Approaches to the evaluation of outbreak detection methods

BACKGROUND: An increasing number of methods are being developed for the early detection of infectious disease outbreaks which could be naturally occurring or as a result of bioterrorism; however, no standardised framework for examining the usefulness of various outbreak detection methods exists. To promote comparability between studies, it is essential that standardised methods are developed for the evaluation of outbreak detection methods. METHODS: This analysis aims to review approaches used to evaluate outbreak detection methods and provide a conceptual framework upon which recommendations for standardised evaluation methods can be based. We reviewed the recently published literature for reports which evaluated methods for the detection of infectious disease outbreaks in public health surveillance data. Evaluation methods identified in the recent literature were categorised according to the presence of common features to provide a conceptual basis within which to understand current approaches to evaluation. RESULTS: There was considerable variation in the approaches used for the evaluation of methods for the detection of outbreaks in public health surveillance data, and appeared to be no single approach of choice. Four main approaches were used to evaluate performance, and these were labelled the Descriptive, Derived, Epidemiological and Simulation approaches. Based on the approaches identified, we propose a basic framework for evaluation and recommend the use of multiple approaches to evaluation to enable a comprehensive and contextualised description of outbreak detection performance. CONCLUSION: The varied nature of performance evaluation demonstrated in this review supports the need for further development of evaluation methods to improve comparability between studies. Our findings indicate that no single approach can fulfil all evaluation requirements. We propose that the cornerstone approaches to evaluation identified provide key contributions to support internal and external validity and comparability of study findings, and suggest these be incorporated into future recommendations for performance assessment

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Does Practice Make Perfect?

Extensive literature supports the correlation between surgical volume and improved clinical outcome in the management of various cancers. It is this evidence that has catalysed the creation of centres of excellence. However, on closer inspection, many of these studies are poor quality, low weight and use vastly heterogenous end points in assessment of both volume and outcome. We critically appraise the English language literature published over the last ten years pertaining to the volume outcome relationship in the context of cancer care. Future balanced unbiased studies may enable equipoise in planning international cancer management strategies

Retaining women in a prenatal care randomized controlled trial in Canada: implications for program planning

<p>Abstract</p> <p>Background:</p> <p>Challenges to retention in prenatal care seem to exist under both universal systems of care, as in Canada, and non-universal systems of care, as in the United States. However, among populations being served by a system of publicly funded health care, the barriers are less well understood and universal uptake of prenatal services has not been realized. Determining the characteristics of women who dropped out of a prenatal care randomized controlled trial can help identify those who may need alternate retention and service approaches.</p> <p>Methods:</p> <p>In this study, pregnant women were randomized to: a) current standard of care; b) 'a' plus nursing support; or c) 'b' plus a paraprofessional home visitor. 16% of 2,015 women did not complete all three telephone interviews (197 dropped out and 124 became unreachable). Responders were compared to non-responders on demographics, lifestyle, psychosocial factors, and life events using chi-squared tests. Logistic regression models were constructed using stepwise logistic regression to determine the probability of not completing the prenatal program.</p> <p>Results:</p> <p>Completion rates did not differ by intervention. In comparison to responders, non-responders were more likely to be younger, less educated, have lower incomes, smoke, have low social support, have a history of depression, and have separated or divorced parents (all p < 0.05). Unreachable women were more likely to be single, use drugs, report distress and adverse life events (all p < 0.05). Non-Caucasian women were more likely to drop out (p = 0.002). Logistic regression modeling indicated that independent key risk factors for dropping out were: less than high school education, separated or divorced parents, lower social support, and being non-Caucasian. Pregnant women who were single/separated/divorced, less than 25 years old, had less than high school education, earned less than $40,000 in annual household income, and/or smoked had greater odds of becoming unreachable at some point during pregnancy and not completing the study.</p> <p>Conclusion:</p> <p>Women at risk due to lifestyle and challenging circumstances were difficult to retain in a prenatal care study, regardless of the intervention. For women with complex health, lifestyle and social issues, lack of retention may reflect incongruence between their needs and the program.</p> <p>Trial registration:</p> <p>Current Controlled Trials ISRCTN64070727</p

Role of Germination in Murine Airway CD8+ T-Cell Responses to Aspergillus Conidia

Pulmonary exposure to Aspergillus fumigatus has been associated with morbidity and mortality, particularly in immunocompromised individuals. A. fumigatus conidia produce β-glucan, proteases, and other immunostimulatory factors upon germination. Murine models have shown that the ability of A. fumigatus to germinate at physiological temperature may be an important factor that facilitates invasive disease. We observed a significant increase in IFN-γ-producing CD8+ T cells in bronchoalveolar lavage fluid (BALF) of immunocompetent mice that repeatedly aspirated A. fumigatus conidia in contrast to mice challenged with A. versicolor, a species that is not typically associated with invasive, disseminated disease. Analysis of tissue sections indicated the presence of germinating spores in the lungs of mice challenged with A. fumigatus, but not A. versicolor. Airway IFN-γ+CD8+ T-cells were decreased and lung germination was eliminated in mice that aspirated A. fumigatus conidia that were formaldehyde-fixed or heat-inactivated. Furthermore, A. fumigatus particles exhibited greater persistence in the lungs of recipient mice when compared to non-viable A. fumigatus or A. versicolor, and this correlated with increased maintenance of airway memory-phenotype CD8+ T cells. Therefore, murine airway CD8+ T cell-responses to aspiration of Aspergillus conidia may be mediated in part by the ability of conidia to germinate in the host lung tissue. These results provide further evidence of induction of immune responses to fungi based on their ability to invade host tissue

Prioritizing single-nucleotide variations that potentially regulate alternative splicing

Recent evidence suggests that many complex diseases are caused by genetic variations that play regulatory roles in controlling gene expression. Most genetic studies focus on nonsynonymous variations that can alter the amino acid composition of a protein and are therefore believed to have the highest impact on phenotype. Synonymous variations, however, can also play important roles in disease pathogenesis by regulating pre-mRNA processing and translational control. In this study, we systematically survey the effects of single-nucleotide variations (SNVs) on binding affinity of RNA-binding proteins (RBPs). Among the 10,113 synonymous SNVs identified in 697 individuals in the 1,000 Genomes Project and distributed by Genetic Analysis Workshop 17 (GAW17), we identified 182 variations located in alternatively spliced exons that can significantly change the binding affinity of nine RBPs whose binding preferences on 7-mer RNA sequences were previously reported. We found that the minor allele frequencies of these variations are similar to those of nonsynonymous SNVs, suggesting that they are in fact functional. We propose a workflow to identify phenotype-associated regulatory SNVs that might affect alternative splicing from exome-sequencing-derived genetic variations. Based on the affecting SNVs on the quantitative traits simulated in GAW17, we further identified two and four functional SNVs that are predicted to be involved in alternative splicing regulation in traits Q1 and Q2, respectively

Glue ear, hearing loss and IQ:an association moderated by the child's home environment

BACKGROUND: Glue ear or otitis media with effusion (OME) is common in children and may be associated with hearing loss (HL). For most children it has no long lasting effects on cognitive development but it is unclear whether there are subgroups at higher risk of sequelae. OBJECTIVES: To examine the association between a score comprising the number of times a child had OME and HL (OME/HL score) in the first four/five years of life and IQ at age 4 and 8. To examine whether any association between OME/HL and IQ is moderated by socioeconomic, child or family factors. METHODS: Prospective, longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). 1155 children tested using tympanometry on up to nine occasions and hearing for speech (word recognition) on up to three occasions between age 8 months and 5 years. An OME/HL score was created and associations with IQ at ages 4 and 8 were examined. Potential moderators included a measure of the child's cognitive stimulation at home (HOME score). RESULTS: For the whole sample at age 4 the group with the highest 10% OME/HL scores had performance IQ 5 points lower [95% CI -9, -1] and verbal IQ 6 points lower [95% CI -10, -3] than the unaffected group. By age 8 the evidence for group differences was weak. There were significant interactions between OME/HL and the HOME score: those with high OME/HL scores and low 18 month HOME scores had lower IQ at age 4 and 8 than those with high OME/HL scores and high HOME scores. Adjusted mean differences ranged from 5 to 8 IQ points at age 4 and 8. CONCLUSIONS: The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss