On Nesting Monte Carlo Estimators

Many problems in machine learning and statistics involve nested expectations and thus do not permit conventional Monte Carlo (MC) estimation. For such problems, one must nest estimators, such that terms in an outer estimator themselves involve calculation of a separate, nested, estimation. We investigate the statistical implications of nesting MC estimators, including cases of multiple levels of nesting, and establish the conditions under which they converge. We derive corresponding rates of convergence and provide empirical evidence that these rates are observed in practice. We further establish a number of pitfalls that can arise from naive nesting of MC estimators, provide guidelines about how these can be avoided, and lay out novel methods for reformulating certain classes of nested expectation problems into single expectations, leading to improved convergence rates. We demonstrate the applicability of our work by using our results to develop a new estimator for discrete Bayesian experimental design problems and derive error bounds for a class of variational objectives.Comment: To appear at International Conference on Machine Learning 201

Life-time monitoring of in service switches and crossings through field experimentation

In financial year 2011/2012, Switches and crossings (S&C) cost the UK rail infrastructure owner, operator and maintainer, Network Rail, over £220m in maintenance and £189m in renewals. This represented 24% of the total track maintenance budget, whilst accounting for only 5% of the network mileage. The large costs are due to the complex S&C design that allows network flexibility whilst supporting a vehicle traversing from the switch rail to the stock rail and through the crossing. The motivation for undertaking this research was to understand how S&C reacts to dynamic loading imposed by the vehicles, and to gain a better knowledge of the deterioration of the asset. The understanding and measurement of S&C degradation has never been scientifically measured in real time before, which means that currently the maintenance schedules are cyclic or reactive. The outcome from this investigation could be used to provide a finely calibrated pre-emptive schedule for more effective S&C maintenance and investment. Eight sites were outlined in the design of experiments, of which four were instrumented as part of the first phase of the research in this thesis. High wear and fatigue rates from prior failure statistical analysis showed the need to understand the loading and degradation of S&C. Strain gauges, geophones and accelerometers were used to understand the system reaction to loading, through strain and the sleeper deflection within S&C. The results show that the largest increase in strain over time was at the stock rail with the closed switch rail. The degradation is due to the increased dynamic forces of the vehicle transferring from one line to another. The change in strain indicates that the additional vibrations / frequencies will occur over time, increasing the rate of material change. As speed increases through switches and crossings, a reduction in the strain generated is seen at the gauge locations. This indicates that switches demonstrate lower levels of wear with a higher speed at the locations of the gauges. Degradation of vertical motion of sleepers at the crossing is shown, with no change in the bending strain generated due to the whole asset deforming at a similar rate. Key words: S&C instrumentation, deterioration, strain gauge, vertical displacementOpen Acces

The Roles of Dopamine and Related Compounds in Reward-Seeking Behavior Across Animal Phyla

Motile animals actively seek out and gather resources they find rewarding, and this is an extremely powerful organizer and motivator of animal behavior. Mammalian studies have revealed interconnected neurobiological systems for reward learning, reward assessment, reinforcement and reward-seeking; all involving the biogenic amine dopamine. The neurobiology of reward-seeking behavioral systems is less well understood in invertebrates, but in many diverse invertebrate groups, reward learning and responses to food rewards also involve dopamine. The obvious exceptions are the arthropods in which the chemically related biogenic amine octopamine has a greater effect on reward learning and reinforcement than dopamine. Here we review the functions of these biogenic amines in behavioral responses to rewards in different animal groups, and discuss these findings in an evolutionary context

Defining adolescent common mental disorders using electronic primary care data: a comparison with outcomes measured using the CIS-R

OBJECTIVE: To compare the prevalence of common mental disorders (CMDs) derived from data held in primary care records with that measured using the revised Clinical Interview Schedule (CIS-R) in order to assess the potential robustness of findings based only on routinely collected data. DESIGN AND SETTING: Comparison study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic primary care records. PARTICIPANTS: We studied 1562 adolescents who had completed the CIS-R in ALSPAC at age 17–18 years and had linkage established to their primary care records. OUTCOME MEASURES: Outcome measures from ALSPAC were whether or not an individual met International Classification of Diseases-10 criteria for a diagnosis of (1) a CMD or, specifically, (2) depression. Lists of Read codes corresponding to diagnoses, symptoms and treatments were used to create 12 definitions of CMD and depression alone using the primary care data. We calculated sensitivities and specificities of these, using CIS-R definitions as the reference standard. RESULTS: Sensitivities ranged from 5.2% to 24.3% for depression and from 3.8% to 19.2% for CMD. The specificities of all definitions were above 98% for depression and above 96% for CMD. For both outcomes, the definition that included current diagnosis, treatment or symptoms identified the highest proportion of CIS-R cases. CONCLUSIONS: Most individuals meeting case definitions for CMD based on primary care data also met CIS-R case definitions. Conversely many individuals identified as cases using the CIS-R had no evidence of CMD in their clinical records. This suggests that clinical databases are likely to yield underestimates of the burden of CMD in the population. However, clinical records appear to yield valid diagnoses which may be useful for studying risk factors and consequences of CMD. The greatest epidemiological value may be obtained when information is available from survey and clinical records

Structure-functional relationship of cellular retinoic acid binding proteins I and II interacting with natural and synthetic ligands

A detailed understanding of the interactions between small-molecule ligands and their proposed binding targets is of the utmost importance for modern drug-development programs. Cellular retinoic acid-binding proteins I and II (CRABPI and CRABPII) facilitate a number of vital retinoid signalling pathways in mammalian cells and offer a gateway to manipulation of signalling that could potentially reduce phenotypes in serious diseases, including cancer and neurodegeneration. Although structurally very similar, the two proteins possess distinctly different biological functions, with their signalling influence being exerted through both genomic and nongenomic pathways. In this article, crystal structures are presented of the L29C mutant of Homo sapiens CRABPI in complex with naturally occurring fatty acids (1.64 A˚ resolution) and with the synthetic retinoid DC645 (2.41 A˚ resolution), and of CRABPII in complex with the ligands DC479 (1.80 A˚ resolution) and DC645 (1.71 A˚ resolution). DC645 and DC479 are two potential drug compounds identified in a recent synthetic retinoid development program. In particular, DC645 has recently been shown to have disease-modifying capabilities in neurodegenerative disease models by activating both genomic and nongenomic signalling pathways. These co-crystal structures demonstrate a canonical binding behaviour akin to that exhibited with all-trans-retinoic acid and help to explain how the compounds are able to exert an influence on part of the retinoid signalling cascade

Modulation Transfer Spectroscopy of the D1 Transition of Potassium: Theory and Experiment

We report on a study of modulation transfer spectroscopy of the $4\textrm{S}_{1/2}\rightarrow 4\textrm{P}_{1/2}$ ($D_{1}$) transition of naturally abundant potassium in a room-temperature vapour cell. This transition is critical for laser cooling and optical pumping of potassium and our study is therefore motivated by the need for robust laser frequency stabilisation. Despite the absence of a closed transition, the small ground-state hyperfine splitting in potassium results in strong crossover features in the $D_{1}$ modulation transfer spectrum. To emphasise this we compare the $D_{1}$ and $D_{2}$ spectra of potassium with those of rubidium. Further, we compare our experimental results with a detailed theoretical simulation, examining different pump-probe polarization configurations to identify the optimal signals for laser frequency stabilisation. We find good agreement between the experiment and the theory, especially for the $\textrm{lin} \parallel \textrm{lin}$ polarization configuration

The impact of cycle proficiency training on cycle-related behaviours and accidents in adolescence:Findings from ALSPAC, a UK longitudinal cohort

Abstract Background Cycle accidents are a common cause of physical injury in children and adolescents. Education is one strategy to reduce cycle-related injuries. In the UK, some children undertake National Cycle Proficiency Scheme [NCPS] training (now known as Bikeability) in their final years of primary school. It aims to promote cycling and safe cycling behaviours but there has been little scientific evaluation of its effectiveness. Methods The sample (n = 5415) were participants in the Avon Longitudinal Study of Parents and Children who reported whether or not they had received NCPS training. Outcomes were self-reported at 14 and 16 years: cycling to school, ownership of cycle helmet, use of cycle helmet and high-visibility clothing on last cycle, and involvement in a cycle accident. An additional outcome, hospital admittance due to a cycle accident from 11 to 16 years, was also included for a subsample (n = 2222) who have been linked to Hospital Episode Statistics (HES) data. Results Approximately 40 % of the sample had received NCPS training. Trained children were more likely to cycle to school and to own a cycle helmet at both 14 and 16 years, to have worn a helmet on their last cycle at age 14, and to have worn high-visibility clothing at age 16, than those who had not attended a course. NCPS training was not associated with self-reported involvement in a cycle accident, and only six of those with HES data had been admitted to hospital due to a cycle accident. Irrespective of training, results indicate very low use of high-visibility clothing, very few girls cycling as part of their school commute, and less than half of helmet owners wearing one on their last cycle. Conclusions Our results suggest cycle training courses for children can have benefits that persist into adolescence. However, the low use of cycle helmets, very low use of high-visibility clothing, and low levels of cycling to school for girls, indicate the further potential for interventions to encourage cycling, and safe cycling behaviours, in young people

Association between tumour somatic mutations and venous thromboembolism in the 100,000 Genomes Project cancer cohort:A study protocol

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with cancer, and there is evidence that specific aberrations in tumour biology contribute to the pathophysiology of this condition. We plan to examine the association between tumour somatic mutations and VTE in an existing cohort of patients with cancer, who were enrolled to the flagship Genomics England 100,000 Genomes Project. Here, we outline an a-priori analysis plan to address this objective, including details on study cohort selection, exposure and outcome definitions, annotation of genetic variants and planned statistical analyses. We will assess the effect of 1) deleterious somatic DNA variants in each gene; 2) tumour mutational burden and 3) tumour mutational signatures on the rate of VTE (outcome) in a pan-cancer cohort. Sensitivity analyses will be performed to examine the robustness of any associations, including adjustment for potentially correlated co-variates including tumour type, stage and systemic anti-cancer therapy. We hope that results from this study may help to identify key genes which are implicated in the development of cancer associated thrombosis, which may shed light on related mechanistic pathways and/or provide data which can be integrated into genetic risk prediction models for these patients

Socio-demographic patterns in hospital admissions and accident and emergency attendances among young people using linkage to NHS Hospital Episode Statistics:results from the Avon Longitudinal Study of Parents and Children

Abstract Background In England emergency hospital admissions among children are increasing and the under 25s are the most frequent attenders of A&E departments. Children of lower socio-economic status (SES) have poorer health outcomes and higher hospital admission rates. NHS Hospital Episode Statistics (HES) are increasingly being used for research but lack detailed data on individual characteristics such as SES. We report the results of an Avon Longitudinal Study of Parents and Children (ALSPAC) study that linked the data of 3,189 consenting participants to HES. We describe rates of hospital admission, emergency readmissions, and A&E attendances and examine socio-demographic correlates of these. Methods Subjects were singletons and twins enrolled in ALSPAC who had provided consent for linkage to their health records by the study cut-off date (31.02.12). Linkage was carried out by the Health and Social Care Information Centre (now NHS Digital). We examined rates of admissions between birth and age 20 and A&E attendances between 14 and 20 years. Socio-demographic information collected in ALSPAC questionnaires during pregnancy were used to examine factors associated with admissions, emergency readmissions (an emergency admission within 30 days of discharge) and A&E attendances. Results Excluding birth records, we found at least one admission for 1,792/3,189 (56.2%) participants and 4,305 admissions in total. Admission rates were highest in the first year of life. Among males, admissions declined until about age 5 and then remained relatively stable; conversely, among females, they increased sharply from the age of 15. ICD 10 chapters for diseases of the digestive system and injury and poisoning accounted for the largest proportions of admissions (15.8 and 14.5%, respectively). Tooth decay was the highest single cause of admission for those aged 5–9 years. Overall, 1,518/3,189 (47.6%) of participants attended A&E at least once, with a total of 3,613 attendances between age 14 and 20 years. Individuals from more deprived backgrounds had higher rates of admissions, readmissions and A&E attendances. Conclusions Linkage between cohort studies such as ALSPAC and HES data provides unique opportunities for detailed insights into socio-demographic and other determinants of hospital activity, which can inform secondary care demand management in the NHS