VictorJuiz/thesis huggingface dataset:
Topic modelling using hierarchical priors on feature distributions with application to genetic association studies

Multiple lines of evidence indicate that different diseases have shared pathological pathways. From an epidemiological perspective, certain diseases frequently cooccur within the same individuals. From a genetic perspective, the phenomenon of pleiotropy is widespread. In this work, I introduce, test and apply statistical methodology that aims to bridge these two perspectives and to better define how genetic risk factors influence the broad spectrum of common human diseases.
The approach taken is to use topic modelling applied to routine healthcare data, specifically hospital records encoded by the International Classification of Disease Version 10 (ICD10) ontology. Due to the sparse nature of the data, we introduce statistical methodology that uses the hierarchical structure of the ontology to create a prior on feature distributions. We combine this with Bayesian non-negative matrix factorization to develop our own methodology, named “treeLFA”, to model the multi-morbidity patterns of common diseases as disease “topics”. The estimated individuals’ weights for topics then provide derived phenotypes for the analysis of association.
We first introduce the methodology and the computational methods used to estimate parameters. Using simulation, we then demonstrate that treeLFA outperforms other commonly used topic models in situation where the training data is small or individuals frequently have multiple topics. We also assess treeLFA’s performance under various aspects of mis-specification.
We then apply the methodology to data from UK Biobank (UKB), finding that inferred disease topics align well with current medical understanding and provide additional power for genetic discovery (69 new loci identified for common diseases in the UKB). However, by comparing patterns of genetic association of topics and single disease codes, we find that the majority of genetic effects (about two thirds of topic-associated loci) are readily identified at the single code level. Nevertheless, we also show that, for about two thirds of diseases, genetic risk prediction can be improved by leveraging the GWAS results for topics. We also explore modelling multi-morbidity at different resolutions (i.e., with different numbers of topics) and find that inference results and most associations are stable across different resolutions.
In summary, treeLFA provides a new data-driven approach to model the hidden structure of the high-dimensional and sparse phenome data in biobanks. In addition, its inference results provide additional insights to genetic and epidemiological studies, in terms of both prediction of risks and the understanding of biology.

Keywords: HLA typing
multimorbidity
topic modeling
treeLFA
topic-GWAS
Advisor: McVean , G
Gerton, L
Mentzer , A
Modelling the rocking dynamics of objects with irregular geometry

Free-standing objects are all around us. Computer monitors and towers, bottles, kitchen containers, museum artifacts, tables, chairs, and medical equipment are just a few of the objects which may be prone to rocking and toppling due to external forcing or support excitation. Many objects with irregular geometry are able to rock about their edges and vertices, twist, topple, and impact their support, and could thus pose hazards to the integrity of the object and also to surrounding structures, objects, and even human life. However, previous rocking models are not adequate to handle objects with irregular geometry due to their assumptions. Thus, this thesis aims to fill the knowledge gap of the dynamics of irregular objects by introducing new rocking models for planar and 3-D rocking which take into account the full irregular geometry of such objects. The planar rocking model assumes a rigid body and rigid support and fully considers sliding, free fight, and a variable location for the impulses at impact. The 3-D model similarly uses a rigid body and rigid support with a variable location for the impulses, but assumes no sliding or free fight, as it focuses on the pure rocking response of such systems and how this can lead to substantially more complicated responses of the body when taking into account the geometry. Examples of objects in both planar and 3-D rocking are provided and conclusions are drawn on the importance of irregular geometry, sliding, free fight, and a variable location for the impulse. Finally, the 3-D model is used to describe the rolling dynamics of various objects with curved geometry, offering a new dynamic model to describe these motions that is efficient and qualitatively similar to the experimental dynamic responses.

Keywords: rigid body dynamics
rocking
irregular geometry
rocking dynamics
engineering dynamics
Advisor: Chatzis, E
Dietary fibre manipulation as a potential endogenous mechanism of radiosensitisation in bladder cancer

New non-toxic radiosensitisers are needed in the treatment of muscle-invasive bladder cancer because elderly patients are very vulnerable to chemotherapy-related toxicity of currently available radiosensitisers. Our previous study showed that high fibre diets sensitised RT112 xenografts to irradiation by modifying the gut microbiota and this phenotype was positively correlated with Bacteroides acidifaciens (BA) abundance. As the gut microbiota can enhance anti-tumoural immune responses, I hypothesised that dietary fibre manipulation and its effects on the gut microbiota can radiosensitise tumours via microbiota secretion of metabolites and/or immunomodulation.
In preclinical mouse experiments, psyllium plus resistant starch (RS) or psyllium plus inulin significantly decreased tumour size (P=0.007 and <0.001, respectively) and they enhanced tumour control when combined with ionising radiation (IR; P<0.001 and 0.028, respectively) compared to 0.2% cellulose.
Psyllium plus inulin raised Bifidobacterium abundance (P<0.001), CD8+ cell numbers (P=0.024), and caecal inosine levels (P<0.001), which have been shown to enhance immunotherapy efficacy. There was a significant correlation between immune response and tumour control versus Clostridiales order abundance. Systemic GM-CSF (granulocyte-macrophage colony-stimulating factor) and IL-2 cytokines levels were increased by IR. The caecal butyrate level was associated with the tumour control in the psyllium plus inulin group of both non-irradiated and irradiated mice (P=0.041). It is noted that threitol also negatively correlated with IR response. Psyllium plus RS increased several metabolite levels that have anti-tumourigenic properties, and significantly radiosensitised the tumours (P=0.004). Furthermore, the two diets mitigated the radiation injury caused by 14 Gy in intestinal crypt assays (P=0.08 and 0.011). All psyllium-containing diets increased caecal short-chain fatty acids (SCFAs, P<0.001), and prevented the delayed weight gain seen with 0.2% cellulose after IR.
We previously found that inulin enhanced the relative abundance of BA. Based on cell experiments, the supernatants of co-cultures of BA and Faecalibactrium prausnitzii (FP, butyrate-producer) conferred greater cytotoxicity than BA alone (P<0.001) or co-cultures of Bifidobacterium (acetate-producer) and FP (P<0.001), and also increased histone acetylation levels. Bacterial supernatants of BA+FP increased DNA damage and delayed DNA repair following 2 Gy IR (P<0.05) and increased radiosensitivity of bladder tumour cells (P=0.008 at 8 Gy). Overall, I demonstrated that dietary fibre supplements radiosensitised bladder tumours, with associated gut microbiota modification and enhancement of immune responses and metabolite levels. Since psyllium plus either RS or inulin achieved a more favourable therapeutic ratio with improved tumour control with decreased side effects, I propose that dietary fibre supplements may be useful adjuncts to radiotherapy in patients with pelvic malignancy.

Advisor: Kiltie, A
Vallis, K
Data-driven discovery of Green's functions

Discovering hidden partial differential equations (PDEs) and operators from data is an important topic at the frontier between machine learning and numerical analysis. Theoretical results and deep learning algorithms are introduced to learn Green's functions associated with linear partial differential equations and rigorously justify PDE learning techniques.
A theoretically rigorous algorithm is derived to obtain a learning rate, which characterizes the amount of training data needed to approximately learn Green's functions associated with elliptic PDEs. The construction connects the fields of PDE learning and numerical linear algebra by extending the randomized singular value decomposition to non-standard Gaussian vectors and Hilbert--Schmidt operators, and exploiting the low-rank hierarchical structure of Green's functions using hierarchical matrices.
Rational neural networks (NNs) are introduced and consist of neural networks with trainable rational activation functions. The highly compositional structure of these networks, combined with rational approximation theory, implies that rational functions have higher approximation power than standard activation functions. In addition, rational NNs may have poles and take arbitrarily large values, which is ideal for approximating functions with singularities such as Green's functions.
Finally, theoretical results on Green's functions and rational NNs are combined to design a human-understandable deep learning method for discovering Green's functions from data. This approach complements state-of-the-art PDE learning techniques, as a wide range of physics can be captured from the learned Green's functions such as dominant modes, symmetries, and singularity locations.

Keywords: PDE learning
Green's functions
deep learning
Advisor: Farrell, P
Rognes, M
Townsend, A
Exploring the molecular underpinnings of neuropathic pain in primary afferent subtypes

Dorsal root ganglia (DRG) neurons have been well described for their role in driving both acute and chronic pain. With cell bodies clustered in the spinal column, these neurons project from the periphery into the dorsal horn. Subtypes convert a range of stimuli into electrical signals, and have been traditionally defined by size, histological markers, projection pathways, and electrophysiological phenotypes. With the advance of sequencing technologies, DRG transcriptomes have been examined through whole ganglia, single cell, and more recently, deep subpopulation sequencing in naïve lines. Here, we study the deep transcriptional profiles of multiple murine DRG populations in acute and chronic pain states while considering sex interactions.
We have exploited currently available transgenics to label and purify subtypes after injury for high throughput sequencing. Using bulk tissue samples, we are able to circumvent the issues of low transcript coverage and drop-outs seen with single cell datasets, increasing our power to detect changes in gene expression.
In one experiment, we have studied the molecular changes in five populations, classified by their functional and molecular signatures in naive states. These include general nociceptors, peptidergic nociceptors, non-peptidergic nociceptors, C-LTMRs, and Ad + AB-RA-LTMRs. We see both stereotyped and unique subtype signatures in injured states after nerve injury at both an acute and chronic timepoint. While all populations contribution to a general injury signature, subtype enrichment changes can also be seen, possibly driven by the loss of transected NP neurons by 4 weeks. Within populations, there is not a strong intersection of sex and injury, but sex differences in na\"ive states - particularly in Ad + AB-RA-LTMRs - still contribute to differences in injured neurons.
Using an SNI model of neuropathic pain, ipsilateral DRG contain both injured and intact neurons. The contributions of these populations to pain have yet to be delineated. Mirroring the techniques above, we next used an Atf3creERT2 line to label and sort fluorescent neurons prior to RNA-seq. We have complemented this with a pilot snATAC-seq study, showing that neurons cluster by subtype in naive and injured states.
We have curated this data into an accessible, online platform. Together, this contributes a resource to the pain community to probe subpopulation and sex-specific differences after nerve injury at multiple timepoints.

Keywords: sensory neuroscience
neuropathic pain
bioinformatics
RNA-seq
scATAC-seq
Advisor: Tucker, S
Bennett, D
Baskozos, G
Systematics of the Stictocardia clade (Ipomoea L., Convolvulaceae)

Botanical monographs are comprehensive taxonomic accounts of a specific group of plants. This thesis reviews relevant taxonomic literature and investigates a subsumed genus – Stictocardia - nested within Ipomoea (Convolvulaceae), one of the species-rich genera of Angiosperms. A large number of specimens representing twelve out of 13 species of Stictocardia, both herbarium sheets and digital images from 35 herbaria, are the source of quantitative morphological data (115 samples) and leaf material for DNA sequencing (36 samples). Morphological characters and DNA sequence data are two lines of evidence that interact through reciprocal illumination within the scope of integrative taxonomy. Principal Component Analysis and Mann-Whitney test were conducted on several indistinct taxa to ensure rigorous hypothesis testing on species delimitation. Phylogenetic study consistently identifies seven species of Stictocardia in a clade named Stictocardia (non-italic) based on independent data sets - nrITS and plastome - and various inference methods (MP, A-ML and BI). This clade of seven species is characterised by a set of homoplastic morphological characters. These seven species are monographed for the first-time including clade circumscription, identification key, distribution maps and a comprehensive taxonomic account (nomenclature, description, illustration, habitat, notes and specimens seen). Conservation assessments based upon Area of Occupancy (AOO) and Extent of Occurrence (EOO) analyses, were conducted to this clade. In addition, four species of Stictocardia are recovered outside of the clade Stictocardia and more closely related to other species of Ipomoea. Two species require further investigation to resolve their placements whether inside or outside the clade Stictocardia.

Keywords: EOO
Stictocardia
Monograph
Ipomoea
AOO
Advisor: Scotland, R
Reginald Pole and the legations of 1537 and 1539 : diplomatic and polemical responses to the break with Rome

The thesis deals with the diplomatic career of Reginald Pole at the beginning of his time as a Roman cardinal. Pole's elevation to the cardinalate in 1536 and his quest to persuade Charles V and Francis I to help re-establishing Roman obedience in England are portrayed. Pole's two legations of 1537 and 1539 both failed, it is argued, because of the ongoing hostilities between the houses of Habsburg and Valois: neither the emperor nor the French king could afford to alienate the powerful English ruler, nor were they interested in taking up a costly and risky enterprise on behalf of religion. The differences between the two legations and the different reasons for their failing are discussed. The reaction of the English policy makers both to the legations themselves and to Pole's activities is also considered. The almost complete annihilation of Pole's family in England is linked with Pole's efforts against the English king, and it is shown that the Poles in England lost their lives not because of their alleged treasonable activities in combination with the so-called "Exeter Conspiracy" but because they were used as hostages by Henry VIII against Reginald Pole: it is argued that the "Exeter Conspiracy" is a misnomer, and that the two families involved suffered for reasons of raison d'état and personal revenge. Pole's major writings against the English king in the 1530s, De ecclesiasticae unitatis defensione and the Apologia ad Carlum Quintum, are then examined with regard to Pole's political maxims and his use of anti-Machiavellism in his fight against the English schism. Overall, it is argued in the thesis that Pole was an able politician whose failure is to be explained by the untimeliness of his attempts to unite Charles V and Francis I in a fight for religion and by his own exclusively religious motivation in political affairs.

Keywords: Reginald Pole
16th century
polemical
break with Rome
diplomatic
legations
sixteenth century
Rome
Advisor: Loach, J
Learning and inference over relational data

Relational data is ubiquitous in modern-day computing, and drives several key applications across multiple domains, such as information retrieval, question answering, recommendation systems, and drug discovery. As a result, a main research question in artificial intelligence (AI) is to build models that exploit relational data in an efficient and reliable way, while injecting the relevant inductive biases and being robust to input noise. In recent years, neural models such as graph neural networks (GNNs) and shallow node embedding models have enabled significant breakthroughs in learning representations over relational structures. However, the abilities and limitations of these systems are not completely understood, and several challenges remain to endow these models with reliability guarantees, enrich their relational inductive bias, and apply them in more challenging problem settings. In this thesis, we study learning and inference over relational data. More specifically, we analyse the properties and limitations of existing models both theoretically and empirically, and propose new approaches with improved relational inductive bias and representation power.

Keywords: Knowledge graph embedding models
Knowledge base completion
Knowledge graph completion
Graph neural networks
Message passing neural networks
Graph representation learning
Graph machine learning
Relational data
Advisor: Ceylan, I
Lukasiewicz, T
Modelling and monitoring the behaviour of predators and prey in the context of anthropogenic risk

Predator-prey dynamics help shape the populations and behavioural interactions of wildlife at all trophic levels. Risk effects are animals’ behavioural responses to the risk of predation and their associated costs. Humans impose risk effects on both predators and prey, and it’s important to understand those effects when developing conservation strategies. Here I examine the behaviours of Uganda kob (Kobus kob thomasi) and African lions (Panthera leo), both living in carnivore-ungulate systems within human-dominated landscapes. By recording kobs’ flight distances relative to road networks and snare poaching activity, I find that kobs’ antipredator responses do not seem to be affected by proximity to roads or local snaring intensity. However, sexual differences in flight distance may suggest intraspecific competition influences kobs’ risk tolerance. I also develop a model of lions’ energy expenditure over space and time as a result of habitat covariates. The construction of behavioural decision-making models could allow researchers to identify how lions and other carnivores perceive anthropogenic risk, given enough data to distinguish risk effects from other variables influencing their decisions. The aim of this thesis is to better understand the extent to which humans influence the behaviours of predators and prey and how human activities influence other animals’ perceptions of risk in dynamic ways.

Keywords: African lion
behavioural ecology
Advisor: Macdonald, D
Bonsall, M
The holographic swampland and other topics in string phenomenology

The main topic of this thesis is to explore the consistency and structure of realistic, 4d vacua of String Theory through the AdS/CFT correspondence. As a first step, we investigate whether Swampland constraints on the low-energy dynamics of weakly coupled, moduli-stabilised string vacua in AdS can be related to inconsistencies of their putative holographic duals or, more generally, recast in terms of CFT data. We find that various swampland consistency constraints are equivalent to a negativity condition on the sign of certain mixed anomalous dimensions. This condition is similar to well-established CFT positivity bounds arising from causality and unitarity, but not known to hold in general. The studied scenarios include LVS, KKLT, the type IIA DGKT flux vacua and both perturbative and racetrack stabilisation. We also point out an intriguing connection to the Swampland Distance Conjecture, both in its original and refined versions. A second, unexpected consequence of this analysis is that the CFT data for some of these vacua takes a universal form, independent of the compactification details. For the type IIA examples, we then give a concise argument that supersymmetric AdS DGKT flux vacua on general Calabi-Yaus always have integer conformal dimensions for all low-lying scalar primaries in the dual CFT. These integers are independent of any compactification details, such as the background fluxes or triple intersection numbers of the compact manifold. We give a tentative discussion of the origin of these integers and effects that would modify these results.
In the last part of the thesis, we take a more phenomenological approach and study the overshoot problem in the context of post-inflationary string cosmology (in particular LVS). We show that in LVS, provided the existence of a large hierarchy between the inflationary and the weak scales, initial seed radiation will localize the system onto a tracker solution where the problem is solved. The consistency require- ment of ending in a stable vacuum containing the weak hierarchy therefore gives a preference for high inflationary scales – an anthropic argument, if one likes, for a large inflation/weak hierarchy. We discuss various origins (both universal and model- dependent) of the initial seed radiation, with a particular emphasis on the possibility of having an LVS fundamental string network.

Keywords: string cosmology
holography
string phenomenology
swampland
Advisor: Conlon, J