Event-Based Modeling with High-Dimensional Imaging Biomarkers for Estimating Spatial Progression of Dementia

Event-based models (EBM) are a class of disease progression models that can be used to estimate temporal ordering of neuropathological changes from cross-sectional data. Current EBMs only handle scalar biomarkers, such as regional volumes, as inputs. However, regional aggregates are a crude summary of the underlying high-resolution images, potentially limiting the accuracy of EBM. Therefore, we propose a novel method that exploits high-dimensional voxel-wise imaging biomarkers: n-dimensional discriminative EBM (nDEBM). nDEBM is based on an insight that mixture modeling, which is a key element of conventional EBMs, can be replaced by a more scalable semi-supervised support vector machine (SVM) approach. This SVM is used to estimate the degree of abnormality of each region which is then used to obtain subject-specific disease progression patterns. These patterns are in turn used for estimating the mean ordering by fitting a generalized Mallows model. In order to validate the biomarker ordering obtained using nDEBM, we also present a framework for Simulation of Imaging Biomarkers' Temporal Evolution (SImBioTE) that mimics neurodegeneration in brain regions. SImBioTE trains variational auto-encoders (VAE) in different brain regions independently to simulate images at varying stages of disease progression. We also validate nDEBM clinically using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In both experiments, nDEBM using high-dimensional features gave better performance than state-of-the-art EBM methods using regional volume biomarkers. This suggests that nDEBM is a promising approach for disease progression modeling.Comment: IPMI 201

Four-year longitudinal impact evaluation of the action for children UK neglect project : outcomes for the children, families, action for children, and the UK

Neglect has a devastating impact on children and is the most pervasive form of child maltreatment in the United Kingdom. The study purpose was to establish outcomes for neglected children following structured assessment and intervention to ascertain what worked and why it worked. This prospective cohort study included 85 cases of neglected children under 8 years of age from 7 centers across the United Kingdom. Data were collected between 2008 and 2012 through serial quantitative recording of the level of concern about neglect. Serial review of qualitative casefile data was undertaken for detail of assessment, interventions, and evidence of outcomes for the child. Data analysis was undertaken by paired t-test, Chi Square, descriptive statics for categorical data, and, for narrative data, identification of recurring factors and patterns, with correlation of presenting factors, interventions, and outcomes. Paired t-test demonstrated significant decrease in overall Action for Children Assessment Tool scores between assessment (M = 43.77, SD = 11.09) and closing the case (M = 35.47,SD = 9.6, t(84) = 6.77, p < 0.01). Improvement in the level of concern about neglect was shown in 79% of cases, with only 21% showing no improvement. In 59% of cases, concern about neglect was removed completely. Use of the assessment tool fostered engagement by parents. The relationship between lack of parental engagement and children being taken into care was statistically significant, with a large effect size (χ2 10.66, df1, p = 0.0001,OR = 17.24). When parents refused or were unable to respond positively to the intervention, children benefited from an expedited move into care

What is the 'problem' that outreach work seeks to address and how might it be tackled? Seeking theory in a primary health prevention programme

&lt;b&gt;Background&lt;/b&gt; Preventive approaches to health are disproportionately accessed by the more affluent and recent health improvement policy advocates the use of targeted preventive primary care to reduce risk factors in poorer individuals and communities. Outreach has become part of the health service response. Outreach has a long history of engaging those who do not otherwise access services. It has, however, been described as eclectic in its purpose, clientele and mode of practice; its effectiveness is unproven. Using a primary prevention programme in the UK as a case, this paper addresses two research questions: what are the perceived problems of non-engagement that outreach aims to address; and, what specific mechanisms of outreach are hypothesised to tackle these.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; Drawing on a wider programme evaluation, the study undertook qualitative interviews with strategically selected health-care professionals. The analysis was thematically guided by the concept of 'candidacy' which theorises the dynamic process through which services and individuals negotiate appropriate service use.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The study identified seven types of engagement 'problem' and corresponding solutions. These 'problems' lie on a continuum of complexity in terms of the challenges they present to primary care. Reasons for non-engagement are congruent with the concept of 'candidacy' but point to ways in which it can be expanded.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; The paper draws conclusions about the role of outreach in contributing to the implementation of inequalities focused primary prevention and identifies further research needed in the theoretical development of both outreach as an approach and candidacy as a conceptual framework

Imagining Sisyphus happy: DNA barcoding and the unnamed majority

The vast majority of life on the Earth is physically small, and is classifiable as micro- or meiobiota. These organisms are numerically dominant and it is likely that they are also abundantly speciose. By contrast, the vast majority of taxonomic effort has been expended on ‘charismatic megabionts’: larger organisms where a wealth of morphology has facilitated Linnaean species definition. The hugely successful Linnaean project is unlikely to be extensible to the totality of approximately 10 million species in a reasonable time frame and thus alternative toolkits and methodologies need to be developed. One such toolkit is DNA barcoding, particularly in its metabarcoding or metagenetics mode, where organisms are identified purely by the presence of a diagnostic DNA sequence in samples that are not processed for morphological identification. Building on secure Linnaean foundations, classification of unknown (and unseen) organisms to molecular operational taxonomic units (MOTUs) and deployment of these MOTUs in biodiversity science promises a rewarding resolution to the Sisyphean task of naming all the world's species. This article is part of the themed issue ‘From DNA barcodes to biomes’

phenosim - A software to simulate phenotypes for testing in genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>There is a great interest in understanding the genetic architecture of complex traits in natural populations. Genome-wide association studies (GWAS) are becoming routine in human, animal and plant genetics to understand the connection between naturally occurring genotypic and phenotypic variation. Coalescent simulations are commonly used in population genetics to simulate genotypes under different parameters and demographic models.</p> <p>Results</p> <p>Here, we present <monospace>phenosim</monospace>, a software to add a phenotype to genotypes generated in time-efficient coalescent simulations. Both qualitative and quantitative phenotypes can be generated and it is possible to partition phenotypic variation between additive effects and epistatic interactions between causal variants. The output formats of <monospace>phenosim</monospace> are directly usable as input for different GWAS tools. The applicability of <monospace>phenosim</monospace> is shown by simulating a genome-wide association study in <it>Arabidopsis thaliana</it>.</p> <p>Conclusions</p> <p>By using the coalescent approach to generate genotypes and <monospace>phenosim</monospace> to add phenotypes, the data sets can be used to assess the influence of various factors such as demography, genetic architecture or selection on the statistical power of association methods to detect causal genetic variants under a wide variety of population genetic scenarios. <monospace>phenosim</monospace> is freely available from the authors' website <url>http://evoplant.uni-hohenheim.de</url></p

Phylogenetic relationships of cone snails endemic to Cabo Verde based on mitochondrial genomes

Background: Due to their great species and ecological diversity as well as their capacity to produce hundreds of different toxins, cone snails are of interest to evolutionary biologists, pharmacologists and amateur naturalists alike. Taxonomic identification of cone snails still relies mostly on the shape, color, and banding patterns of the shell. However, these phenotypic traits are prone to homoplasy. Therefore, the consistent use of genetic data for species delimitation and phylogenetic inference in this apparently hyperdiverse group is largely wanting. Here, we reconstruct the phylogeny of the cones endemic to Cabo Verde archipelago, a well-known radiation of the group, using mitochondrial (mt) genomes. Results: The reconstructed phylogeny grouped the analyzed species into two main clades, one including Kalloconus from West Africa sister to Trovaoconus from Cabo Verde and the other with a paraphyletic Lautoconus due to the sister group relationship of Africonus from Cabo Verde and Lautoconus ventricosus from Mediterranean Sea and neighboring Atlantic Ocean to the exclusion of Lautoconus endemic to Senegal (plus Lautoconus guanche from Mauritania, Morocco, and Canary Islands). Within Trovaoconus, up to three main lineages could be distinguished. The clade of Africonus included four main lineages (named I to IV), each further subdivided into two monophyletic groups. The reconstructed phylogeny allowed inferring the evolution of the radula in the studied lineages as well as biogeographic patterns. The number of cone species endemic to Cabo Verde was revised under the light of sequence divergence data and the inferred phylogenetic relationships. Conclusions: The sequence divergence between continental members of the genus Kalloconus and island endemics ascribed to the genus Trovaoconus is low, prompting for synonymization of the latter. The genus Lautoconus is paraphyletic. Lautoconus ventricosus is the closest living sister group of genus Africonus. Diversification of Africonus was in allopatry due to the direct development nature of their larvae and mainly triggered by eustatic sea level changes during the Miocene-Pliocene. Our study confirms the diversity of cone endemic to Cabo Verde but significantly reduces the number of valid species. Applying a sequence divergence threshold, the number of valid species within the sampled Africonus is reduced to half.Spanish Ministry of Science and Innovation [CGL2013-45211-C2-2-P, CGL2016-75255-C2-1-P, BES-2011-051469, BES-2014-069575, Doctorado Nacional-567]info:eu-repo/semantics/publishedVersio

De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology

Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Smoking in preeclamptic women is associated with higher birthweight for gestational age and lower soluble fms-like tyrosine kinase-1 levels: a nested case control study

<p>Abstract</p> <p>Background</p> <p>Smoking paradoxically increases the risk of small-for-gestational-age (SGA) birth but protects against preeclampsia. Some studies have reported a "U-shaped" distribution of fetal growth in preeclamptic pregnancies, but reasons for this are unknown. We investigated whether cigarette smoking interacts with preeclampsia to affect fetal growth, and compared levels of soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein, in preeclamptic smokers and non-smokers.</p> <p>Methods</p> <p>From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia (cases) and 443 controls. Smoking exposure was assessed by self-report and maternal hair nicotine levels. Fetal growth was assessed as z-score of birthweight for gestational age (BWGA). sFlt-1 was measured in plasma samples collected at the 24-26-week visit.</p> <p>Results</p> <p>In linear regression, smoking and preeclampsia were each associated with lower BWGA z-scores (β = -0.29; p = 0.008, and β = -0.67; p < 0.0001), but positive interaction was observed between smoking and preeclampsia (β = +0.86; p = 0.0008) such that smoking decreased z-score by -0.29 in controls but increased it by +0.57 in preeclampsia cases. Results were robust to substituting log hair nicotine for self-reported smoking and after adjustment for confounding variables. Mean sFlt-1 levels were lower in cases with hair nicotine levels above vs. below the median (660.4 pg/ml vs. 903.5 pg/ml; p = 0.0054).</p> <p>Conclusions</p> <p>Maternal smoking seems to protect against preeclampsia-associated fetal growth restriction and may account, at least partly, for the U-shaped pattern of fetal growth described in preeclamptic pregnancies. Smoking may exert this effect by reducing levels of the anti-angiogenic protein sFlt-1.</p