Methods for estimating the case fatality ratio for a novel, emerging infectious disease.

During the course of an epidemic of a potentially fatal disease, it is important that the case fatality ratio be well estimated. The authors propose a novel method for doing so based on the Kaplan-Meier survival procedure, jointly considering two outcomes (death and recovery), and evaluate its performance by using data from the 2003 epidemic of severe acute respiratory syndrome in Hong Kong, People's Republic of China. They compare this estimate obtained at various points in the epidemic with the case fatality ratio eventually observed; with two commonly quoted, naïve estimates derived from cumulative incidence and mortality statistics at single time points; and with estimates in which a parametric mixture model is used. They demonstrate the importance of patient characteristics regarding outcome by analyzing subgroups defined by age at admission to the hospital

A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

Differences in smoking associated DNA methylation patterns in South Asians and Europeans

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Background DNA methylation is strongly associated with smoking status at multiple sites across the genome. Studies have largely been restricted to European origin individuals yet the greatest increase in smoking is occurring in low income countries, such as the Indian subcontinent. We determined whether there are differences between South Asians and Europeans in smoking related loci, and if a smoking score, combining all smoking related DNA methylation scores, could differentiate smokers from non-smokers. Results Illumina HM450k BeadChip arrays were performed on 192 samples from the Southall And Brent REvisited (SABRE) cohort. Differential methylation in smokers was identified in 29 individual CpG sites at 18 unique loci. Interaction between smoking status and ethnic group was identified at the AHRR locus. Ethnic differences in DNA methylation were identified in non-smokers at two further loci, 6p21.33 and GNG12. With the exception of GFI1 and MYO1G these differences were largely unaffected by adjustment for cell composition. A smoking score based on methylation profile was constructed. Current smokers were identified with 100% sensitivity and 97% specificity in Europeans and with 80% sensitivity and 95% specificity in South Asians. Conclusions Differences in ethnic groups were identified in both single CpG sites and combined smoking score. The smoking score is a valuable tool for identification of true current smoking behaviour. Explanations for ethnic differences in DNA methylation in association with smoking may provide valuable clues to disease pathways.Wellcome Trust Enhancement grantMedical Research CouncilDiabetes UKthe British Heart Foundatio

Bayesian Best-Arm Identification for Selecting Influenza Mitigation Strategies

Pandemic influenza has the epidemic potential to kill millions of people. While various preventive measures exist (i.a., vaccination and school closures), deciding on strategies that lead to their most effective and efficient use remains challenging. To this end, individual-based epidemiological models are essential to assist decision makers in determining the best strategy to curb epidemic spread. However, individual-based models are computationally intensive and it is therefore pivotal to identify the optimal strategy using a minimal amount of model evaluations. Additionally, as epidemiological modeling experiments need to be planned, a computational budget needs to be specified a priori. Consequently, we present a new sampling technique to optimize the evaluation of preventive strategies using fixed budget best-arm identification algorithms. We use epidemiological modeling theory to derive knowledge about the reward distribution which we exploit using Bayesian best-arm identification algorithms (i.e., Top-two Thompson sampling and BayesGap). We evaluate these algorithms in a realistic experimental setting and demonstrate that it is possible to identify the optimal strategy using only a limited number of model evaluations, i.e., 2-to-3 times faster compared to the uniform sampling method, the predominant technique used for epidemiological decision making in the literature. Finally, we contribute and evaluate a statistic for Top-two Thompson sampling to inform the decision makers about the confidence of an arm recommendation

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

An empirical approach towards the efficient and optimal production of influenza-neutralizing ovine polyclonal antibodies demonstrates that the novel adjuvant CoVaccine HT(TM) is functionally superior to Freund's adjuvant

Passive immunotherapies utilising polyclonal antibodies could have a valuable role in preventing and treating infectious diseases such as influenza, particularly in pandemic situations but also in immunocompromised populations such as the elderly, the chronically immunosuppressed, pregnant women, infants and those with chronic diseases. The aim of this study was to optimise current methods used to generate ovine polyclonal antibodies. Polyclonal antibodies to baculovirus-expressed recombinant influenza haemagglutinin from A/Puerto Rico/8/1934 H1N1 (PR8) were elicited in sheep using various immunisation regimens designed to investigate the priming immunisation route, adjuvant formulation, sheep age, and antigen dose, and to empirically ascertain which combination maximised antibody output. The novel adjuvant CoVaccine HT™ was compared to Freund’s adjuvant which is currently the adjuvant of choice for commercial production of ovine polyclonal Fab therapies. CoVaccine HT™ induced significantly higher titres of functional ovine anti-haemagglutinin IgG than Freund’s adjuvant but with fewer side effects, including reduced site reactions. Polyclonal hyperimmune sheep sera effectively neutralised influenza virus in vitro and, when given before or after influenza virus challenge, prevented the death of infected mice. Neither the age of the sheep nor the route of antigen administration appeared to influence antibody titre. Moreover, reducing the administrated dose of haemagglutinin antigen minimally affected antibody titre. Together, these results suggest a cost effective way of producing high and sustained yields of functional ovine polyclonal antibodies specifically for the prevention and treatment of globally significant diseases.Natalie E. Stevens, Cara K. Fraser, Mohammed Alsharifi, Michael P. Brown, Kerrilyn R. Diener, John D. Haybal

Social representations and the politics of participation

Recent work has called for the integration of different perspectives into the field of political psychology (Haste, 2012). This chapter suggests that one possible direction that such efforts can take is studying the role that social representations theory (SRT) can play in understanding political participation and social change. Social representations are systems of common-sense knowledge and social practice; they provide the lens through which to view and create social and political realities, mediate people's relations with these sociopolitical worlds and defend cultural and political identities. Social representations are therefore key for conceptualising participation as the activity that locates individuals and social groups in their sociopolitical world. Political participation is generally seen as conditional to membership of sociopolitical groups and therefore is often linked to citizenship. To be a citizen of a society or a member of any social group one has to participate as such. Often political participation is defined as the ability to communicate one's views to the political elite or to the political establishment (Uhlaner, 2001), or simply explicit involvement in politics and electoral processes (Milbrath, 1965). However, following scholars on ideology (Eagleton, 1991; Thompson, 1990) and social knowledge (Jovchelovitch, 2007), we extend our understanding of political participation to all social relations and also develop a more agentic model where individuals and groups construct, develop and resist their own views, ideas and beliefs. We thus adopt a broader approach to participation in comparison to other political-psychological approaches, such as personality approaches (e.g. Mondak and Halperin, 2008) and cognitive approaches or, more recently, neuropsychological approaches (Hatemi and McDermott, 2012). We move away from a focus on the individual's political behaviour and its antecedents and outline an approach that focuses on the interaction between psychological and political phenomena (Deutsch and Kinnvall, 2002) through examining the politics of social knowledge

Perceived risk, anxiety, and behavioural responses of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands: Results of three consecutive online surveys

Background: Research into risk perception and behavioural responses in case of emerging infectious diseases is still relatively new. The aim of this study was to examine perceptions and behaviours of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands. Methods. Two cross-sectional and one follow-up online survey (survey 1, 30 April-4 May; survey 2, 15-19 June; survey 3, 11-20 August 2009). Adults aged 18 years and above participating in a representative Internet panel were invited (survey 1, n = 456; survey 2, n = 478; follow-up survey 3, n = 934). Main outcome measures were 1) time trends in risk perception, feelings of anxiety, and behavioural responses (survey 1-3) and 2) factors associated with taking preventive measures and strong intention to comply with government-advised preventive measures in the future (survey 3). Results. Between May and August 2009, the level of knowledge regarding Influenza A (H1N1) increased, while perceived severity of the new flu, perceived self-efficacy, and intention to comply with preventive measures decreased. The perceived reliability of information from the government decreased from May to August (62% versus 45%). Feelings of anxiety decreased from May to June, and remained stable afterwards. From June to August 2009, perceived vulnerability increased and more respondents took preventive measures (14% versus 38%). Taking preventive measures was associated with no children in the household, high anxiety, high self-efficacy, more agreement with statements on avoidance, and paying much attention to media information regarding Influenza A (H1N1). Having a strong intention to comply with government-advised preventive measures in the future was associated with higher age, high perceived severity, high anxiety, high perceived efficacy of measures, high self-efficacy, and finding governmental information to be reliable. Conclusions. Decreasing tren

Evolutionary genetics of immunological supertypes reveals two faces of the Red Queen

Red Queen host-parasite co-evolution can drive adaptations of immune-genes by positive selection that erodes genetic variation (Red Queen Arms Race), or result in a balanced polymorphism (Red Queen Dynamics) and the long-term preservation of genetic variation (trans-species polymorphism). These two Red Queen processes are opposite extremes of the co-evolutionary spectrum. Here we show that both Red Queen processes can operate simultaneously, analyzing the Major Histocompatibility Complex (MHC) in guppies (Poecilia reticulata and P. obscura), and swamp guppies (Micropoecilia picta). Sub-functionalization of MHC alleles into “supertypes” explains how polymorphisms persist during rapid host-parasite co-evolution. Simulations show the maintenance of supertypes as balanced polymorphisms, consistent with Red Queen Dynamics, whereas alleles within supertypes are subject to positive selection in a Red Queen Arms Race. Building on the Divergent Allele Advantage hypothesis, we show that functional aspects of allelic diversity help to elucidate the evolution of polymorphic genes involved in Red Queen co-evolution