Mathematical Modeling of Virus Dynamics in Immunology

A simplified dynamical model of immune response to uncomplicated influenza virus infection is presented, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells. Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov & Romanyukha (Bocharov and Romanyukha, 1994), the model is constructed as a system of 10 ordinary differential equations with 27 parameters. In the first part, parameter values for the model are obtained either from published experimental data or by estimation based on fitting available data about the time course of IAV infection in a naïve host. Sensitivity analysis is performed on the model parameters. To account for the variability and speed of adaptation, a variable is introduced that quantifies the antigenic compatibility between the virus and the antibodies. It is found that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load. In the second part, an ensemble model of immune response is developed, which consists of multiple ODE models that are identical in form but differ in parameter values. A probabilistic measure of goodness of fit of the ODE model is used to derive an a posteriori probability density on the space of parameter values. This probability density is sampled using the Metropolis Monte Carlo method and sampling is enhanced using parallel tempering algorithm. The ensemble model is employed to compute probabilistic estimates on trajectory of the immune response, duration of disease, maximum damage, likelihood of rebound in the disease and the probability of occurrence of superspreaders. The effectiveness of using antiviral drug to treat the infection is addressed and optimal treatment scenarios are discussed

Measuring Coverage in MNCH:A Validation Study Linking Population Survey Derived Coverage to Maternal, Newborn, and Child Health Care Records in Rural China

Accurate data on coverage of key maternal, newborn, and child health (MNCH) interventions are crucial for monitoring progress toward the Millennium Development Goals 4 and 5. Coverage estimates are primarily obtained from routine population surveys through self-reporting, the validity of which is not well understood. We aimed to examine the validity of the coverage of selected MNCH interventions in Gongcheng County, China.We conducted a validation study by comparing women's self-reported coverage of MNCH interventions relating to antenatal and postnatal care, mode of delivery, and child vaccinations in a community survey with their paper- and electronic-based health care records, treating the health care records as the reference standard. Of 936 women recruited, 914 (97.6%) completed the survey. Results show that self-reported coverage of these interventions had moderate to high sensitivity (0.57 [95% confidence interval (CI): 0.50-0.63] to 0.99 [95% CI: 0.98-1.00]) and low to high specificity (0 to 0.83 [95% CI: 0.80-0.86]). Despite varying overall validity, with the area under the receiver operating characteristic curve (AUC) ranging between 0.49 [95% CI: 0.39-0.57] and 0.90 [95% CI: 0.88-0.92], bias in the coverage estimates at the population level was small to moderate, with the test to actual positive (TAP) ratio ranging between 0.8 and 1.5 for 24 of the 28 indicators examined. Our ability to accurately estimate validity was affected by several caveats associated with the reference standard. Caution should be exercised when generalizing the results to other settings.The overall validity of self-reported coverage was moderate across selected MNCH indicators. However, at the population level, self-reported coverage appears to have small to moderate degree of bias. Accuracy of the coverage was particularly high for indicators with high recorded coverage or low recorded coverage but high specificity. The study provides insights into the accuracy of self-reports based on a population survey in low- and middle-income countries. Similar studies applying an improved reference standard are warranted in the future

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1

Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway

mHealth Series:mHealth project in Zhao County, rural China - Description of objectives, field site and methods

BACKGROUND: We set up a collaboration between researchers in China and the UK that aimed to explore the use of mHealth in China. This is the first paper in a series of papers on a large mHealth project part of this collaboration. This paper included the aims and objectives of the mHealth project, our field site, and the detailed methods of two studies. FIELD SITE: The field site for this mHealth project was Zhao County, which lies 280 km south of Beijing in Hebei Province, China. METHODS: We described the methodology of two studies: (i) a mixed methods study exploring factors influencing sample size calculations for mHealth–based health surveys and (ii) a cross–over study determining validity of an mHealth text messaging data collection tool. The first study used mixed methods, both quantitative and qualitative, including: (i) two surveys with caregivers of young children, (ii) interviews with caregivers, village doctors and participants of the cross–over study, and (iii) researchers’ views. We combined data from caregivers, village doctors and researchers to provide an in–depth understanding of factors influencing sample size calculations for mHealth–based health surveys. The second study, a cross–over study, used a randomised cross–over study design to compare the traditional face–to–face survey method to the new text messaging survey method. We assessed data equivalence (intrarater agreement), the amount of information in responses, reasons for giving different responses, the response rate, characteristics of non–responders, and the error rate. CONCLUSIONS: This paper described the objectives, field site and methods of a large mHealth project part of a collaboration between researchers in China and the UK. The mixed methods study evaluating factors that influence sample size calculations could help future studies with estimating reliable sample sizes. The cross–over study comparing face–to–face and text message survey data collection could help future studies with developing their mHealth tools

Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host

The cellular adaptive immune response plays a key role in resolving influenza infection. Experiments where individuals are successively infected with different strains within a short timeframe provide insight into the underlying viral dynamics and the role of a cross-reactive immune response in resolving an acute infection. We construct a mathematical model of within-host influenza viral dynamics including three possible factors which determine the strength of the cross-reactive cellular adaptive immune response: the initial naive T cell number, the avidity of the interaction between T cells and the epitopes presented by infected cells, and the epitope abundance per infected cell. Our model explains the experimentally observed shortening of a second infection when cross-reactivity is present, and shows that memory in the cellular adaptive immune response is necessary to protect against a second infection.Comment: 35 pages, 12 figure

Does global progress on sanitation really lag behind water? An analysis of global progress on community- and household-level access to safe water and sanitation.

Safe drinking water and sanitation are important determinants of human health and wellbeing and have recently been declared human rights by the international community. Increased access to both were included in the Millennium Development Goals under a single dedicated target for 2015. This target was reached in 2010 for water but sanitation will fall short; however, there is an important difference in the benchmarks used for assessing global access. For drinking water the benchmark is community-level access whilst for sanitation it is household-level access, so a pit latrine shared between households does not count toward the Millennium Development Goal (MDG) target. We estimated global progress for water and sanitation under two scenarios: with equivalent household- and community-level benchmarks. Our results demonstrate that the "sanitation deficit" is apparent only when household-level sanitation access is contrasted with community-level water access. When equivalent benchmarks are used for water and sanitation, the global deficit is as great for water as it is for sanitation, and sanitation progress in the MDG-period (1990-2015) outstrips that in water. As both drinking water and sanitation access yield greater benefits at the household-level than at the community-level, we conclude that any post-2015 goals should consider a household-level benchmark for both

Does global progress on sanitation really lag behind water? An analysis of global progress on community- and household-level access to safe water and sanitation.

Safe drinking water and sanitation are important determinants of human health and wellbeing and have recently been declared human rights by the international community. Increased access to both were included in the Millennium Development Goals under a single dedicated target for 2015. This target was reached in 2010 for water but sanitation will fall short; however, there is an important difference in the benchmarks used for assessing global access. For drinking water the benchmark is community-level access whilst for sanitation it is household-level access, so a pit latrine shared between households does not count toward the Millennium Development Goal (MDG) target. We estimated global progress for water and sanitation under two scenarios: with equivalent household- and community-level benchmarks. Our results demonstrate that the "sanitation deficit" is apparent only when household-level sanitation access is contrasted with community-level water access. When equivalent benchmarks are used for water and sanitation, the global deficit is as great for water as it is for sanitation, and sanitation progress in the MDG-period (1990-2015) outstrips that in water. As both drinking water and sanitation access yield greater benefits at the household-level than at the community-level, we conclude that any post-2015 goals should consider a household-level benchmark for both

A Mathematical Framework for Estimating Pathogen Transmission Fitness and Inoculum Size Using Data from a Competitive Mixtures Animal Model

We present a method to measure the relative transmissibility (“transmission fitness”) of one strain of a pathogen compared to another. The model is applied to data from “competitive mixtures” experiments in which animals are co-infected with a mixture of two strains. We observe the mixture in each animal over time and over multiple generations of transmission. We use data from influenza experiments in ferrets to demonstrate the approach. Assessment of the relative transmissibility between two strains of influenza is important in at least three contexts: 1) Within the human population antigenically novel strains of influenza arise and compete for susceptible hosts. 2) During a pandemic event, a novel sub-type of influenza competes with the existing seasonal strain(s). The unfolding epidemiological dynamics are dependent upon both the population's susceptibility profile and the inherent transmissibility of the novel strain compared to the existing strain(s). 3) Neuraminidase inhibitors (NAIs), while providing significant potential to reduce transmission of influenza, exert selective pressure on the virus and so promote the emergence of drug-resistant strains. Any adverse outcome due to selection and subsequent spread of an NAI-resistant strain is exquisitely dependent upon the transmission fitness of that strain. Measurement of the transmission fitness of two competing strains of influenza is thus of critical importance in determining the likely time-course and epidemiology of an influenza outbreak, or the potential impact of an intervention measure such as NAI distribution. The mathematical framework introduced here also provides an estimate for the size of the transmitted inoculum. We demonstrate the framework's behaviour using data from ferret transmission studies, and through simulation suggest how to optimise experimental design for assessment of transmissibility. The method introduced here for assessment of mixed transmission events has applicability beyond influenza, to other viral and bacterial pathogens

Comparison of text messaging data collection vs face-to-face interviews for public health surveys:a cluster randomized crossover study of care-seeking for childhood pneumonia and diarrhoea in rural China

Background To compare text messaging and face-to-face interviews to conduct a survey on childhood diarrhoea and pneumonia. Methods Caregivers of young children able to send text messages in Zhao County in rural China were included in this crossover study. Villages (clusters) were randomized into two groups using the ratio 1:1.6 to account for an expected higher drop-out in group 2. In group 1, participants first completed the face-to-face and then text messaging survey; this order was reversed in group 2. We determined data equivalence of 17 questions that were answered by participants who were the same person in both surveys. For the text messaging survey, we assessed the overall and item response rate. Results We included 1014 participants between 16 and 28 March 2013: 371 in 15 villages in group 1 and 643 in 27 villages in group 2. A total of 662 (65.3%) out of 1014 participants responded (first text message question) and a significantly higher proportion who did not respond were from rural areas (P = 0.005). Of 651 participants willing to participate, 356 (54.7%) completed the text messaging survey, which was marginally significantly different between the groups (P = 0.05). In total, 409 participants took part in both surveys: 183 in group 1 and 226 in group 2. There was a significantly higher proportion of caregivers from rural areas in Zhao County in the non-responder group compared to the responder group (P = 0.004). Kappas were substantial for six (0.61–0.80), moderate for two (0.58 and 0.60), and fair for three questions (0.31, 0.35 and 0.37). The proportion of agreement was >90% for five questions; 80.0%-90.0% for five questions; 70.0%, 65.0% and 45.5%. The remaining questions had too small numbers to calculate these values. Conclusions This study shows that text messaging data collection produces data similar to data from face-to-face interviews in a middle-income setting, but the response rate was insufficient for use in public health surveys. Improving the response rate is important, because text message surveys could be of greater value in rural remote areas due to the cost-saving potential