A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands : challenges for malaria diagnostics in an elimination setting

Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Interrupting malaria transmission: quantifying the impact of interventions in regions of low to moderate transmission

Malaria has been eliminated from over 40 countries with an additional 39 currently planning for, or committed to, elimination. Information on the likely impact of available interventions, and the required time, is urgently needed to help plan resource allocation. Mathematical modelling has been used to investigate the impact of various interventions; the strength of the conclusions is boosted when several models with differing formulation produce similar data. Here we predict by using an individual-based stochastic simulation model of seasonal Plasmodium falciparum transmission that transmission can be interrupted and parasite reintroductions controlled in villages of 1,000 individuals where the entomological inoculation rate is <7 infectious bites per person per year using chemotherapy and bed net strategies. Above this transmission intensity bed nets and symptomatic treatment alone were not sufficient to interrupt transmission and control the importation of malaria for at least 150 days. Our model results suggest that 1) stochastic events impact the likelihood of successfully interrupting transmission with large variability in the times required, 2) the relative reduction in morbidity caused by the interventions were age-group specific, changing over time, and 3) the post-intervention changes in morbidity were larger than the corresponding impact on transmission. These results generally agree with the conclusions from previously published models. However the model also predicted changes in parasite population structure as a result of improved treatment of symptomatic individuals; the survival probability of introduced parasites reduced leading to an increase in the prevalence of sub-patent infections in semi-immune individuals. This novel finding requires further investigation in the field because, if confirmed, such a change would have a negative impact on attempts to eliminate the disease from areas of moderate transmission.

Spatial analysis of risk factors for transmission of the Barmah forest virus in Queensland, Australia

Barmah Forest virus (BFV) disease is the second most common mosquito-borne disease in Australia but few data are available on the risk factors. We assessed the impact of spatial climatic, socioeconomic and ecological factors on the transmission of BFV disease in Queensland, Australia, using spatial regression. All our analyses indicate that spatial lag models provide a superior fit to the data compared to spatial error and ordinary least square models. The residuals of the spatial lag models were found to be uncorrelated, indicating that the models adequately account for spatial and temporal autocorrelation. Our results revealed that minimum temperature, distance from coast and low tide were negatively and rainfall was positively associated with BFV disease in coastal areas, whereas minimum temperature and high tide were negatively and rainfall was positively associated with BFV disease (all P-value.

The hereditary transmission of the glutathione transferase hGSTT1-1 conjugator phenotype in a large family

The polymorphism of human glutathione transferase hGSTT1-1 is expressed in three phenotypes. Experimentally, individuals can be classified as non-conjugators, low conjugators and 'high' conjugators depending on the enzyme activity in blood towards methylene chloride using a gas chromatographic assay. Non-conjugators do not have a functional hGSTT1 gene; however, little is known about the molecular basis of the three conjugator phenotypes. The higher hGSTT1-1 activity in high conjugators may be the result of enzyme induction or be genetically determined. Twenty-nine members of a large family, including three generations were phenotyped and genotyped with respect to hGSTT1-1. The hGSTT1-1 enzyme activity of high conjugators was twice as high as that of low conjugators. The distribution of hGSTT1-1 phenotypes strongly indicates a Mendelian intermediary inheritance, in which a gene-dosage effect results in a doubled enzyme expression in the presence of two functional alleles. The Mendelian intermediary inheritance is further supported by the findings of a semiquantitative polymerase chain reaction method designed to distinguish the three genotypes of hGSTT1 for rapid screening of large study groups.

Model choice problems using approximate Bayesian computation with applications to pathogen transmission data sets

Analytically or computationally intractable likelihood functions can arise in complex statistical inferential problems making them inaccessible to standard Bayesian inferential methods. Approximate Bayesian computation (ABC) methods address such inferential problems by replacing direct likelihood evaluations with repeated sampling from the model. ABC methods have been predominantly applied to parameter estimation problems and less to model choice problems due to the added difficulty of handling multiple model spaces. The ABC algorithm proposed here addresses model choice problems by extending Fearnhead and Prangle (2012, Journal of the Royal Statistical Society, Series B 74, 1–28) where the posterior mean of the model parameters estimated through regression formed the summary statistics used in the discrepancy measure. An additional stepwise multinomial logistic regression is performed on the model indicator variable in the regression step and the estimated model probabilities are incorporated into the set of summary statistics for model choice purposes. A reversible jump Markov chain Monte Carlo step is also included in the algorithm to increase model diversity for thorough exploration of the model space. This algorithm was applied to a validating example to demonstrate the robustness of the algorithm across a wide range of true model probabilities. Its subsequent use in three pathogen transmission examples of varying complexity illustrates the utility of the algorithm in inferring preference of particular transmission models for the pathogens.

Treatment for prevention of HIV transmission in a localised epidemic : the case for South Australia

Background: Discussion is currently taking place among international HIV/AIDS groups around increasing HIV testing and initiating earlier use of antiretroviral therapy (ART) among people diagnosed with HIV as a method to reduce the spread of HIV. In this study, we explore the expected epidemiological impact of this strategy in a small population in which HIV transmission is predominantly confined to men who have sex with men (MSM). Methods: A deterministic mathematical transmission model was constructed to investigate the impacts of strategies that increase testing and treatment rates, and their likely potential to mitigate HIV epidemics among MSM. Our novel model distinguishes men in the population who are more easily accessible to prevention campaigns through engagement with the gay community from men who are not. This model is applied to the population of MSM in South Australia. Results: Our model-based findings suggest that increasing testing rates alone will have minimal impact on reducing the expected number of infections compared to current conditions. However, in combination with increases in treatment coverage, this strategy could lead to a 59–68% reduction in the number of HIV infections over the next 5 years. Targeting men who are socially engaged with the gay community would result in the majority of potential reductions in incidence, with only minor improvements possible by reaching all other MSM. Conclusions: Investing in strategies that will achieve higher coverage and earlier initiation of treatment to reduce infectiousness of HIV-infected individuals could be an effective strategy for reducing incidence in a population of MSM.

Spatial and temporal patterns of locally-acquired dengue transmission in northern Queensland, Australia, 1993-2012

BACKGROUND: Dengue has been a major public health concern in Australia since it re-emerged in Queensland in 1992-1993. We explored spatio-temporal characteristics of locally-acquired dengue cases in northern tropical Queensland, Australia during the period 1993-2012. METHODS: Locally-acquired notified cases of dengue were collected for northern tropical Queensland from 1993 to 2012. Descriptive spatial and temporal analyses were conducted using geographic information system tools and geostatistical techniques. RESULTS: 2,398 locally-acquired dengue cases were recorded in northern tropical Queensland during the study period. The areas affected by the dengue cases exhibited spatial and temporal variation over the study period. Notified cases of dengue occurred more frequently in autumn. Mapping of dengue by statistical local areas (census units) reveals the presence of substantial spatio-temporal variation over time and place. Statistically significant differences in dengue incidence rates among males and females (with more cases in females) (χ(2) = 15.17, d.f.  = 1, p<0.01). Differences were observed among age groups, but these were not statistically significant. There was a significant positive spatial autocorrelation of dengue incidence for the four sub-periods, with the Moran's I statistic ranging from 0.011 to 0.463 (p<0.01). Semi-variogram analysis and smoothed maps created from interpolation techniques indicate that the pattern of spatial autocorrelation was not homogeneous across the northern Queensland. CONCLUSIONS: Tropical areas are potential high-risk areas for mosquito-borne diseases such as dengue. This study demonstrated that the locally-acquired dengue cases have exhibited a spatial and temporal variation over the past twenty years in northern tropical Queensland, Australia. Therefore, this study provides an impetus for further investigation of clusters and risk factors in these high-risk areas.

Optimal HMM filtering and decision feedback equalisation for differential encoded transmission systems

In this paper conditional hidden Markov model (HMM) filters and conditional Kalman filters (KF) are coupled together to improve demodulation of differential encoded signals in noisy fading channels. We present an indicator matrix representation for differential encoded signals and the optimal HMM filter for demodulation. The filter requires O(N3) calculations per time iteration, where N is the number of message symbols. Decision feedback equalisation is investigated via coupling the optimal HMM filter for estimating the message, conditioned on estimates of the channel parameters, and a KF for estimating the channel states, conditioned on soft information message estimates. The particular differential encoding scheme examined in this paper is differential phase shift keying. However, the techniques developed can be extended to other forms of differential modulation. The channel model we use allows for multiplicative channel distortions and additive white Gaussian noise. Simulation studies are also presented.

Weather variability and influenza A (H7N9) transmission in Shanghai, China: A Bayesian spatial analysis

Abstract Background A novel avian influenza A (H7N9) virus was first found in humans in Shanghai, and infected over 433 patients in China. To date, very little is known about the spatiotemporal variability or environmental drivers of the risk of H7N9 infection. This study explored the spatial and temporal variation of H7N9 infection and assessed the effects of temperature and rainfall on H7N9 incidence. Methods A Bayesian spatial conditional autoregressive (CAR) model was used to assess the spatiotemporal distribution of the risk of H7N9 infection in Shanghai, by district and fortnight for the period 19th February–14th April 2013. Data on daily laboratory-confirmed H7N9 cases, and weather variability including temperature (°C) and rainfall (mm) were obtained from the Chinese Information System for Diseases Control and Prevention and Chinese Meteorological Data Sharing Service System, respectively, and aggregated by fortnight. Results High spatial variations in the H7N9 risk were mainly observed in the east and centre of Shanghai municipality. H7N9 incidence rate was significantly associated with fortnightly mean temperature (Relative Risk (RR): 1.54; 95% credible interval (CI): 1.22–1.94) and fortnightly mean rainfall (RR: 2.86; 95% CI: 1.47–5.56). Conclusion There was a substantial variation in the spatiotemporal distribution of H7N9 infection across different districts in Shanghai. Optimal temperature and rainfall may be one of the driving forces for H7N9.

Broadening the perspective on the airborne transmission of respiratory infection

Airborne bioaerosols are becoming increasingly recognized as a potential route of transmission for the spread of bacterial and viral respiratory tract infections.

Volatility transmission in global financial markets

As financial markets have become increasingly integrated internationally, the topic of volatility transmission across these markets has become more important. This thesis investigates how the volatility patterns of the world's main financial centres differ across foreign exchange, equity, and bond markets.

Spatiotemporal transmission dynamics of hemorrhagic fever with renal syndrome in China, 2005-2012

Background Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures. Methods Data on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff's space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences. Results A total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran's I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties. Conclusions This study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.