New Zealand archipelago. It was concluded that combined geographical and physicochemical constraints prevent this taxon from distributing on a broader scale, resulting in the establishment of an endemic bacterial genus. Collectively, the findings from this thesis provide an insight into ecological behaviour in geothermal springs, highlighting the diverse controls between different taxa within the same habitat-type, and expand understanding of microbial biogeography in extreme ecosystems

    A Meeting of Minds: In Recognition of the Contributions of Randall J. Cohrs

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    A Special Issue in memory of Randall J. Cohrs, Ph.D. Topics include original research reports on a variety of viruses as well as reviews and commentaries on Randy’s contributions to many investigations

    Cyanotoxins in Bloom

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    At present, cyanobacteria and their toxins (also known as cyanotoxins) constitute a major threat for freshwater resources worldwide. Cyanotoxin occurrence in water bodies around the globe is constantly increasing, whereas emerging, less studied or completely new variants and congeners of various chemical classes of cyanotoxins, as well as their degradation/transformation products are often detected. In addition to planctic cyanobacteria, benthic cyanobacteria, in many cases, appear to be important toxin producers, although far less studied and more difficult to manage and control. This Special Issue highlights novel research results on the structural diversity of cyanotoxins from planktic and benthic cyanobacteria, as well as on their expanding global geographical spread in freshwaters
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