Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling

Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.

Predicting white matter integrity from multiple common genetic variants

Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single-nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20-30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ∼ 6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected.

White matter integrity measured by fractional anisotropy correlates poorly with actual individual fiber anisotropy

Fractional anisotropy (FA), a very widely used measure of fiber integrity based on diffusion tensor imaging (DTI), is a problematic concept as it is influenced by several quantities including the number of dominant fiber directions within each voxel, each fiber's anisotropy, and partial volume effects from neighboring gray matter. High-angular resolution diffusion imaging (HARDI) can resolve more complex diffusion geometries than standard DTI, including fibers crossing or mixing. The tensor distribution function (TDF) can be used to reconstruct multiple underlying fibers per voxel, representing the diffusion profile as a probabilistic mixture of tensors. Here we found that DTIderived mean diffusivity (MD) correlates well with actual individual fiber MD, but DTI-derived FA correlates poorly with actual individual fiber anisotropy, and may be suboptimal when used to detect disease processes that affect myelination. Analysis of the TDFs revealed that almost 40% of voxels in the white matter had more than one dominant fiber present. To more accurately assess fiber integrity in these cases, we here propose the differential diffusivity (DD), which measures the average anisotropy based on all dominant directions in each voxel.

Scalar connectivity measures from fast-marching tractography reveal heritability of white matter architecture

Recent advances in diffusion-weighted MRI (DWI) have enabled studies of complex white matter tissue architecture in vivo. To date, the underlying influence of genetic and environmental factors in determining central nervous system connectivity has not been widely studied. In this work, we introduce new scalar connectivity measures based on a computationally-efficient fast-marching algorithm for quantitative tractography. We then calculate connectivity maps for a DTI dataset from 92 healthy adult twins and decompose the genetic and environmental contributions to the variance in these metrics using structural equation models. By combining these techniques, we generate the first maps to directly examine genetic and environmental contributions to brain connectivity in humans. Our approach is capable of extracting statistically significant measures of genetic and environmental contributions to neural connectivity.

Automatic clustering and population analysis of white matter tracts using maximum density paths

We introduce a framework for population analysis of white matter tracts based on diffusion-weighted images of the brain. The framework enables extraction of fibers from high angular resolution diffusion images (HARDI); clustering of the fibers based partly on prior knowledge from an atlas; representation of the fiber bundles compactly using a path following points of highest density (maximum density path; MDP); and registration of these paths together using geodesic curve matching to find local correspondences across a population. We demonstrate our method on 4-Tesla HARDI scans from 565 young adults to compute localized statistics across 50 white matter tracts based on fractional anisotropy (FA). Experimental results show increased sensitivity in the determination of genetic influences on principal fiber tracts compared to the tract-based spatial statistics (TBSS) method. Our results show that the MDP representation reveals important parts of the white matter structure and considerably reduces the dimensionality over comparable fiber matching approaches.

Changes in white matter connectivity following therapy for anomia post stroke

Background. The majority of studies investigating the neural mechanisms underlying treatment-induced recovery in aphasia have focused on the cortical regions associated with language processing. However, the integrity of the white matter connecting these regions may also be crucial to understanding treatment mechanisms. Objective. This study investigated the integrity of the arcuate fasciculus (AF) and uncinate fasciculus (UF) before and after treatment for anomia in people with aphasia. Method. Eight people with aphasia received 12 treatment sessions to improve naming; alternating between phonologically-based and semantic-based tasks, with high angular resolution diffusion imaging conducted pre and post treatment. The mean generalized fractional anisotropy (GFA), a measure of fiber integrity, and number of fibers in the AF and UF were compared pre and post treatment, as well as with a group of 14 healthy older controls. Results. Pre treatment, participants with aphasia had significantly fewer fibers and lower mean GFA in the left AF compared with controls. Post treatment, mean GFA increased in the left AF to be statistically equivalent to controls. Additionally, mean GFA in the left AF pre and post treatment positively correlated with maintenance of the phonologically based treatment. No differences were found in the right AF, or the UF in either hemisphere, between participants with aphasia and controls, and no changes were observed in these tracts following treatment. Conclusions. Anomia treatments may improve the integrity of the white matter connecting cortical language regions. These preliminary results add to the understanding of the mechanisms underlying treatment outcomes in people with aphasia post stroke.

Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.

Identifying candidate gene effects by restricting search space in a multivariate genetic analysis of white matter microstructure

Several genetic variants are thought to influence white matter (WM) integrity, measured with diffusion tensor imaging (DTI). Voxel based methods can test genetic associations, but heavy multiple comparisons corrections are required to adjust for searching the whole brain and for all genetic variants analyzed. Thus, genetic associations are hard to detect even in large studies. Using a recently developed multi-SNP analysis, we examined the joint predictive power of a group of 18 cholesterol-related single nucleotide polymorphisms (SNPs) on WM integrity, measured by fractional anisotropy. To boost power, we limited the analysis to brain voxels that showed significant associations with total serum cholesterol levels. From this space, we identified two genes with effects that replicated in individual voxel-wise analyses of the whole brain. Multivariate analyses of genetic variants on a reduced anatomical search space may help to identify SNPs with strongest effects on the brain from a broad panel of genes.

Robotic detection and tracking of Crown-Of-Thorns starfish

This paper presents a novel vision-based underwater robotic system for the identification and control of Crown-Of-Thorns starfish (COTS) in coral reef environments. COTS have been identified as one of the most significant threats to Australia's Great Barrier Reef. These starfish literally eat coral, impacting large areas of reef and the marine ecosystem that depends on it. Evidence has suggested that land-based nutrient runoff has accelerated recent outbreaks of COTS requiring extensive use of divers to manually inject biological agents into the starfish in an attempt to control population numbers. Facilitating this control program using robotics is the goal of our research. In this paper we introduce a vision-based COTS detection and tracking system based on a Random Forest Classifier (RFC) trained on images from underwater footage. To track COTS with a moving camera, we embed the RFC in a particle filter detector and tracker where the predicted class probability of the RFC is used as an observation probability to weight the particles, and we use a sparse optical flow estimation for the prediction step of the filter. The system is experimentally evaluated in a realistic laboratory setup using a robotic arm that moves a camera at different speeds and heights over a range of real-size images of COTS in a reef environment.

The impact of the health insurance program on the near-poor in Vietnam

This thesis is a cross-sectional study of a health insurance scheme for a representative sample of the near-poor in Cao Lanh district, Dong Thap province, Vietnam. It examines insurance coverage, health service utilisation, out-of-pocket expenditures and their associated factors. The research findings contribute evidence for policy makers who seek to improve the health insurance scheme for socioeconomically disadvantaged people in Vietnam, which is an important component of national efforts to implement universal health insurance. This community-level research adds to the evidence-base needed to improve the insurance system and thereby influence the quality of health care services.

An exploration of The Virtues Project: Ontological, educational and cross-cultural inquiries into a moral education program within a Mongolian school setting

This thesis explores The Virtues Project's ontological, educational and cross-cultural dimensions taking Charles Taylor's philosophical perspective of an anthropological account of the self and a phenomenological account of moral life and engagement. The experience of Mongolian schoolteachers implementing this moral education program is analyzed using a narrative inquiry method. The globally attractive project appears in moral education and virtues ethics research and surveys, yet no critical evaluation has been undertaken. Its conceptual features are appraised from a Taylorean perspective. The Listening Guide analysis of teacher experiences is presented in two narratives. The first is about the teachers' implementation experiences of moral flourishing as selves, in relationships and in community. The second is about their experience of becoming Mongolian in their modern day context. In conclusion, the project is coherent, constructive and potentially suitable cross-culturally.

Making connections within the Asia-Pacific region: Case study around the Mentoring for Effective Teaching (MET) program

University strategic plans emphasise the essential nature of partnerships at national and international levels. Along with establishing collaborative research partnerships, providing professional development to key stakeholders is considered a crucial activity for making and sustaining partnerships. Utilising knowledge from professional development in Australian contexts can be managed creatively for making connections internationally. Indeed, knowledge transfer is a cornerstone for the globalisation of education and needs to occur as a multiplex dialogue between participating countries. This paper presents a qualitative study around the Mentoring for Effective Teaching (MET) program, its growth and development nationally (e.g., scope and impact) along with insights into making connections within the Asia-Pacific region. At a national level, we outline how to facilitate a program though relationship building and face-to-face implementation of professional learning. Internationally, we highlight how to mould and shape Australian professional learning for the Asia-Pacific region, particularly with regard to facilitating fluid interactions within environments outside of Australia. The contexts for the study include a university in Hong Kong and another university in the Philippines. In this presentation, examples will be provided from the MET program to demonstrate contextual differences and similarities for implementation in Australian and Asian contexts. For instance, determining strategies for mentoring pedagogical knowledge can elicit viewpoints that align between cultures (e.g., use of specific teaching and questioning strategies) and also present alternative ideas as a result of cultural differences. We have learnt about having a structured program that draws on the research yet has sufficient flexibility to cater for cultures and contexts. With openmindedness, facilitating professional learning can become a two-way knowledge transfer, where learnings from other cultures and contexts can be refined for advancing programs in Australia.

Neo-Piagetian Theory and the novice programmer

This PhD project studied the genetic epistemology of novice programmers, and provides empirical evidence that the development of programming skills can be described using the neo-Piagetian cognitive development framework. The thesis identifies the manifestations of each of the early neo-Piagetian stages of development in the programming domain – that is: sensorimotor, preoperational and concrete operational. This research informs not only tertiary pedagogy, but teaching and learning of computer programming in any setting. It will enable educators to (a) identify the developmental stage of their students, (b) provide stage-appropriate learning resources and (c) assist students in transitioning to the next more mature stage of reasoning.

Transnationalism and the Karen wrist-tying ceremony: An ethnographic account of Karen settlement practice in Brisbane

When settling, people often use cultural schema from their original homeland to build familiarity in unfamiliar surrounds. This paper draws on ethnographic fieldwork conducted by the first author in Brisbane, with the Karen community from Burma, during which participant observation and interview methods were used. We present an ethnographic account of the Brisbane Karen wrist-tying ceremony. The ceremony acts as an insight into the challenges for Karen whilst settling into Australia. It reflects multiple accounts of history and tradition, but simultaneously speaks to emerging, contemporary Karen contexts. This research contributes to richer understandings of settlement: it frames transnational cultural practice as a flexible mode of integration, rather than an exclusionary mode of othering. We propose that the integrative discourse of the ceremony creates familiarity and social connection in local and diasporic spaces. This acts as a counter to the challenges of Karen settlement including the negotiations of local/global identity politics.

Validity of BMI as a measure of obesity in Australian white Caucasian and Australian Sri Lankan children

Background: Body mass index (BMI) is used to diagnose obesity. However, its ability to predict the percentage fat mass (%FM) reliably is doubtful. Therefore validity of BMI as a diagnostic tool of obesity is questioned. Aim: This study is focused on determining the ability of BMI-based cut-off values in diagnosing obesity among Australian children of white Caucasian and Sri Lankan origin. Subjects and methods: Height and weight was measured and BMI (W/H2) calculated. Total body water was determined by deuterium dilution technique and fat free mass and hence fat mass derived using age- and gender-specific constants. A %FM of 30% for girls and 20% for boys was considered as the criterion cut-off level for obesity. BMI-based obesity cut-offs described by the International Obesity Task Force (IOTF), CDC/NCHS centile charts and BMI-Z were validated against the criterion method. Results: There were 96 white Caucasian and 42 Sri Lankan children. Of the white Caucasians, 19 (36%) girls and 29 (66%) boys, and of the Sri Lankans 7 (46%) girls and 16 (63%) boys, were obese based on %FM. The FM and BMI were closely associated in both Caucasians (r = 0.81, P<0.001) and Sri Lankans (r = 0.92, P<0.001). Percentage FM and BMI also had a lower but significant association. Obesity cut-off values recommended by IOTF failed to detect a single case of obesity in either group. However, NCHS and BMI-Z cut-offs detected cases of obesity with low sensitivity. Conclusions: BMI is a poor indicator of percentage fat and the commonly used cut-off values were not sensitive enough to detect cases of childhood obesity in this study. In order to improve the diagnosis of obesity, either BMI cut-off values should be revised to increase the sensitivity or the possibility of using other indirect methods of estimating the %FM should be explored.