Applying the ROBINS-I tool to natural experiments: an example from public health

Background: A new tool to assess Risk of Bias In Non-randomised Studies of Interventions (ROBINS-I) was published in Autumn 2016. ROBINS-I uses the Cochrane-approved risk of bias (RoB) approach and focusses on internal validity. As such, ROBINS-I represents an important development for those conducting systematic reviews which include non-randomised studies (NRS), including public health researchers. We aimed to establish the applicability of ROBINS-I using a group of NRS which have evaluated non-clinical public health natural experiments. Methods: Five researchers, all experienced in critical appraisal of non-randomised studies, used ROBINS-I to independently assess risk of bias in five studies which had assessed the health impacts of a domestic energy efficiency intervention. ROBINS-I assessments for each study were entered into a database and checked for consensus across the group. Group discussions were used to identify reasons underpinning lack of consensus for specific questions and bias domains. Results: ROBINS-I helped to systematically articulate sources of bias in NRS. However, the lack of consensus in assessments for all seven bias domains raised questions about ROBINS-I’s reliability and applicability for natural experiment studies. The two RoB domains with least consensus were selection (Domain 2) and performance (Domain 4). Underlying the lack of consensus were difficulties in applying an intention to treat or per protocol effect of interest to the studies. This was linked to difficulties in determining whether the intervention status was classified retrospectively at follow-up, i.e. post hoc. The overall risk of bias ranged from moderate to critical; this was most closely linked to the assessment of confounders. Conclusion: The ROBINS-I tool is a conceptually rigorous tool which focusses on risk of bias due to the counterfactual. Difficulties in applying ROBINS-I may be due to poor design and reporting of evaluations of natural experiments. While the quality of reporting may improve in the future, improved guidance on applying ROBINS-I is needed to enable existing evidence from natural experiments to be assessed appropriately and consistently. We hope future refinements to ROBINS-I will address some of the issues raised here to allow wider use of the tool

Suv4-20h Histone Methyltransferases Promote Neuroectodermal Differentiation by Silencing the Pluripotency-Associated Oct-25 Gene

Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and specific downregulation of genes controlling neural induction, thereby effectively blocking differentiation of the neuroectoderm. Global transcriptome analysis supports the notion that these effects arise from the transcriptional deregulation of specific genes rather than widespread, pleiotropic effects. Interestingly, morphant embryos fail to repress the Oct4-related Xenopus gene Oct-25. We validate Oct-25 as a direct target of xSu4-20h enzyme mediated gene repression, showing by chromatin immunoprecipitaton that it is decorated with the H4K20me3 mark downstream of the promoter in normal, but not in double-morphant, embryos. Since knockdown of Oct-25 protein significantly rescues the neural differentiation defect in xSuv4-20h double-morphant embryos, we conclude that the epistatic relationship between Suv4-20h enzymes and Oct-25 controls the transit from pluripotent to differentiation-competent neural cells. Consistent with these results in Xenopus, murine Suv4-20h1/h2 double-knockout embryonic stem (DKO ES) cells exhibit increased Oct4 protein levels before and during EB formation, and reveal a compromised and biased capacity for in vitro differentiation, when compared to normal ES cells. Together, these results suggest a regulatory mechanism, conserved between amphibians and mammals, in which H4K20me3-dependent restriction of specific POU-V genes directs cell fate decisions, when embryonic cells exit the pluripotent state

Geometric modeling of 3D woven preforms in composite T-joints

A common method to fabricate net-shaped three-dimensional (3D) woven preforms for composite T-joints is to weave flat 3D preforms via a standard weaving machine with variation in binder yarn path and then separate the preform in the form of a bifurcation. Folding introduces fiber architecture deformation at the 3D woven bifurcation area. In this paper, a geometric modeling approach is proposed to represent the realistic fiber architecture, as a preprocessor for finite element analyses to predict composite structural performance. Supported by X-ray micro-computed tomography (mCT), three important deformation mechanisms are observed including yarn stack shifting, cross-section bending, and cross-section flattening resulting from the folding process. Furthermore, a set of mathematical formulae for simulation of the deformations in the junction region are developed and satisfactory agreement is observed when compared with mCT scan results

Estimating Receptive Fields from Responses to Natural Stimuli with Asymmetric Intensity Distributions

The reasons for using natural stimuli to study sensory function are quickly mounting, as recent studies have revealed important differences in neural responses to natural and artificial stimuli. However, natural stimuli typically contain strong correlations and are spherically asymmetric (i.e. stimulus intensities are not symmetrically distributed around the mean), and these statistical complexities can bias receptive field (RF) estimates when standard techniques such as spike-triggered averaging or reverse correlation are used. While a number of approaches have been developed to explicitly correct the bias due to stimulus correlations, there is no complementary technique to correct the bias due to stimulus asymmetries. Here, we develop a method for RF estimation that corrects reverse correlation RF estimates for the spherical asymmetries present in natural stimuli. Using simulated neural responses, we demonstrate how stimulus asymmetries can bias reverse-correlation RF estimates (even for uncorrelated stimuli) and illustrate how this bias can be removed by explicit correction. We demonstrate the utility of the asymmetry correction method under experimental conditions by estimating RFs from the responses of retinal ganglion cells to natural stimuli and using these RFs to predict responses to novel stimuli

Pore-scale numerical investigation of pressure drop behaviour across open-cell metal foams

The development and validation of a grid-based pore-scale numerical modelling methodology applied to five different commercial metal foam samples is described. The 3-D digital representation of the foam geometry was obtained by the use of X-ray microcomputer tomography scans, and macroscopic properties such as porosity, specific surface and pore size distribution are directly calculated from tomographic data. Pressure drop measurements were performed on all the samples under a wide range of flow velocities, with focus on the turbulent flow regime. Airflow pore-scale simulations were carried out solving the continuity and Navier–Stokes equations using a commercial finite volume code. The feasibility of using Reynolds-averaged Navier–Stokes models to account for the turbulence within the pore space was evaluated. Macroscopic transport quantities are calculated from the pore-scale simulations by averaging. Permeability and Forchheimer coefficient values are obtained from the pressure gradient data for both experiments and simulations and used for validation. Results have shown that viscous losses are practically negligible under the conditions investigated and pressure losses are dominated by inertial effects. Simulations performed on samples with varying thickness in the flow direction showed the pressure gradient to be affected by the sample thickness. However, as the thickness increased, the pressure gradient tended towards an asymptotic value

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Measurement of B(t->Wb)/B(t->Wq) at the Collider Detector at Fermilab

We present a measurement of the ratio of top-quark branching fractions R= B(t -> Wb)/B(t -> Wq), where q can be a b, s or a d quark, using lepton-plus-jets and dilepton data sets with integrated luminosity of ~162 pb^{-1} collected with the Collider Detector at Fermilab during Run II of the Tevatron. The measurement is derived from the relative numbers of t-tbar events with different multiplicity of identified secondary vertices. We set a lower limit of R > 0.61 at 95% confidence level.Comment: 7 pages, 2 figures, published in Physical Review Letters; changes made to be consistent with published versio

Search for ZZ and ZW Production in ppbar Collisions at sqrt(s) = 1.96 TeV

We present a search for ZZ and ZW vector boson pair production in ppbar collisions at sqrt(s) = 1.96 TeV using the leptonic decay channels ZZ --> ll nu nu, ZZ --> l l l' l' and ZW --> l l l' nu. In a data sample corresponding to an integrated luminosity of 194 pb-1 collected with the Collider Detector at Fermilab, 3 candidate events are found with an expected background of 1.0 +/- 0.2 events. We set a 95% confidence level upper limit of 15.2 pb on the cross section for ZZ plus ZW production, compared to the standard model prediction of 5.0 +/- 0.4 pb.Comment: 7 pages, 2 figures. This version is accepted for publication by Phys. Rev. D Rapid Communication