Biology subjects

White, T.

Publications and source records attributed to White, T..

9 recordsLinked to original sources

bioRxiv2018

Beyond Bonferroni Revisited: Concerns over inflated false positives in conservation genetics, genetics, and neuroscience

In 2006, Narum published a paper in Conservation Genetics that was motivated by the stringent nature of the Bonferroni approach for family wise error correction. That work suggested that the approach of Benjamini and Yekutieli in 2001 provided adequate correction and was more biologically relevant. However, there are crucial differences between the original Benjamini and Yekutieli procedure and that described by Narum. After carefully reviewing both papers, we believe that the Narum procedure is both different than the Benjamini and Yekutieli procedure and does not adequately control for family wise error. We provide an overview of approaches for FWE correction as well as evidence for the faulty implementation of the Benjamini and Yekutieli procedure by Narum using the equations from the respective papers, data from both papers, and the results of simulation.

genetics↗

bioRxiv2018

Defining the core essential genome of Pseudomonas aeruginosa

Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but the results fell short of the promise. It is becoming clear that a major limitation was that essential genes for a bacterial species were often defined based on a single or limited number of strains grown under a single or limited number of in vitro laboratory conditions. In fact, the essentiality of a gene can depend on both genetic background and growth condition. We thus developed a strategy for more rigorously defining the core essential genome of a bacterial species by studying many pathogen strains and growth conditions. We assessed how many strains must be examined to converge on a set of core essential genes for a species. We used transposon insertion sequencing (Tn-Seq) to define essential genes in nine strains of Pseudomonas aeruginosa on five different media and developed a novel statistical model, FiTnEss, to classify genes as essential versus non-essential across all strain-media combinations. We defined a set of 321 core essential genes, representing 6.6% of the genome. We determined that analysis of 4 strains was typically sufficient in P. aeruginosa to converge on a set of core essential genes likely to be essential across the species across a wide range of conditions relevant to in vivo infection, and thus to represent attractive targets for novel drug discovery.

microbiology↗

bioRxiv2018

Estimating energy expenditure from wrist and thigh accelerometry in free-living adults: a doubly labelled water study

BackgroundMany large studies have implemented wrist or thigh accelerometry to capture physical activity, but the accuracy of these measurements to infer Activity Energy Expenditure (AEE) and consequently Total Energy Expenditure (TEE) has not been demonstrated. The purpose of this study was to assess the validity of acceleration intensity at wrist and thigh sites as estimates of AEE and TEE under free-living conditions using a gold-standard criterion.\n\nMethodsMeasurements for 193 UK adults (105 men, 88 women, aged 40-66 years, BMI 20.4-36.6 kg{middle dot}m-2) were collected with triaxial accelerometers worn on the dominant wrist, non-dominant wrist and thigh in free-living conditions for 9-14 days. In a subsample (50 men, 50 women) TEE was simultaneously assessed with doubly labelled water (DLW). AEE was estimated from non-dominant wrist using an established estimation model, and novel models were derived for dominant wrist and thigh in the non-DLW subsample. Agreement with both AEE and TEE from DLW was evaluated by mean bias, Root Mean Squared Error (RMSE) and Pearson correlation.\n\nResultsMean TEE and AEE derived from DLW was 11.6 (2.3) MJ{middle dot}day-1 and 49.8 (16.3) kJ{middle dot}day-1{middle dot}kg-1. Dominant and non-dominant wrist acceleration were highly correlated in free-living (r=0.93), but less so with thigh (r=0.73 and 0.66, respectively). Estimates of AEE were 48.6 (11.8) kJ{middle dot}day-1{middle dot}kg-1 from dominant wrist, 48.6 (12.3) from non-dominant wrist, and 46.0 (10.1) from thigh; these agreed strongly with AEE (RMSE ~12.2 kJ{middle dot}day-1{middle dot}kg-1, r ~0.71) with small mean biases at the population level (~6%). Only the thigh estimate bias was statistically significantly different from the criterion. When combining these AEE estimates with estimated REE, agreement was stronger with the criterion (RMSE ~1.0 MJ{middle dot}day-1, r ~0.90). Conclusions: In UK adults, acceleration measured at either wrist or thigh can be used to estimate population levels of AEE and TEE in free-living conditions with high precision.

epidemiology↗

bioRxiv2018

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

Abstract/SummaryO_ST_ABSBackground and aimsC_ST_ABSUnderstanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a persons susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).\n\nMaterials and methodsFrom a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.\n\nResultsUsing ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].\n\nConclusionThe epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.\n\nAbbreviations

epidemiology↗

bioRxiv2018

Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia complaints. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.

genetics↗

bioRxiv2017

Authentic Enzyme Intermediates Captured "on-the-fly" by Mix-and-Inject Serial Crystallography

Ever since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases. Here, we demonstrate a general method for capturing enzyme catalysis in-action by mix-and-inject serial crystallography. Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis -lactamase with the 3rd generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation on the millisecond to second time scales including the crossover from transition state kinetics to steady-state kinetics.\n\nSynopsisAn enzymatically catalyzed reaction is initiated by diffusion based mixing of substrate and followed at runtime by time-resolved serial crystallography using a free electron laser.

biophysics↗

bioRxiv2017

GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimers dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.

genetics↗

bioRxiv2017

GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways

Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4-6. Previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci10-12. Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts (P=3x10-8), medium spiny neurons (P=4x10-8) and serotonergic neurons (P=1x10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4x10-9), behavioural response to cocaine processes (P=1.84x10-7), and axon part (P=5.26x10-8). We show that neuroticisms genetic signal partly originates in two genetically distinguishable subclusters13 (depressed affect and worry, the former being genetically strongly related to depression, rg=0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.

genetics↗

bioRxiv2017

Comparing colours using visual models

Lay SummaryAn outstanding challenge for the study of colour traits is how best to use \"colour spaces\" to represent their visual perception, particularly when asking questions of colour-difference (e.g. the (dis)similarity of males and females, mimics and models, or sister species, to a given viewer). We use simulations to show that existing methods fail to statistically and biologically estimate the separation of groups in colour space, and we suggest a flexible, robust, alternative that avoids those pitfalls.\n\nAbstractColour in nature presents a striking dimension of variation, though understanding its function and evolution largely depends on our ability to capture the perspective of relevant viewers. This goal has been radically advanced by the development and widespread adoption of colour spaces, which allow for the viewer-subjective estimation of colour appearance. Most studies of colour in camouflage, aposematism, sexual selection, and other signalling contexts draw on these models, with the shared analytical objective of estimating how similar (or dissimilar) colour samples are to a given viewer. We summarise popular approaches for estimating the separation of samples in colour space, and use a simulation-based approach to test their efficacy with common data structures. We show that these methods largely fail to estimate the separation of colour samples by neglecting (i) the statistical distribution and within-group variation of the data, and/or (ii) the discriminability of groups relative to the observers visual capabilities. Instead, we formalize the two questions that must be answered to establish both the statistical presence and theoretical magnitude of colour differences, and propose a two-step, permutation-based approach that achieves this goal. Unlike previous methods, our suggested approach accounts for the multidimensional nature of visual model data, and is robust against common colour-data features such as heterogeneity and outliers. We demonstrate the pitfalls of current methods and the flexibility of our suggested framework using an example from the literature, with recommendations for future inquiry.

animal behavior and cognition↗