Integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents

Parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. A multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, Plasmodium berghei-mouse, Trypanosoma brucei brucei-mouse, Schistosoma mansoni-mouse, and Fasciola hepatica-rat were statistically coanalyzed. 1H NMR spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and noninfected animals. Each parasite generated a unique metabolic signature in the host. Plasma cytokine concentrations were obtained using the ‘Meso Scale Discovery’ multi cytokine assay platform. Multivariate data integration methods were subsequently used to elucidate the component of the metabolic signature which is associated with inflammation and to determine specific metabolic correlates with parasite-induced changes in plasma cytokine levels. For example, the relative levels of acetyl glycoproteins extracted from the plasma metabolite profile in the P. berghei-infected mice were statistically correlated with IFN-γ, whereas the same cytokine was anticorrelated with glucose levels. Both the metabolic and the cytokine data showed a similar spatial distribution in principal component analysis scores plots constructed for the combined murine data, with samples from all infected animals clustering according to the parasite species and whereby the protozoan infections (P. berghei and T. b. brucei) grouped separately from the helminth infection (S. mansoni). For S. mansoni, the main infection-responsive cytokines were IL-4 and IL-5, which covaried with lactate, choline, and D-3-hydroxybutyrate. This study demonstrates that the inherently differential immune response to single and multicellular parasites not only manifests in the cytokine expression, but also consequently imprints on the metabolic signature, and calls for in-depth analysis to further explore direct links between immune features and biochemical pathways.

The Gly482Ser genotype at the PPARGC1A gene and elevated blood pressure: a meta-analysis involving 13,949 individuals.

The protein encoded by the PPARGC1A gene is expressed at high levels in metabolically active tissues and is involved in the control of oxidative stress via reactive oxygen species detoxification. Several recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used conventional meta-analysis methods to assess the association between Gly482Ser and systolic (SBP) or diastolic blood pressures (DBP) or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The studies comprised cohorts of white European, Asian, and American Indian adults, and adolescents from South America. Stratified analyses were conducted to control for population stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser), and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP [Gly482Gly: mean = 131.0 mmHg, 95% confidence interval (CI) = 130.5-131.5 mmHg; Gly482Ser mean = 133.1 mmHg, 95% CI = 132.6-133.6 mmHg; Ser482Ser: mean = 133.5 mmHg, 95% CI = 132.5-134.5 mmHg; P = 0.409] or DBP (Gly482Gly: mean = 80.3 mmHg, 95% CI = 80.0-80.6 mmHg; Gly482Ser mean = 81.5 mmHg, 95% CI = 81.2-81.8 mmHg; Ser482Ser: mean = 82.1 mmHg, 95% CI = 81.5-82.7 mmHg; P = 0.651). Contrary to previous reports, we did not observe significant effect modification by sex (SBP, P = 0.966; DBP, P = 0.715). We were also unable to confirm the previously reported association between the Ser482 allele and hypertension [odds ratio: 0.97, 95% CI = 0.87-1.08, P = 0.585]. These results were materially unchanged when analyses were focused on whites only. However, statistical evidence of gene-age interaction was apparent for DBP [Gly482Gly: 73.5 (72.8, 74.2), Gly482Ser: 77.0 (76.2, 77.8), Ser482Ser: 79.1 (77.4, 80.9), P = 4.20 x 10(-12)] and SBP [Gly482Gly: 121.4 (120.4, 122.5), Gly482Ser: 125.9 (124.6, 127.1), Ser482Ser: 129.2 (126.5, 131.9), P = 7.20 x 10(-12)] in individuals <50 yr (n = 2,511); these genetic effects were absent in those older than 50 yr (n = 5,088) (SBP, P = 0.41; DBP, P = 0.51). Our findings suggest that the PPARGC1A Ser482 allele may be associated with higher blood pressure, but this is only apparent in younger adults.

Medieval foreign exchange: a time series analysis

This chapter applies rigorous statistical analysis to existing datasets of medieval exchange rates quoted in merchants’ letters sent from Barcelona, Bruges and Venice between 1380 and 1310, which survive in the archive of Francesco di Marco Datini of Prato. First, it tests the exchange rates for stationarity. Second, it uses regression analysis to examine the seasonality of exchange rates at the three financial centres and compares them against contemporary descriptions by the merchant Giovanni di Antonio da Uzzano. Third, it tests for structural breaks in the exchange rate series.

Can knowledge of the state of the stratosphere be used to improve statistical forecasts of the troposphere?

Recent analysis of the Arctic Oscillation (AO) in the stratosphere and troposphere has suggested that predictability of the state of the tropospheric AO may be obtained from the state of the stratospheric AO. However, much of this research has been of a purely qualitative nature. We present a more thorough statistical analysis of a long AO amplitude dataset which seeks to establish the magnitude of such a link. A relationship between the AO in the lower stratosphere and on the 1000 hPa surface on a 10-45 day time-scale is revealed. The relationship accounts for 5% of the variance of the 1000 hPa time series at its peak value and is significant at the 5% level. Over a similar time-scale the 1000 hPa time series accounts for 1% of itself and is not significant at the 5% level. Further investigation of the relationship reveals that it is only present during the winter season and in particular during February and March. It is also demonstrated that using stratospheric AO amplitude data as a predictor in a simple statistical model results in a gain of skill of 5% over a troposphere-only statistical model. This gain in skill is not repeated if an unrelated time series is included as a predictor in the model. Copyright © 2003 Royal Meteorological Society

Estimators in capture–recapture studies with two sources

This paper investigates the applications of capture–recapture methods to human populations. Capture–recapture methods are commonly used in estimating the size of wildlife populations but can also be used in epidemiology and social sciences, for estimating prevalence of a particular disease or the size of the homeless population in a certain area. Here we focus on estimating the prevalence of infectious diseases. Several estimators of population size are considered: the Lincoln–Petersen estimator and its modified version, the Chapman estimator, Chao’s lower bound estimator, the Zelterman’s estimator, McKendrick’s moment estimator and the maximum likelihood estimator. In order to evaluate these estimators, they are applied to real, three-source, capture-recapture data. By conditioning on each of the sources of three source data, we have been able to compare the estimators with the true value that they are estimating. The Chapman and Chao estimators were compared in terms of their relative bias. A variance formula derived through conditioning is suggested for Chao’s estimator, and normal 95% confidence intervals are calculated for this and the Chapman estimator. We then compare the coverage of the respective confidence intervals. Furthermore, a simulation study is included to compare Chao’s and Chapman’s estimator. Results indicate that Chao’s estimator is less biased than Chapman’s estimator unless both sources are independent. Chao’s estimator has also the smaller mean squared error. Finally, the implications and limitations of the above methods are discussed, with suggestions for further development.

Estimators in capture-recapture studies with two sources

This paper investigates the applications of capture-recapture methods to human populations. Capture-recapture methods are commonly used in estimating the size of wildlife populations but can also be used in epidemiology and social sciences, for estimating prevalence of a particular disease or the size of the homeless population in a certain area. Here we focus on estimating the prevalence of infectious diseases. Several estimators of population size are considered: the Lincoln-Petersen estimator and its modified version, the Chapman estimator, Chao's lower bound estimator, the Zelterman's estimator, McKendrick's moment estimator and the maximum likelihood estimator. In order to evaluate these estimators, they are applied to real, three-source, capture-recapture data. By conditioning on each of the sources of three source data, we have been able to compare the estimators with the true value that they are estimating. The Chapman and Chao estimators were compared in terms of their relative bias. A variance formula derived through conditioning is suggested for Chao's estimator, and normal 95% confidence intervals are calculated for this and the Chapman estimator. We then compare the coverage of the respective confidence intervals. Furthermore, a simulation study is included to compare Chao's and Chapman's estimator. Results indicate that Chao's estimator is less biased than Chapman's estimator unless both sources are independent. Chao's estimator has also the smaller mean squared error. Finally, the implications and limitations of the above methods are discussed, with suggestions for further development.

CAMCR: Computer assisted mixture model analysis for capture-recapture count data

Population size estimation with discrete or nonparametric mixture models is considered, and reliable ways of construction of the nonparametric mixture model estimator are reviewed and set into perspective. Construction of the maximum likelihood estimator of the mixing distribution is done for any number of components up to the global nonparametric maximum likelihood bound using the EM algorithm. In addition, the estimators of Chao and Zelterman are considered with some generalisations of Zelterman’s estimator. All computations are done with CAMCR, a special software developed for population size estimation with mixture models. Several examples and data sets are discussed and the estimators illustrated. Problems using the mixture model-based estimators are highlighted.

Methodological rigour in assessing participatory development

There have been few rigorous assessments of the effectiveness of participatory processes for natural resource management. In Bangladesh an approach known as Participatory Action Plan Development (PAPD) has been developed and applied. By combining problem identification and solution analysis by separate stakeholder groups with plenary sessions it is claimed to result in consensus and more effective community based management. Methodological issues in assessing the effectiveness of such development are discussed and good practice illustrated. Under the same project there were sites where PAPD had been used and others without its use so a comparative assessment could be made. However, for an appropriate assessment it is important to identify clear testable hypotheses regarding the expected benefits, appropriate measures, and other factors which may affect or confound the outcome. The paper illustrates how participatory assessment involving both individual opinions and focus groups can be systematically recorded, quantified and used with other data in statistical analysis. By using statistical modelling methods at an appropriate level of aggregation and controlling for other factors, benefits from PAPD were found to be significant. The systematic approaches and practices recommended from this example can be applied in similar situations to test the effectiveness of participatory processes using participatory assessments.

Comparison of dietary fat and fatty acid intake estimated by the duplicate diet collection technique and estimated dietary records

Introduction A high saturated fatty acid intake is a well recognized risk factor for coronary heart disease development. More recently a high intake of n-6 polyunsaturated fatty acids (PUFA) in combination with a low intake of the long chain n-3 PUFA, eicosapentaenoic acid and docosahexaenoic acid has also been implicated as an important risk factor. Aim To compare total dietary fat and fatty acid intake measured by chemical analysis of duplicate diets with nutritional database analysis of estimated dietary records, collected over the same 3-day study period. Methods Total fat was analysed using soxhlet extraction and subsequently the individual fatty acid content of the diet was determined by gas chromatography. Estimated dietary records were analysed using a nutrient database which was supplemented with a selection of dishes commonly consumed by study participants. Results Bland & Altman statistical analysis demonstrated a lack of agreement between the two dietary assessment techniques for determining dietary fat and fatty acid intake. Conclusion The lack of agreement observed between dietary evaluation techniques may be attributed to inadequacies in either or both assessment techniques. This study highlights the difficulties that may be encountered when attempting to accurately evaluate dietary fat intake among the population.

CAMCR: Computer-Assisted Mixture model analysis for Capture–Recapture count data

Population size estimation with discrete or nonparametric mixture models is considered, and reliable ways of construction of the nonparametric mixture model estimator are reviewed and set into perspective. Construction of the maximum likelihood estimator of the mixing distribution is done for any number of components up to the global nonparametric maximum likelihood bound using the EM algorithm. In addition, the estimators of Chao and Zelterman are considered with some generalisations of Zelterman’s estimator. All computations are done with CAMCR, a special software developed for population size estimation with mixture models. Several examples and data sets are discussed and the estimators illustrated. Problems using the mixture model-based estimators are highlighted.

Part load operation coefficient of air-conditioning system of public building

IPLV overall coefficient, presented by Air-Conditioning and Refrigeration Institute (ARI) of America, shows running/operation status of air-conditioning system host only. For overall operation coefficient, logical solution has not been developed, to reflect the whole air-conditioning system under part load. In this research undertaking, the running time proportions of air-conditioning systems under part load have been obtained through analysis on energy consumption data during practical operation in all public buildings in Chongqing. This was achieved by using analysis methods, based on the statistical energy consumption data distribution of public buildings month-by-month. Comparing with the weight number of IPLV, part load operation coefficient of air-conditioning system, based on this research, does not only show the status of system refrigerating host, but also reflects and calculate energy efficiency of the whole air-conditioning system. The coefficient results from the processing and analyzing of practical running data, shows the practical running status of area and building type (actual and objective) – not clear. The method is different from model analysis which gets IPLV weight number, in the sense that this method of coefficient results in both four equal proportions and also part load operation coefficient of air-conditioning system under any load rate as necessary.

A structural analysis of M protein in coronavirus assembly and morphology

The M protein of coronavirus plays a central role in virus assembly, turning cellular membranes into workshops where virus and host factors come together to make new virus particles. We investigated how M structure and organization is related to virus shape and size using cryo-electron microscopy, tomography and statistical analysis. We present evidence that suggests M can adopt two conformations and that membrane curvature is regulated by one M conformer. Elongated M protein is associated with rigidity, clusters of spikes and a relatively narrow range of membrane curvature. In contrast, compact M protein is associated with flexibility and low spike density. Analysis of several types of virus-like particles and virions revealed that S protein, N protein and genomic RNA each help to regulate virion size and variation, presumably through interactions with M. These findings provide insight into how M protein functions to promote virus assembly.

The use of trajectory cluster analysis to interpret trace gas measurements at Mace Head, Ireland

A first step in interpreting the wide variation in trace gas concentrations measured over time at a given site is to classify the data according to the prevailing weather conditions. In order to classify measurements made during two intensive field campaigns at Mace Head, on the west coast of Ireland, an objective method of assigning data to different weather types has been developed. Air-mass back trajectories calculated using winds from ECMWF analyses, arriving at the site in 1995–1997, were allocated to clusters based on a statistical analysis of the latitude, longitude and pressure of the trajectory at 12 h intervals over 5 days. The robustness of the analysis was assessed by using an ensemble of back trajectories calculated for four points around Mace Head. Separate analyses were made for each of the 3 years, and for four 3-month periods. The use of these clusters in classifying ground-based ozone measurements at Mace Head is described, including the need to exclude data which have been influenced by local perturbations to the regional flow pattern, for example, by sea breezes. Even with a limited data set, based on 2 months of intensive field measurements in 1996 and 1997, there are statistically significant differences in ozone concentrations in air from the different clusters. The limitations of this type of analysis for classification and interpretation of ground-based chemistry measurements are discussed.

Modeling data with structural and temporal correlation using lower level and higher level multilevel models

Novel imaging techniques are playing an increasingly important role in drug development, providing insight into the mechanism of action of new chemical entities. The data sets obtained by these methods can be large with complex inter-relationships, but the most appropriate statistical analysis for handling this data is often uncertain - precisely because of the exploratory nature of the way the data are collected. We present an example from a clinical trial using magnetic resonance imaging to assess changes in atherosclerotic plaques following treatment with a tool compound with established clinical benefit. We compared two specific approaches to handle the correlations due to physical location and repeated measurements: two-level and four-level multilevel models. The two methods identified similar structural variables, but higher level multilevel models had the advantage of explaining a greater proportion of variation, and the modeling assumptions appeared to be better satisfied.