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Improving Polygenic Risk Score Accuracy Through Integration of Epistatic Gene-Gene and Gene-Gene-Environment Interactions for Type 2 Diabetes and Celiac Disease
No full textPolygenic diseases, as herein subject diseases Type 2 Diabetes (T2D) and Celiac disease (CD), result from numerous genetic variants with small effect sizes, where cumulative effects may be captured for polygenic risk scores (PRS). While PRS can help identify individuals at higher risk before disease onset, they currently explain only a small portion of heritability, limiting their accuracy and clinical utility. Current PRS methods seek to improve accuracy by increasing the number of variants analysed at the expense of decreased interpretability for the resulting thousands to hundreds of thousands of disease-associated variant SNPs. In this thesis such high dimensional data was used to develop a novel PRS pipeline to improve risk predictions for T2D and CD developed using a training population of 235,986 and 235,987 genotyped people in the UK Biobank respectively. This PRS pipeline was then applied to T2D and CD validation sets for improved PRS predictions.I addressed the high-dimensionality issue with feature reduction methods which utilises machine learning (ML) and importance algorithms to prioritize selected features for inclusion in association studies, the output of which are effect sizes (beta coefficients) used in PRS calculations. Currently published PRS methodology is limited to marginal effect sizes of single SNPs (G) calculated with genome-wide association studies (GWAS) prompting me to improve accuracy by integrating the contribution of epistatic SNP-SNP interactions (GxG) and SNP-SNP-environment interactions (GxGxE) into risk calculations.To enable such enhancements, I developed methods to include GxG and GxGxE features into four PRS risk calculations in the validation set, namely PRSG, PRSGxG, PRSG+(GxG), and PRSGxGxE, and integrated them into combined PRScr-mult calculation. PRScr-mult significantly enhances stratified risk predictions for T2D and CD across clinical quintiles and genetic decile risk thresholds to provide a more personalized risk assessment. The construction and utility of these are described in this thesis.Aim 1 (Chapter 3) of my thesis was to produce, validate and benchmark a workflow pipeline that accommodates genetic and environmental factors contributing to PRS. This pipeline included higher order interactions from an exhaustive epistatic interaction search followed by novel feature selection and GxGxE discovery methods. Feature weights were calculated with a penalised regression model and used to develop four PRS calculations. Aim 2 (Chapter 4) was to utilise the pipeline to improve accuracy and heritability for T2D and Aim 3 (Chapter 5) was to achieve the same outcome for CD.Overall, my novel approach improved PRS risk predictions, identifying an additional 27% and 10% cases at-risk in the validation set for T2D and CD, respectively, compared to the traditional PRSG. Finally, I used machine learning (ML) techniques to combine the PRS calculations, for an improved PRS I termed “PRScr-mult“ and identify unique genetic features driving risk within each PRS calculation.</p
‘Just because we can, does it mean we should?’ The integrated data infrastructure in Aotearoa, and its implications for Māori
No full textIntroduction. This paper discusses the importance of data in Māori society and Māori Data Sovereignty in Aotearoa New Zealand. Method. A descriptive case study is presented of the Integrated Data Infrastructure (IDI), a trove of interlinked and de-identified data about people that is the cornerstone for evidence-based policy decisions in Aotearoa New Zealand. The case study highlights existing issues Māori have with regards to the collection and use of their data. Analysis. The IDI is examined in relation to its historical and cultural context, taking into account the ongoing impacts of colonisation with respect to the ownership and management of data. Discussed are the safety mechanisms of the IDI, secondary data use, and social & cultural licence. Conclusion. The paper concludes by acknowledging that the right of Māori to exercise their self-determination of how data is collected, stored, and accessed remains aspirational and there is a need for Māori to have greater control over the data and who has access to it
Where is the Classroom? Digital Transformation and the Reverberation of Knowledge Spaces in Post-COVID Aotearoa
No full textCOVID-19, a global health crisis, facilitated rapid and major disruptive transformations in universities worldwide. In Aotearoa, learning management systems (LMS) such as Blackboard, Canvas, and Moodle became essential to universities in 2020 when we entered our first period of self-isolation to reduce the spread of SARS-CoV-2. These digital platforms transformed how knowledge circulated within the university and created new infrastructural nodes of connection between learners, educators, and content. Although COVID-19 restrictions have since eased, most lecturers have not quite pivoted back to pre-pandemic modes of teaching (due in part to "dual delivery" and lecture recording mandates from university leadership), and tertiary students have not yet returned to their pre-COVID lecture attendance rates, instead accessing course content through learning management systems. In 2022, we (Grant Otsuki and Lorena Gibson) began researching how these evolving digital infrastructures are reshaping knowledge ecologies at Te Herenga Waka - Victoria University of Wellington. Inspired by China Miéville's novel The City & The City - where citizens of distinct cities occupy the exact same physical space, but are trained from birth to psychologically "unsee" the people, buildings, and activities of the other city - this paper discusses interviewee responses to the question "Where is the classroom?", to argue that changing socio-technical infrastructures are changing classrooms into sites where multiple and conflicting educational realities coexist
Resilience through Vulnerability: Post-Disclosure Trajectories of Male Childhood Sexual Abuse Survivors
No full textResearch has identified key factors that facilitate or hinder disclosure of childhood sexual abuse (CSA) in male survivors and has shown that disclosure can lead to support and positive health outcomes. However, hegemonic masculine norms such as vulnerability avoidance can prevent men from disclosing and seeking support, therefore contributing to the invisibility of this population. There is a paucity of qualitative research that explores male survivors’ experiences of disclosure, what it means for them to disclose, and what happens to them post-disclosure. This study explored male CSA survivors’ experiences of disclosure and focused on the outcomes they attributed to disclosure. Phenomenological in-depth one-on-one interviews were conducted with ten adult male survivors in Aotearoa/New Zealand. Interpretive Phenomenological Analysis (IPA) identified the overarching theme of embracing vulnerability and seven super-ordinate themes related to disclosure and its outcomes. Disclosure was related to improved physical and mental health, optimised social relationships, and positive identity development. Facilitators of disclosure included social support, peer support, chance conversations, intoxication, and crisis points. The analysis also showed that although health professionals were influential in survivors’ recoveries, social networks were pivotal in providing support in more diverse ways. The findings highlight the need for: interconnected trauma-informed health services, initiatives that encourage male disclosure, professionals to adopt humanistic approaches, and training for people in survivor’s social networks so they can provide adequate and more accessible support. Overall, the study showed how structural components and interpersonal relationships can support male survivors and prevent or reverse the accumulation of health deficits that are often associated with CSA non-disclosure.</p
Nationwide Implementation of Unguided Cognitive Behavioral Therapy for Adolescent Depression: Observational Study of SPARX
No full textAbstract
Background
Internet-based cognitive behavioral therapy (iCBT) interventions are effective in clinical trials; however, iCBT implementation data are seldom reported.
Objective
The objective of this study is to evaluate uptake, adherence, and changes in symptoms of depression for 12‐ to 19-year-olds using an unguided pure self-help iCBT intervention (SPARX; Smart, Positive, Active, Realistic, X-factor thoughts) during the first 7 years of it being publicly available without referral in Aotearoa New Zealand.
Methods
SPARX is a 7-module, self-help intervention designed for adolescents with mild to moderate depression. It is freely accessible to anyone with a New Zealand Internet Protocol address, without the need for a referral, and is delivered in an unguided “serious game” format. The New Zealand implementation of SPARX includes 1 symptom measure—the Patient Health Questionnaire adapted for Adolescents (PHQ-A)—which is embedded at the start of modules 1, 4, and 7. We report on uptake, the number of modules completed, and changes in depressive symptoms as measured by the PHQ-A.
Results
In total, 21,320 adolescents aged 12 to 19 years (approximately 2% of New Zealand 12‐ to 19-year-olds) registered to use SPARX. Of these, 63.6% (n=13,564; comprising n=8499, 62.7% female, n=4265, 31.4% male, and n=800, 5.9% another gender identity or gender not specified; n=8741, 64.4% New Zealand European, n=1941, 14.3% Māori, n=1202, 8.9% Asian, n=538, 4.0% Pacific, and n=1142, 8.4% another ethnic identity; mean age 14.9, SD 1.9 years) started SPARX. The mean PHQ-A at baseline was 13.6 (SD 7.7) with 16.1% (n=1980) reporting no or minimal symptoms, 37.4% (n=4609) reporting mild to moderate symptoms (ie, the target group) and 46.7% (n=5742) reporting moderately severe or severe symptoms. Among those who started, 51.1% (n=6927) completed module 1, 7.4% (n=997) completed at least 4 modules, and 3.1% (n=416) completed all 7 modules. The severity of symptoms reduced from baseline to modules 4 and 7. Mean PHQ-A scores for baseline, module 4, and module 7 for those who completed 2 or more assessments were 14.0 (SD 7.0), 11.8 (SD 7.9), and 10.5 (SD 8.5), respectively; mean difference for modules 1-4 was 2.2 (SD 5.7; P<.001) and for modules 1-7 was 3.6 (SD 7.0; P<.001). Corresponding effect sizes were 0.38 (modules 1-4) and 0.51 (modules 1-7).
Conclusions
SPARX reached a meaningful proportion of the adolescent population. The effect size for those who engaged with it was comparable to trial results. However, completion was low. Key challenges included logistical barriers such as slow download speeds and compatibility with some devices. Ongoing attention to rapidly evolving technologies and engagement with them are required. Real-world implementation analyses offer important insights for understanding and improving the impact of evidence-based digital tools and should be routinely reported
Investigating Depth of Field Blur as a Strategy for Mitigating Cybersickness in Virtual Reality
No full textIn recent years, Virtual Reality (VR) on Head Mounted Displays (HMD) has been used in a wide variety of both serious and entertainment applications, including therapy, training, and gaming. However, while these technologies are more widely accessible than ever before, their use continues to be impeded by cybersickness, a condition characterized by symptoms including nausea, headaches, eye-strain, and dizziness. This malaise has historically stymied generations of VR devices, and presents a considerable barrier to the wide-scale adoption of VR.The rendering of Depth of Field (DoF) blur is a promising tool for mitigating cybersickness in HMD VR. This rendering manipulation can be applied to existing applications with relatively little developer effort or computational cost. DoF blur is theorized to improve comfort through multiple mechanisms, including the provision of a reliable depth cue to minimize the accommodation-vergence conflict, manipulation of visual attention to avoid discomfiting shifts in vergence, or allocation of visual attention to the periphery, and/or through masking rendering imperfections.This thesis involves four user studies, investigating the role and effect of DoF blur in mitigating cybersickness. Study 1 involves assessing the impact of DoF blur on the accommodation-vergence conflict in modern HMD using a sparse environment, in which monocular depth cues are omitted, and the view position and orientation are fixed. Results suggest that cybersickness in such a constrained environment and interaction scheme is minimal, and while DoF aids the speed and accuracy of depth perceptions, it has no effect on cybersickness. Study 2 expands on the design of Study 1, with the introduction of a more interesting visual background, some monocular depth cues, and wide angle head motions. Again, results show minimal cybersickness, suggesting that neither a static nor dynamic accommodation-vergence conflict contribute significantly to cybersickness. The rendering of DoF improves the speed and accuracy of depth perceptions, but this did not translate into any improvement in cybersickness outcomes.Study 3 assesses the effects of DoF on cybersickness caused by exploration of a fully featured virtual environment. Unlike in the first two studies, participants experienced severe cybersickness from locomoting through this environment, resulting in multiple participants withdrawing from the severity of their sickness. The rendering of DoF results in a significant decrease in this withdrawal rate, suggesting that even in modern HMDs, this algorithm is effective in improving comfort outcomes. Finally, Study 4 compares the effect of DoF blur to a virtual cursor, which provides a fixation point in the centre of the field of view and is known to guide attention. Results suggest that while the DoF blur may guide attention, it does not do so in the same way as a cursor.This thesis concludes that the rendering of DoF blur is effective in mitigating cybersickness on modern HMDs. We found no evidence that this reduction is achieved through mitigation of the accommodation-vergence conflict. Exploratory analysis of the effect of this blur on participant head movement shows it to be limited, implying an attentional or otherwise purely visual mechanism.</p
Carbohydrate-derived molecules as ligands for immune cell receptors
No full textThe macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor on myeloid cells that recognises both pathogen-associated and danger-associated molecular patterns. Trehalose dimycolate (TDM), the most abundant glycolipid in the cell wall of Mycobacterium species, and its synthetic analogue trehalose dibehenate (TDB), were among the first non-proteinaceous potent Mincle agonists to be identified. Further studies have uncovered the potential of Mincle ligands as adjuvants in vaccine formulations due to the ability of the agonists to elicit a TH1-polarising immune response. There has been much recent interest in glucose-based Mincle ligands as they are capable of inducing potent Mincle-dependent immune responses similar to those elicited by TDM and TDB. However, much is still unknown about the structural requirements for glucose ligands to induce optimal Mincle signalling. Thus, the first section of this thesis focuses on the synthesis of rationally designed α-branched and aromatic glucose monoesters and glucosides, followed by biological evaluation of the derivatives using murine and human cell-based assays. From this work, it was determined that docosyl α-glucoside induces potent human Mincle activity and superior immune responses than TDB by human monocytes, thereby warranting further research as a potential adjuvant.Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells that play an important role in many pathologies ranging from viral and bacterial infections, to autoimmune disorders and cancer. Accordingly, MAIT cells represent an attractive target for immunotherapeutics. MAIT cells are activated via the presentation of ligands by major histocompatibility complex (MHC) class I-related molecule, MR1, to their invariant T cell receptor (TCR). In 2012, the first class of agonist for MAIT cells was identified as the ribityllumazines, followed by the discovery of a more potent but unstable agonist, 5-(2-oxopropylideneamino)-6-ᴅ-ribitylaminouracil (5-OP-RU), in 2014. To date, few studies have explored the effects of systematic changes to the ligand structure on MAIT cell activation. Additional insight into the structural motifs required for regulating MAIT cell activity would contribute greatly towards the design of future MAIT cell agonists and antagonists. Accordingly, the next section of this thesis focusses on investigating how changes to the sugar motif of MR1 ligands 7-hydroxy-6-methyl-8-ᴅ-ribityllumazine (RL-6-Me-7-OH) and 5-OP-RU influence MAIT cell activation. A highly efficient protecting group-free three step synthesis of lumazines was developed, which facilitated the substitution of different sugar residues to afford the target lumazine and 5-OP-RU glyco-analogues. Biological assays and docking studies revealed the importance of the 2′-OH group on the sugar side chain for MAIT cell activity.To further examine the effect of gross structural changes to the 6-amino side chain of 5-OP-RU, uracil analogues containing monohydroxyalkylamine or unfunctionalised alkylamine side chains were synthesised and assessed for their ability to bind MR1 and activate MAIT cells. In doing so, a new simplified MAIT cell agonist with a functional profile similar to 5-OP-RU was identified, and a new structural class of MAIT cell antagonist was discovered. Furthermore, for the first time, it was demonstrated that changing the 6-amino side chain of 5-OP-RU can switch the function of the MAIT cell ligand from agonist to antagonist.The unstable nature of 5-OP-RU in aqueous conditions makes it challenging to prepare samples of this compound for biological assays, thereby requiring the generation of 5-OP-RU immediately before testing. In order to harness MAIT cells as a potential target for vaccines, the development of a stable MAIT cell ligand is crucial to allow for its incorporation into vaccine formulations. Accordingly, the last section of this thesis focusses on the generation of stable MAIT cell agonists, followed by studies into their ability to bind MR1 and activate MAIT cells. A series of amide and carbamate analogues of 5-OP-RU were synthesised and biologically assessed using a murine MAIT cell line, which resulted in the identification of three new amide MAIT cell agonists. Two amide analogues were found to be more stable than 5-OP-RU in aqueous conditions, with preliminary studies demonstrating their ability to induce a functional response by both murine and human MAIT cells. Accordingly, the stable amine agonists represent attractive targets for further MAIT cell research.</p
The impacts of sedimentation on the spatial distribution of animal-dominated reefs in Wellington Harbour
No full textCoastal ecosystems contain some of the most productive habitats worldwide, yet they are increasingly threatened by anthropogenic activities. The increased input and resuspension of sediments represents a major threat to global marine biodiversity. Elevated sediment levels can have severe impacts on marine habitats by reducing light penetration, smothering benthic organisms, and clogging feeding apparatus. Animal-dominated reefs (ADRs), which are dominated by sessile suspension feeders, are particularly vulnerable to increases in sedimentation. Recent habitat mapping in Wellington Harbour, New Zealand has revealed the existence of many shallow-water (In my second chapter I collected environmental data over a one year period to examine how environmental conditions vary both spatially and temporally across four sites within Wellington Harbour. I then quantified the composition of ADRs at each site and used a modelling approach to explore the relationships between community composition and environmental variables. I found that most environmental variables (temperature, chlorophyll-a, and oxygen concentration) varied seasonally, but not spatially within the harbour, while sedimentation varied significantly between sites and seasons. Substrate composition and ADR community composition varied significantly between all sites. Statistical modelling revealed that 54% of the variation in community composition was driven by the environmental factors measured. Sedimentation and substrate composition were found to be a significant drivers of ADR community composition in Wellington Harbour.In my third chapter I investigated how a sponge species common across all sites, Suberites australiensis, responded to elevated deposited and suspended sediment loads. Two ex-situ experimental studies were conducted. The first experiment exposed sponges to a range of sedimentation rates over the course of 16 days, while the second experiment used pulses of suspended sediment for 19 days. The main finding was that S. australiensis was highly tolerant to both forms of sediment, with high survival rates and no significant negative effects. My study provided evidence that this species may employ a combination of passive and active mechanisms to mitigate sediment accumulation and clogging. These adaptations may allow S. australiensis to survive in highly-sedimented areas where other suspension feeders may be excluded.Overall, my results demonstrate that ADR community composition in Wellington Harbour may be vulnerable to shifts in sediment regimes. Increases in sediment deposition at low-sedimentation sites may drive shifts in ADR community structure by favouring sediment-tolerant species, such as S. australiensis, and potentially causing declines in biodiversity as sediment-intolerant species are excluded. Conversely, highly-sedimented communities may be vulnerable to decreased sediment input as it could allow species that were previously excluded from these areas to become established. My findings, alongside similar patterns in other countries, demonstrate the importance of sediment in structuring benthic communities in coastal areas. Additionally, it highlights the vulnerability of ADRs to anthropogenic activities that may alter the input or resuspension of sediment in marine environments. My research provides valuable insights that may be used to inform the management and conservation of these ecologically important habitats on a local and global scale.</p
An investigation into Varroa mite resistance in New Zealand honey bees
No full textHoney bees are the most prolific pollinators in agriculture, making them critical to maintaining global food chains, and ecological biodiversity. The Varroa destructor mite poses a significant threat to western bee populations, and therefore to the future sustainability of agriculture. Current miticidal treatments are increasingly ineffective against Varroa, prompting investigation into alternative sustainable solutions to address the growing impact of Varroa to the apiculture industry. This study aims to identify resistant traits in New Zealand honey bees bred for mite resistance, with the goal of providing a more sustainable option to help mitigate Varroa’s impact. The proposed resistant strain (PRS) of honey bee investigated in this study was bred over many years for mite resistance and is purported to be resistant via a shorter bee development duration restricting a mite’s ability to reproduce. Over two seasons, experiments were conducted at Victoria University of Wellington and at a field site to measure the mite population growth and development duration of honey bees in the PRS, and in a standard Italian strain. The PRS were observed to have slower mite population growth across all sites and seasons, culminating in lower mite numbers at the conclusion of the study. Honey bee development duration varied largely, both within and between strains, resulting in no consistent difference in the development duration between strains that can be associated with the lower mite numbers. Consequently, while the proposed resistant strain does demonstrate a degree of resistance to Varroa through lower mite numbers, the evidence does not support the hypothesis that this mite resistance can be attributed to a shorter development duration in this population of bees. The lower mite population growth across all sites and years in the PRS indicates a possible resistance trait that was not identified in this investigation.The spatial distribution of Varroa mites on honey bees during the mites’ dispersal phase was investigated in a standard Italian strain and the PRS. No significant differences were observed in the spatial distribution of Varroa mites between the strains. In line with previous investigations, mites were found at higher rates on the side of the bees’ abdomen in the inter-tergite space, with the majority on the left side. Possible reasons for most of the mites being found at this location on the bee are discussed.A second population of bees bred over many years for heightened Varroa-sensitive hygiene behaviour was examined. Variation in Varroa-sensitive hygiene behaviour, as measured by the ratio of reproducing versus non-reproducing mites, was identified in this population, with the ratio of non-reproducing mites ranging up to 100%. Investigation into the relationship between the mite non-reproduction ratio and a previously identified Varroa-sensitive hygiene (VSH)-associated genotype was limited by the small proportion of the relevant genotype in the population sampled. However, further analysis suggested a complex relationship with the VSH-associated genotype and multiple colony traits, including the mite non-reproduction ratio, that may be elucidated with further investigation. Additionally, an observation of VSH-associated behaviours in response to previously identified parasitism specific hydrocarbons (Varroa-specific compounds, VSC) found no association with mite-non reproduction. These findings emphasise the complexity of traits that attribute to mite resistance in different bee populations, and the difficulties in breeding for mite resistance. An apparent mite-resistant population was identified in the PRS but the mechanism underlying resistance was not determined. Additionally, VSH was identified in local populations, but new methods of selecting for resistant traits were unable to conclusively identify resistant colonies, though this may be due to the limitations of the study. Future research should aim to identify and characterise mite resistance traits in these populations and others, and continue to explore novel methods of trait selection to understand the underlying mechanisms of mite resistance, to support efforts toward sustainable beekeeping in New Zealand.</p
Dual Liminality and Violation of Rights: Transgender Asylum Seekers and Access to Institutions, Social Services and Support in Aotearoa New Zealand
No full textTransgender people face criminalisation and persecution in many countries due to legislation and inequitable social norms. This predicament, which leads to experiential and institutional violence, has prompted some transgender people to seek refuge in nations reputed for upholding transgender rights. Aotearoa New Zealand is recognised internationally as a country supportive of transgender rights. While there is a body of literature that examines the challenges facing transgender people in accessing institutions, services and support in Aotearoa New Zealand, there is limited empirical research that focuses on the experiences of transgender asylum seekers. Within global literature, the focus has been on the legal adjudication process, with little exploration of their access to the legal challenges before and after the adjudication process and access to other institutions, services and support.Addressing these gaps in the literature, this qualitative study examines the experiences of asylum-seeking by transgender people in Aotearoa New Zealand, particularly in terms of institutional access and support. I conducted in-depth interviews with four transgender former asylum seekers and seven members of key non-governmental organisations, as well as a cross-case analysis of 12 legal cases related to asylum seeking. Theoretically, the study draws on aspects of critical race theory, queer theory, and questions around the social construction of ‘illegality’ to understand a unique set of challenges that arise from the intersection between transgender asylum seeker participants’ gender identities and their immigration status. I employ the framework of dual liminality to illustrate how their complex identities lead to the experiences of uncertainty, marginalisation and precarity during and after the asylum-seeking process. This research finds that, in contrast to international literature, transgender claims and evidence are less of a barrier during the asylum adjudication process. Instead, concerns regarding an applicant’s potential burden on healthcare, character assessments, and the country-of-origin requirements may be more pivotal. A significant issue reported by study participants is the lack of access to gender-concordant identification documents, which in turn severely affects their access to institutions, services and support during and after the asylum-seeking process. Due to their intersecting identities as transgender persons and asylum seekers, study findings show that participants experience gaps in policies, discrimination and a lack of awareness among service providers about transgender asylum seekers’ entitlements. Consequently, the support available to transgender asylum seekers in Aotearoa New Zealand may often be minimal and inconsistent, leading to their liminal gender and legal status being perpetuated. These findings illuminate how the international refugee frameworks, local policies and legal frameworks, as well as civil society collectively fail to sufficiently address the needs of transgender asylum seekers, thereby leading to the continuation of rights violations. As a result, this study recommends the introduction of policies and anti-discrimination legislation both at international and local stages to ensure better the rights of transgender asylum seekers in accessing the institutions, social services and support they need. By doing so, Aotearoa New Zealand can legitimately claim its international reputation of being friendly towards transgender people, and international refugee laws can effectively protect transgender asylum seekers.</p
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