Making connections: Social identification with new treatment groups for lifestyle management of severe obesity

Groups are regularly used to deliver healthcare services, including the management of obesity, and there is growing evidence that patients' experiences of such groups fundamentally shape treatment effects. This study investigated factors related to patients' shared social identity formed within the context of a treatment group for the management of severe obesity. A cross-sectional survey was administered to patients registered with a UK medical obesity service and enrolled on a group-based education and support programme. Patients (N = 78; MBMI = 48 on entry to the service) completed measures of group demographics (e.g., group membership continuity) and psychosocial variables (e.g., past experiences of weight discrimination) and reported their social identification with the treatment group. The results showed that patients identified with the treatment group to the extent that there was continuity in membership across the programme and they perceived themselves more centrally in terms of their weight status. Weight centrality was negatively associated with external social support and positively associated with experiences of weight discrimination. Group continuity was positively correlated with session attendance frequency. Patients presenting to clinical treatment services with severe obesity often do so after sustained weight loss failure and exposure to negative societal experiences. This study highlights that providing a treatment environment wherein these experiences can be shared with other patients may provide common ground for development of a new, positive social identity that can structure programme engagement and progression.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This research was supported by a grant from Leverhulme Trust (RPG-368) awarded to Mark Tarrant, Claire Farrow, Katarina Kos and MarkDaly and also by the National Institute for Health Research (NIHR)Collaboration for Leadership in Applied Health Research and Care ofthe South West Peninsula (PenCLAHRC).published version, accepted version (12 month embargo), submitted versio

Genz and Mendell-Elston Estimation of the High-Dimensional Multivariate Normal Distribution

Statistical analysis of multinomial data in complex datasets often requires estimation of the multivariate normal (MVN) distribution for models in which the dimensionality can easily reach 10–1000 and higher. Few algorithms for estimating the MVN distribution can offer robust and efficient performance over such a range of dimensions. We report a simulation-based comparison of two algorithms for the MVN that are widely used in statistical genetic applications. The venerable Mendell- Elston approximation is fast but execution time increases rapidly with the number of dimensions, estimates are generally biased, and an error bound is lacking. The correlation between variables significantly affects absolute error but not overall execution time. The Monte Carlo-based approach described by Genz returns unbiased and error-bounded estimates, but execution time is more sensitive to the correlation between variables. For ultra-high-dimensional problems, however, the Genz algorithm exhibits better scale characteristics and greater time-weighted efficiency of estimation

Making Connections:Social identification with New Treatment Groups for Lifestyle Management of Severe Obesity

Groups are regularly used to deliver healthcare services, including the management of obesity, and there is growing evidence that patients' experiences of such groups fundamentally shape treatment effects. This study investigated factors related to patients' shared social identity formed within the context of a treatment group for the management of severe obesity. A cross-sectional survey was administered to patients registered with a UK medical obesity service and enrolled on a group-based education and support programme. Patients (N=78; MBMI = 48 on entry to the service) completed measures of group demographics (e.g., group membership continuity) and psychosocial variables (e.g., past experiences of weight discrimination), and reported their social identification with the treatment group. The results showed that patients identified with the treatment group to the extent that there was continuity in membership across the programme and they perceived themselves more centrally in terms of their weight status. Weight centrality was negatively associated with external social support and positively associated with experiences of weight discrimination. Group continuity was positively correlated with session attendance frequency. Patients presenting to clinical treatment services with severe obesity often do so after sustained weight loss failure and exposure to negative societal experiences. This study highlights that providing a treatment environment wherein these experiences can be shared with other patients may provide common ground for development of a new, positive social identity that can structure programme engagement and progression

A pilot investigation of differential hydroxymethylation levels in patient-derived neural stem cells implicates altered cortical development in bipolar disorder

Introduction: Bipolar disorder (BD) is a chronic mental illness characterized by recurrent episodes of mania and depression and associated with social and cognitive disturbances. Environmental factors, such as maternal smoking and childhood trauma, are believed to modulate risk genotypes and contribute to the pathogenesis of BD, suggesting a key role in epigenetic regulation during neurodevelopment. 5-hydroxymethylcytosine (5hmC) is an epigenetic variant of particular interest, as it is highly expressed in the brain and is implicated in neurodevelopment, and psychiatric and neurological disorders. Methods: Induced pluripotent stem cells (iPSCs) were generated from the white blood cells of two adolescent patients with bipolar disorder and their same-sex age-matched unaffected siblings (n = 4). Further, iPSCs were differentiated into neuronal stem cells (NSCs) and characterized for purity using immuno-fluorescence. We used reduced representation hydroxymethylation profiling (RRHP) to perform genome-wide 5hmC profiling of iPSCs and NSCs, to model 5hmC changes during neuronal differentiation and assess their impact on BD risk. Functional annotation and enrichment testing of genes harboring differentiated 5hmC loci were performed with the online tool DAVID. Results: Approximately 2 million sites were mapped and quantified, with the majority (68.8%) located in genic regions, with elevated 5hmC levels per site observed for 3\u27 UTRs, exons, and 2-kb shorelines of CpG islands. Paired t-tests of normalized 5hmC counts between iPSC and NSC cell lines revealed global hypo-hydroxymethylation in NSCs and enrichment of differentially hydroxymethylated sites within genes associated with plasma membrane (FDR = 9.1 × 10-12) and axon guidance (FDR = 2.1 × 10-6), among other neuronal processes. The most significant difference was observed for a transcription factor binding site for the KCNK9 gene (p = 8.8 × 10-6), encoding a potassium channel protein involved in neuronal activity and migration. Protein-protein-interaction (PPI) networking showed significant connectivity (p = 3.2 × 10-10) between proteins encoded by genes harboring highly differentiated 5hmC sites, with genes involved in axon guidance and ion transmembrane transport forming distinct sub-clusters. Comparison of NSCs of BD cases and unaffected siblings revealed additional patterns of differentiation in hydroxymethylation levels, including sites in genes with functions related to synapse formation and regulation, such as CUX2 (p = 2.4 × 10-5) and DOK-7 (p = 3.6 × 10-3), as well as an enrichment of genes involved in the extracellular matrix (FDR = 1.0 × 10-8). Discussion: Together, these preliminary results lend evidence toward a potential role for 5hmC in both early neuronal differentiation and BD risk, with validation and more comprehensive characterization to be achieved through follow-up study

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10-5; ΔAIC = -10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10-141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10-6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies

Contribution of Inbred Singletons to Variance Component Estimation of Heritability and Linkage

Objectives: An interesting consequence of consanguinity is that the inbred singleton becomes informative for genetic variance. We determine the contribution of an inbred singleton to variance component analysis of heritability and linkage. Methods: Statistical theory for the power of variance component analysis of quantitative traits is used to determine the expected contribution of an inbred singleton to likelihood-ratio tests of heritability and linkage. Results: In variance component models an inbred singleton contributes relatively little to a test of heritability, but can contribute substantively to a test of linkage. For small to moderate QTL effects and a level of inbreeding comparable to matings between first cousins (the preferred form of union in many human populations), an inbred singleton can carry nearly 25% the information of a non-inbred sibpair. In more highly inbred contexts available with experimental animal populations, nonhuman primate colonies, and some human subpopulations, the contribution of an inbred singleton relative to a sibpair can exceed 50%. Conclusions: Inbred individuals, even in isolation from other members of a sample, can contribute to variance component estimation and tests of heritability and linkage. Under certain conditions the informativeness of the inbred singleton can approach that of non-inbred sibpair

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P \u3c 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman\u27s rank correlations between PBMCs and the brain regions are all highly significant (r s = 0.47-0.57; P \u3c 2.2 × 10-16), although pairwise correlations among the brain regions are markedly stronger (r s = 0.86-0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (\u3e70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes

Time domain measurement of phase noise in a spin torque oscillator

We measure oscillator phase from the zero crossings of the voltage vs. time waveform of a spin torque nanocontact oscillating in a vortex mode. The power spectrum of the phase noise varies with Fourier frequency $f$ as $1/f^2$, consistent with frequency fluctuations driven by a thermal source. The linewidth implied by phase noise alone is about 70 % of that measured using a spectrum analyzer. A phase-locked loop reduces the phase noise for frequencies within its 3 MHz bandwidth.Comment: 6 pages, 5 figures, supplementary material. Submitted to {Appl. Phys. Lett.

Whole genome sequence data implicate RBFOX1 in epilepsy risk in baboons

Background: Baboons exhibit a genetic generalized epilepsy (GGE) that resembles juvenile myoclonic epilepsy and may represent a suitable genetic model for human epilepsy. The genetic underpinnings of epilepsy were investigated in a baboon colony at the Southwest National Primate Research Center (San Antonio, TX) through the analysis of whole-genome sequence (WGS) data. Methods: Baboon WGS data were obtained for 38 cases and 19 healthy controls from the NCBI Sequence Read Archive and, after standard QC filtering, two subsets of variants were examined: (1) 20,881 SNPs from baboon homologs of 19 candidate GGE genes; and (2) 36,169 protein-altering SNPs. Association tests were conducted in SOLAR, and gene set enrichment analyses (GSEA) and protein-protein interaction (PPI) network construction were performed on genome-wide significant association results (Pn= 441 genes). Results: Heritability for epileptic seizure in the pedigreed baboon sample was estimated at 0.76 (SE=0.77; P=0.07). A significant association was detected for an intronic SNP in RBFOX1 (P=5.92 × 10-6; adjusted P=0.016). For protein-altering variants, GSEA revealed significant positive enrichment for genes involved in the extracellular matrix structure (ECM; FDR=0.0072) and collagen formation (FDR=0.017). Conclusions: SNP association results implicate RBFOX1 in baboon epilepsy, a gene that plays a key role in neuronal excitation and transcriptomic regulation, and has been previously linked to human epilepsy, both focal and generalized. Moreover, protein-damaging variants from across the baboon genome exhibit a wider pattern of association that links collagen-containing ECM to epilepsy risk. These findings suggest a shared genetic etiology between baboon and human forms of GGE

Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10-5; ΔAIC = −10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10−141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10−6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies