Weibull regression with Bayesian variable selection to identify prognostic tumour markers of breast cancer survival.

As data-rich medical datasets are becoming routinely collected, there is a growing demand for regression methodology that facilitates variable selection over a large number of predictors. Bayesian variable selection algorithms offer an attractive solution, whereby a sparsity inducing prior allows inclusion of sets of predictors simultaneously, leading to adjusted effect estimates and inference of which covariates are most important. We present a new implementation of Bayesian variable selection, based on a Reversible Jump MCMC algorithm, for survival analysis under the Weibull regression model. A realistic simulation study is presented comparing against an alternative LASSO-based variable selection strategy in datasets of up to 20,000 covariates. Across half the scenarios, our new method achieved identical sensitivity and specificity to the LASSO strategy, and a marginal improvement otherwise. Runtimes were comparable for both approaches, taking approximately a day for 20,000 covariates. Subsequently, we present a real data application in which 119 protein-based markers are explored for association with breast cancer survival in a case cohort of 2287 patients with oestrogen receptor-positive disease. Evidence was found for three independent prognostic tumour markers of survival, one of which is novel. Our new approach demonstrated the best specificity.PJN and SR were funded by the Medical Research Council. PJN also acknowledges partial support from the NIHR Cambridge Biomedical Research Centre.This is the accepted manuscript. The final version is available from SAGE at http://dx.doi.org/10.1177/096228021454874

A two-step method for variable selection in the analysis of a case-cohort study.

Background: Accurate detection and estimation of true exposure-outcome associations is important in aetiological analysis; when there are multiple potential exposure variables of interest, methods for detecting the subset of variables most likely to have true associations with the outcome of interest are required. Case-cohort studies often collect data on a large number of variables which have not been measured in the entire cohort (e.g. panels of biomarkers). There is a lack of guidance on methods for variable selection in case-cohort studies. Methods: We describe and explore the application of three variable selection methods to data from a case-cohort study. These are: (i) selecting variables based on their level of significance in univariable (i.e. one-at-a-time) Prentice-weighted Cox regression models; (ii) stepwise selection applied to Prentice-weighted Cox regression; and (iii) a two-step method which applies a Bayesian variable selection algorithm to obtain posterior probabilities of selection for each variable using multivariable logistic regression followed by effect estimation using Prentice-weighted Cox regression. Results: Across nine different simulation scenarios, the two-step method demonstrated higher sensitivity and lower false discovery rate than the one-at-a-time and stepwise methods. In an application of the methods to data from the EPIC-InterAct case-cohort study, the two-step method identified an additional two fatty acids as being associated with incident type 2 diabetes, compared with the one-at-a-time and stepwise methods. Conclusions: The two-step method enables more powerful and accurate detection of exposure-outcome associations in case-cohort studies. An R package is available to enable researchers to apply this method.P.J.N. and S.R. were supported by the Medical Research Council [www.mrc.ac.uk] (Unit Programme number MC_UP_0801/1). P.J.N. also acknowledges partial support from the NIHR Cambridge Biomedical Research Centre. S.S. and S.C. were supported by the Medical Research Council [www.mrc.ac.uk] (Unit Programme number MC_U105260558). S.J.S. was supported by the Medical Research Council [www.mrc.ac.uk] (Unit Programme number MC_UU_12015/1). Funding for the EPIC-InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197)

Advanced magnetic resonance imaging and neuropsychological assessment for detecting brain injury in a prospective cohort of university amateur boxers

$\textbf{Background/aim:}$ The safety of amateur and professional boxing is a contentious issue. We hypothesised that advanced magnetic resonance imaging and neuropsychological testing could provide evidence of acute and early brain injury in amateur boxers. $\textbf{Methods:}$ We recruited 30 participants from a university amateur boxing club in a prospective cohort study. Magnetic resonance imaging (MRI) and neuropsychological testing was performed at three time points: prior to starting training; within 48 hours following a first major competition to detect acute brain injury; and one year follow-up. A single MRI acquisition was made from control participants. Imaging analysis included cortical thickness measurements with Advanced Normalization Tools (ANTS) and FreeSurfer, voxel based morphometry (VBM), and Tract Based Spatial Statistics (TBSS). A computerized battery of neuropsychological tests was performed assessing attention, learning, memory and impulsivity. $\textbf{Results:}$ During the study period, one boxer developed seizures controlled with medication while another developed a chronic subdural hematoma requiring neurosurgical drainage. A total of 10 boxers contributed data at to the longitudinal assessment protocol. Reasons for withdrawal were: logistics (10), stopping boxing (7), withdrawal of consent (2), and development of a chronic subdural hematoma (1). No significant changes were detected using VBM, TBSS, cortical thickness measured with FreeSurfer or ANTS, either cross-sectionally at baseline, or longitudinally. Neuropsychological assessment of boxers found attention/concentration improved over time while planning and problem solving ability latency decreased after a bout but recovered after one year. $\textbf{Conclusion:}$ While this neuroimaging and neuropsychological assessment protocol could not detect any evidence of brain injury, one boxer developed seizures and another developed a chronic sub-dural haematoma.PJH is supported by a NIHR Research Professorship. VFJN is supported by a Health Foundation / Academy of Medical Sciences Clinician Scientist Fellowship. BJS holds a grant from the NIHR Brain Injury Healthcare Technology Co-operative. This study was supported through the Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). Control data were acquired with the support of the Medical Research Council as part of their Addiction Initiative (grant number G1000018), and a Pathfinder award from Medical Research Council (G0401099)

Verification of Decision Making Software in an Autonomous Vehicle: An Industrial Case Study

Correctness of autonomous driving systems is crucial as\ua0incorrect behaviour may have catastrophic consequences. Many different\ua0hardware and software components (e.g. sensing, decision making, actuation,\ua0and control) interact to solve the autonomous driving task, leading to a level of complexity that brings new challenges for the formal verification\ua0community. Though formal verification has been used to prove\ua0correctness of software, there are significant challenges in transferring\ua0such techniques to an agile software development process and to ensure\ua0widespread industrial adoption. In the light of these challenges, the identification\ua0of appropriate formalisms, and consequently the right verification\ua0tools, has significant impact on addressing them. In this paper, we\ua0evaluate the application of different formal techniques from supervisory\ua0control theory, model checking, and deductive verification to verify existing\ua0decision and control software (in development) for an autonomous\ua0vehicle. We discuss how the verification objective differs with respect tothe choice of formalism and the level of formality that can be applied.\ua0Insights from the case study show a need for multiple formal methods to\ua0prove correctness, the difficulty to capture the right level of abstraction\ua0to model and specify the formal properties for the verification objectives

Potential of heart fatty-acid binding protein, neurofilament light, interleukin-10 and S100 calcium-binding protein B in the acute diagnostics and severity assessment of traumatic brain injury

Background: There is substantial interest in blood biomarkers as fast and objective diagnostic tools for traumatic brain injury (TBI) in the acute setting. Methods: Adult patients (≥18) with TBI of any severity and indications for CT scanning and orthopaedic injury controls were prospectively recruited during 2011–2013 at Turku University Hospital, Finland. The severity of TBI was classified with GCS: GCS 13–15 was classified as mild (mTBI); GCS 9–12 as moderate (moTBI) and GCS 3–8 as severe (sTBI). Serum samples were collected within 24 hours of admission and biomarker levels analysed with high-performance kits. The ability of biomarkers to distinguish between severity of TBI and CT-positive and CT-negative patients was assessed. Results: Among 189 patients recruited, neurofilament light (NF-L) was obtained from 175 patients with TBI and 40 controls. S100 calcium-binding protein B (S100B), heart fatty-acid binding protein (H-FABP) and interleukin-10 (IL-10) were analysed for 184 patients with TBI and 39 controls. There were statistically significant differences between levels of all biomarkers between the severity classes, but none of the biomarkers distinguished patients with moTBI from patients with sTBI. Patients with mTBI discharged from the ED had lower levels of IL-10 (0.26, IQR=0.21, 0.39 pg/mL), H-FABP (4.15, IQR=2.72, 5.83 ng/mL) and NF-L (8.6, IQR=6.35, 15.98 pg/mL) compared with those admitted to the neurosurgical ward, IL-10 (0.55, IQR=0.31, 1.42 pg/mL), H-FABP (6.022, IQR=4.19, 20.72 ng/mL) and NF-L (13.95, IQR=8.33, 19.93 pg/mL). We observed higher levels of H-FABP and NF-L in older patients with mTBI. None of the biomarkers or their combinations was able to distinguish CT-positive (n=36) or CT-negative (n=58) patients with mTBI from controls. Conclusions: S100B, H-FABP, NF-L and IL-10 levels in patients with mTBI were significantly lower than in patients with moTBI and sTBI but alone or in combination, were unable to distinguish patients with mTBI from orthopaedic controls. This suggests these biomarkers cannot be used alone to diagnose mTBI in trauma patients in the acute setting. Data availability statement: Data are available on reasonable request. De-identified clinical, imaging and biochemical data not published within the article can be shared with a qualified investigator by request

Extended Cognition Hypothesis Applied to Computational Thinking in Computer Science Education

Computational thinking is a much-used concept in computer science education. Here we examine the concept from the viewpoint of the extended cognition hypothesis. The analysis reveals that the extent of the concept is limited by its strong historical roots in computer science and software engineering. According to the extended cognition hypothesis, there is no meaningful distinction between human cognitive functions and the technology. This standpoint promotes a broader interpretation of the human-technology interaction. Human cognitive processes spontaneously adapt available technology enhanced skills when technology is used in cognitively relevant levels and modalities. A new concept technology synchronized thinking is presented to denote this conclusion. More diverse and practical approach is suggested for the computer scienceeducation.Peer reviewe

Admission Levels of Interleukin 10 and Amyloid β 1–40 Improve the Outcome Prediction Performance of the Helsinki Computed Tomography Score in Traumatic Brain Injury

BACKGROUND: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). OBJECTIVE: To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. MATERIALS AND METHODS: ighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of β-amyloid isoforms 1–40 (Aβ40) and 1–42 (Aβ42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale—Extended 5–8, n = 49) and unfavorable (Glasgow Outcome Scale—Extended 1–4, n = 33) groups. The outcome was assessed 6–12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90–100%. RESULTS: The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9–100) and specificity of 22.4% (95% CI: 10.2–32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1–4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were Aβ40, Aβ42, and neurofilament light. The optimal panel included IL-10, Aβ40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7–6.2) with a sensitivity of 90.9% (95% CI: 81.8–100) and specificity of 59.2% (95% CI: 40.8–69.4). CONCLUSION: Admission plasma levels of IL-10 and Aβ40 significantly improve the prognostication ability of the HCTS after TBI

Cross-Sectional Surveys of the Prevalence of Follicular Trachoma and Trichiasis in The Gambia: Has Elimination Been Reached?

BACKGROUND: The Gambia's National Eye Health Programme has made a concerted effort to reduce the prevalence of trachoma. The present study had two objectives. The first was to conduct surveillance following mass drug administrations to determine whether The Gambia has reached the World Health Organization's (WHO) criteria for trachoma elimination, namely a prevalence of trachomatous inflammation-follicular (TF) of less than 5% in children aged 1 to 9 years. The second was to determine the prevalence of trichiasis (TT) cases unknown to the programme and evaluate whether these meet the WHO criteria of less than 0.1% in the total population. METHODOLOGY/PRINCIPAL FINDINGS: Three cross-sectional surveys were conducted between 2011 and 2013 to determine the prevalence of TF and TT in each of nine surveillance zones. Each zone was of similar size, with a population of 60,000 to 90,000, once urban settlements were excluded. Trachoma grading was carried out according to the WHO's simplified trachoma grading system. The prevalence of TF in children aged 1 to 9 years was less than 5% in each surveillance zone at each of the three surveys. The prevalence of TT cases varied by zone from 0 to 1.7% of adults greater than 14 years while the prevalence of TT cases unknown to the country's National Eye Health Programme was estimated at 0.15% total population. CONCLUSIONS/SIGNIFICANCE: The Gambia has reached the elimination threshold for TF in children. Further work is needed to bring the number of unknown TT cases below the elimination threshold

Mapping of Schistosomiasis and Soil-Transmitted Helminthiasis in the Regions of Centre, East and West Cameroon

Schistosomiasis and soil-transmitted helminthiasis (STH) are a major public health problem in Cameroon. The national control strategy of these diseases was based on historical data collected 25 years ago, which might be outdated in some situations due to several factors including control activities, improved or degraded sanitation and hygiene, socio-economic improvement and disease transmission dynamics. To help planning, improving control strategies and evaluation of control activities, there was a need to update the distribution of schistosomiasis and STH. We conducted parasitological surveys in three regions of Cameroon, i.e. Centre, East and West. Our results showed a significant decrease of STH infection prevalence and intensities in all these three regions, in comparison to previous mapping data, with an overall decline of prevalence from 81.1–93% to 10.5–46.6%. These results show the positive impact of annual deworming campaigns, and illustrate the progressive success of the national programme for the control of schistosomiasis and STH in Cameroon. Furthermore, our results showed an increase of the number of high transmission foci of schistosomiasis, and allowed identifying new health districts requiring mass treatment with praziquantel, and those where deworming should be reinforced

Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study

BACKGROUND: Coagulase negative staphylococcus (CONS) is the main cause of late-onset sepsis in Neonatal Intensive Care Units (NICU). Although CONS rarely causes fulminant sepsis, vancomycin is frequently used as empiric therapy. Indiscriminate use of vancomycin has been linked to the emergence of vancomycin resistant organisms. The objective of this study was to compare duration of CONS sepsis and mortality before and after implementation of a policy of selective vancomycin use and compare use of vancomycin between the 2 time periods. METHODS: A retrospective study was conducted of infants ≥4 days old, experiencing signs of sepsis with a first positive blood culture for CONS, during two 12-month periods. Late-onset sepsis was treated empirically with vancomycin and gentamicin during period 1, and cloxacillin and gentamicin during period 2. The confidence interval method was used to assess non-inferiority of the outcomes between the two study groups. RESULTS: There were 45 episodes of CONS sepsis during period 1 and 37 during period 2. Duration of sepsis was similar between periods (hazard ratio of 1.00, 95%CI: 0.64, 1.57). One death during period 2 was possibly related to CONS sepsis versus none in period 1. Vancomycin was used in 97.8% of episodes in period 1 versus 81.1% of episodes in period 2. CONCLUSION: Although we failed to show non-inferiority of duration of sepsis in the cloxacillin and gentamicin group compared to the vancomycin and gentamicin group, duration of sepsis was clinically similar. Restricting vancomycin for confirmed cases of CONS sepsis resistant to oxacillin appears effective and safe, and significantly reduces vancomycin use in the NICU