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.

Dynamics of gray matter loss in Alzheimer's disease

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere > right hemisphere) and correlated with progressively declining cognitive status (p < 0.0006). Novel brain mapping methods allowed us to visualize dynamic patterns of atrophy in 52 high-resolution magnetic resonance image scans of 12 patients with AD (age 68.4 ± 1.9 years) and 14 elderly matched controls (age 71.4 ± 0.9 years) scanned longitudinally (two scans; interscan interval 2.1 ± 0.4 years). A cortical pattern matching technique encoded changes in brain shape and tissue distribution across subjects and time. Cortical atrophy occurred in a well defined sequence as the disease progressed, mirroring the sequence of neurofibrillary tangle accumulation observed in cross sections at autopsy. Advancing deficits were visualized as dynamic maps that change over time. Frontal regions, spared early in the disease, showed pervasive deficits later (< 15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 ± 2.3% per year in AD v 0.9 ± 0.9% per year in controls) were faster in the left hemisphere (p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.

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.

Stabilization of stormwater biofilters: Impacts of wetting and drying phases and the addition of organic matter to filter media

Ripening period refers to a phase of stabilization in sand filters in water treatment systems that follows a new installation or cleaning of the filter. Intermittent wetting and drying, a unique property of stormwater biofilters, would similarly be subjected to a phase of stabilization. Suspended solids, is an important parameter that is often used to monitor the stabilization of sand filters in water treatment systems. Stormwater biofilters however, contain organic material that is added to the filter layer to enhance nitrate removal, the dynamics of which is seldom analysed in stabilization of stormwater biofilters. Therefore, in this study of stormwater biofiltration in addition to suspended solids (Turbidity), organic matter (TOC, DOC, TN and TKN) was also monitored as a parameter for stabilization of the stormwater biofilter. One Perspex bioretention column (94 mm internal diameter) was fabricated with filter layer that contained 8% organic material and fed with tapwater with different antecedent dry days (0 – 40 day) at 100 mL/min. Samples were collected from the outflow at different time intervals between 2 – 150 minutes and were tested for Total Organic Carbon, Dissolved Organic Carbon, Total Nitrogen, Total Kjeldhal Nitrogen and Turbidity. The column was observed to experience two phases of stabilization, one at the beginning of each event that lasted for 30 minutes while the other phase was observed across subsequent events that related to the age of filter.

Frequent (flier) frustration and the dark side of word‐of‐web: exploring online dysfunctional behavior in online feedback forums

Purpose Following the perspective of frustration theory customer frustration incidents lead to frustration behavior such as protest (negative word‐of‐mouth). On the internet customers can express their emotions verbally and non‐verbally in numerous web‐based review platforms. The purpose of this study is to investigate online dysfunctional customer behavior, in particular negative “word‐of‐web” (WOW) in online feedback forums, among customers who participate in frequent‐flier programs in the airline industry. Design/methodology/approach The study employs a variation of the critical incident technique (CIT) referred to as the critical internet feedback technique (CIFT). Qualitative data of customer reviews of 13 different frequent‐flier programs posted on the internet were collected and analyzed with regard to frustration incidents, verbal and non‐verbal emotional effects and types of dysfunctional word‐of‐web customer behavior. The sample includes 141 negative customer reviews based on non‐recommendations and low program ratings. Findings Problems with loyalty programs evoke negative emotions that are expressed in a spectrum of verbal and non‐verbal negative electronic word‐of‐mouth. Online dysfunctional behavior can vary widely from low ratings and non‐recommendations to voicing switching intentions to even stronger forms such as manipulation of others and revenge intentions. Research limitations/implications Results have to be viewed carefully due to methodological challenges with regard to the measurement of emotions, in particular the accuracy of self‐report techniques and the quality of online data. Generalization of the results is limited because the study utilizes data from only one industry. Further research is needed with regard to the exact differentiation of frustration from related constructs. In addition, large‐scale quantitative studies are necessary to specify and test the relationships between frustration incidents and subsequent dysfunctional customer behavior expressed in negative word‐of‐web. Practical implications The study yields important implications for the monitoring of the perceived quality of loyalty programs. Management can obtain valuable information about program‐related and/or relationship‐related frustration incidents that lead to online dysfunctional customer behavior. A proactive response strategy should be developed to deal with severe cases, such as sabotage plans. Originality/value This study contributes to knowledge regarding the limited research of online dysfunctional customer behavior as well as frustration incidents of loyalty programs. Also, the article presents a theoretical “customer frustration‐defection” framework that describes different levels of online dysfunctional behavior in relation to the level of frustration sensation that customers have experienced. The framework extends the existing perspective of the “customer satisfaction‐loyalty” framework developed by Heskett et al.

Effects of biodiesel chemical composition on the chemical and physical properties of the primary and secondary diesel particulate matter

This thesis improves our insight towards the effects of using biodiesels on the particulate matter emission of diesel engines and contributes to our understanding of their potential adverse health effects. The novelty of this project is the use of biodiesel fuel with controlled chemical composition that enables us to relate changes of physiochemical properties of particles to specific properties of the biodiesel. For the first time, the possibility of a correlation of the volatility and the Reactive Oxygen Species concentration of the particles is investigated versus the saturation, oxygen content and carbon chain length of the fuel.

Can’t see the trees for the forest? Why IS-ServQual items matter

Despite longstanding concern with the dimensionality of the service quality construct as measured by ServQual and IS-ServQual instruments, variations on the IS-ServQual instrument have been enduringly prominent in both academic research and practice in the field of IS. We explain the continuing popularity of the instrument based on the salience of the item set for predicting overall customer satisfaction, suggesting that the preoccupation with the dimensions has been a distraction. The implicit mutual exclusivity of the items suggests a more appropriate conceptualization of IS-ServQual as a formative index. This conceptualization resolves the paradox in IS-ServQual research, that of how an instrument with such well-known and well-documented weaknesses continue to be very influential and widely used by academics and practitioners. A formative conceptualization acknowledges and addresses the criticisms of IS-ServQual, while simultaneously explaining its enduring salience by focusing on the items rather than the “dimensions.” By employing an opportunistic sample and adopting the most recent IS-ServQual instrument published in a leading IS journal (virtually, any valid IS- ServQual sample in combination with a previously tested instrument variant would suffice for study purposes), we demonstrate that when re-specified as both first-order and second-order formatives, IS-ServQual has good model quality metrics and high predictive power on customer satisfaction. We conclude that this formative specification has higher practical use and is more defensible theoretically.

Adaptive immunity to rhinoviruses: Sex and age matter

Background: Rhinoviruses (RV) are key triggers in acute asthma exacerbations. Previous studies suggest that men suffer from infectious diseases more frequently and with greater severity than women. Additionally, the immune response to most infections and vaccinations decreases with age. Most immune function studies do not account for such differences, therefore the aim of this study was to determine if the immune response to rhinovirus varies with sex or age. Methods: Blood mononuclear cells were isolated from 63 healthy individuals and grouped by sex and age (≤50 years old and ≥52 years old). Cells were cultured with rhinovirus 16 at a multiplicity of infection of 1. The chemokine IP-10 was measured at 24 h as an index of innate immunity while IFNγ and IL-13 were measured at 5 days as an index of adaptive immunity. Results: Rhinovirus induced IFNγ and IL-13 was significantly higher in ≤50 year old women than in age matched men (p < 0.02 and p < 0.05) and ≥52 year old women (p < 0.02 and p > 0.005). There was no sex or age based difference in rhinovirus induced IP-10 expression. Both IFNγ and IL-13 were negatively correlated with age in women but not in men. Conclusions: This study suggests that pre-menopausal women have a stronger adaptive immune response to rhinovirus infection than men and older people, though the mechanisms responsible for these differences remain to be determined. Our findings highlight the importance of gender and age balance in clinical studies and in the development of new treatments and vaccines.

Does size matter? Knowledge-based development of second-order city-regions in Finland

Achieving knowledge-based urban development (KBUD) profoundly depends on not only encouraging the development of economic activities, but also strengthening the societal, environmental and governance bases of city-regions. In recent years, a number of global city-regions have been investigated from the angle of this multidimensional perspective, which has provided a new comprehension in the development processes of primate city-regions. However, there is a knowledge gap in understanding how KBUD works in the second-order city-region (SOCR) context. This warrants more attention as SOCRs potentially help secure balanced development and territorial cohesion. This paper aims to empirically investigate KBUD performances of SOCRs in order to generate new insights. An assessment framework is utilised in the Finnish context, where the findings provide a nationally benchmarked snapshot of the degree of achievements of SOCRs based on numerous KBUD performance areas. The results shed light on the unique Finnish urban and regional development process, and provide lessons for other SOCRs.