The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer.

BACKGROUND: Pulmonary imaging often identifies suspicious abnormalities resulting in supplementary diagnostic procedures. This study aims to investigate whether the metabolic fingerprint of plasma allows to discriminate between patients with lung inflammation and patients with lung cancer. METHODS: Metabolic profiles of plasma from 347 controls, 269 cancer patients and 108 patients with inflammation were obtained by 1H-NMR spectroscopy. Models to discriminate between groups were trained by PLS-LDA. A test set was used for independent validation. A ROC curve was built to evaluate the diagnostic performance of potential biomarkers. RESULTS: Sensitivity, specificity, PPV and NPV of PET-CT to diagnose cancer are 96, 23, 76 and 71%. Metabolic profiles differentiate between cancer and inflammation with a sensitivity of 89%, a specificity of 87% and a MCE of 12%. Removal of the glutamate metabolite results in an increase of MCE (38%) and a decrease of both sensitivity and specificity (62%), demonstrating the importance of glutamate for discrimination. At the cut-off point 0.31 on the ROC curve, the relative glutamate concentration discriminates between cancer and inflammation with a sensitivity of 85%, a specificity of 81%, and an AUC of 0.88. PPV and NPV are 92 and 69%. In PET-positive patients with a relative glutamate level ≤ 0.31 the sensitivity to diagnose cancer reaches 100% with a PPV of 94%. In PET-negative patients, a relative glutamate level > 0.31 increases the specificity of PET from 23% to 58% and results in a high NPV of 100%. In case of discrepancy between SUVmax and the glutamate concentration, lung cancer is missed in 19% of the cases. CONCLUSION: This study indicates that the 1H-NMR-derived relative plasma concentration of glutamate allows discrimination between lung cancer and lung inflammation. A glutamate level ≤ 0.31 in PET-positive patients corresponds to the diagnosis of lung cancer with a higher specificity and PPV than PET-CT. Glutamate levels > 0.31 in patients with PET negative lung lesions is likely to correspond with inflammation. Caution is needed for patients with conflicting SUVmax values and glutamate concentrations. Confirmation is needed in a prospective study with external validation and by another analytical technique such as HPLC-MS.

Real-time parameter estimation of Zika outbreaks using model averaging.

Early prediction of the final size of any epidemic and in particular for Zika disease outbreaks can be useful for health authorities in order to plan the response to the outbreak. The Richards model is often been used to estimate epidemiological parameters for arboviral diseases based on the reported cumulative cases in single- and multi-wave outbreaks. However, other non-linear models can also fit the data as well. Typically, one follows the so called post selection estimation procedure, i.e., selects the best fitting model out of the set of candidate models and ignores the model uncertainty in both estimation and inference since these procedures are based on a single model. In this paper we focus on the estimation of the final size and the turning point of the epidemic and conduct a real-time prediction for the final size of the outbreak using several non-linear models in which these parameters are estimated via model averaging. The proposed method is applied to Zika outbreak data in four cities from Colombia, during the outbreak ocurred in 2015-2016.

Malnutrition in Healthy Individuals Results in Increased Mixed Cytokine Profiles, Altered Neutrophil Subsets and Function.

Malnutrition is commonly associated with increased infectious disease susceptibility and severity. Whereas malnutrition might enhance the incidence of disease as well as its severity, active infection can in turn exacerbate malnutrition. Therefore, in a malnourished individual suffering from a severe infection, it is not possible to determine the contribution of the pre-existing malnutrition and/or the infection itself to increased disease severity. In the current study we focussed on two groups of malnourished, but otherwise healthy individuals: moderately malnourished (BMI: 18.4-16.5) and severely malnourished (BMI <16.5) and compared several immune parameters with those of individuals with a normal BMI (≥18.5). Our results show a similar haematological profile in all three groups, as well as a similar ratio of CD4+ and CD8+ T cells. We found significant correlations between low BMI and increased levels of T helper (Th) 1 (Interferon (IFN)-γ, (interleukin (IL)-2, IL-12), Th2 (IL-4, IL-5, IL-13), as well as IL-10, IL-33 and tumor necrosis factor-α, but not IL-8 or C reactive protein. The activities of arginase, an enzyme associated with immunosuppression, were similar in plasma, peripheral blood mononuclear cells (PBMC) and neutrophils from all groups and no differences in the expression levels of CD3ζ, a marker of T cell activation, were observed in CD4+ and CD8+T cells. Furthermore, whereas the capacity of neutrophils from the malnourished groups to phagocytose particles was not impaired, their capacity to produce reactive oxygen species was impaired. Finally we evaluated the frequency of a subpopulation of low-density neutrophils and show that they are significantly increased in the malnourished individuals. These differences were more pronounced in the severely malnourished group. In summary, our results show that even in the absence of apparent infections, healthy malnourished individuals display dysfunctional immune responses that might contribute to increased susceptibility and severity to infectious diseases.

Estimating the force of infection for HCV in injecting drug users using interval-censored data.

Injecting drug users (IDUs) account for most new HCV infections. The objectives of this study were: to estimate the force of infection for hepatitis C virus in IDUs within the interval-censoring framework and to determine the impact of risk factors such as frequency of injection, drug injected, sharing of syringes and time of first injection on the time to HCV infection. We used data from the Amsterdam Cohort Study collected in The Netherlands and focused on those individuals who were HCV negative upon entry into the study. Based on the results, the force of infection was found to vary with time of first injection. The risk of infection was higher in the first 3 years of an IDU's career, implying estimates based on single cross-sectional studies could be biased. Frequency of injection and type of drug injected were found to be highly significant predictors, whereas sharing syringes was not.

A frequentist approach to estimating the force of infection for a respiratory disease using repeated measurement data from a birth cohort.

This article aims to develop a probability-based model involving the use of direct likelihood formulation and generalised linear modelling (GLM) approaches useful in estimating important disease parameters from longitudinal or repeated measurement data. The current application is based on infection with respiratory syncytial virus. The force of infection and the recovery rate or per capita loss of infection are the parameters of interest. However, because of the limitation arising from the study design and subsequently, the data generated only the force of infection is estimable. The problem of dealing with time-varying disease parameters is also addressed in the article by fitting piecewise constant parameters over time via the GLM approach. The current model formulation is based on that published in White LJ, Buttery J, Cooper B, Nokes DJ and Medley GF. Rotavirus within day care centres in Oxfordshire, UK: characterization of partial immunity. Journal of Royal Society Interface 2008; 5: 1481-1490 with an application to rotavirus transmission and immunity.

Seventy-five years of estimating the force of infection from current status data.

The force of infection, describing the rate at which a susceptible person acquires an infection, is a key parameter in models estimating the infectious disease burden, and the effectiveness and cost-effectiveness of infectious disease prevention. Since Muench formulated the first catalytic model to estimate the force of infection from current status data in 1934, exactly 75 years ago, several authors addressed the estimation of this parameter by more advanced statistical methods, while applying these to seroprevalence and reported incidence/case notification data. In this paper we present an historical overview, discussing the relevance of Muench's work, and we explain the wide array of newer methods with illustrations on pre-vaccination serological survey data of two airborne infections: rubella and parvovirus B19. We also provide guidance on deciding which method(s) to apply to estimate the force of infection, given a particular set of data.

Intersectoral coordination, community empowerment and dengue prevention: six years of controlled interventions in Playa Municipality, Havana, Cuba.

OBJECTIVE: To document the process, outcome and effectiveness of a community-based intervention for dengue control. METHODS: The primary intervention, focused on strengthening intersectoral coordination, was initiated by researchers in January 2000 in a pilot area in Playa municipality, Havana. In August 2002 health authorities extended the intervention to neighbouring areas, one of which was selected for evaluation. In August 2003 a complementary strategy, focused on community empowerment, was initiated in half of the pilot area. In our control area, routine dengue activities continued throughout the study period. Longitudinal process assessment was carried out using document analysis, interviews and group discussions. Random population surveys in 1999, 2002 and 2005 assessed levels of participation and behavioural changes. Entomological surveillance data from 1999 to 2005 were used to determine effectiveness. RESULTS: Mean scores for participation in the pilot area were 1.6, 3.4 and 4.4 at baseline, and 2 years after initiating intersectoral coordination and intersectoral coordination plus community empowerment interventions, respectively. While in the control area little behavioural change was observed over time, changes were considerable in the pilot and extension areas, with 80% of households involved in the community empowerment intervention showed adequate behavioural patterns. The pilot and extension areas attained comparable entomological effectiveness with significantly lower Breteau indices (BIs) than the control area. The pilot (sub-) area with the community empowerment intervention reached BIs below 0.1 that continued to be significantly lower than the one in the control area until the end of the study. CONCLUSION: The study showed a trend in the levels and quality of participation, behavioural change and effectiveness of Aedes control from the routine activities only over an intervention with intersectoral coordination to one that combined intersectoral coordination and community empowerment approach.

Contact patterns and their implied basic reproductive numbers: an illustration for varicella-zoster virus.

The WAIFW matrix (Who Acquires Infection From Whom) is a central parameter in modelling the spread of infectious diseases. The calculation of the basic reproductive number (R0) depends on the assumptions made about the transmission within and between age groups through the structure of the WAIFW matrix and different structures might lead to different estimates for R0 and hence different estimates for the minimal immunization coverage needed for the elimination of the infection in the population. In this paper, we estimate R0 for varicella in Belgium. The force of infection is estimated from seroprevalence data using fractional polynomials and we show how the estimate of R0 is heavily influenced by the structure of the WAIFW matrix.

An investigation on performance of Significance Analysis of Microarray (SAM) for the comparisons of several treatments with one control in the presence of small-variance genes.

One of multiple testing problems in drug finding experiments is the comparison of several treatments with one control. In this paper we discuss a particular situation of such an experiment, i.e., a microarray setting, where the many-to-one comparisons need to be addressed for thousands of genes simultaneously. For a gene-specific analysis, Dunnett's single step procedure is considered within gene tests, while the FDR controlling procedures such as Significance Analysis of Microarrays (SAM) and Benjamini and Hochberg (BH) False Discovery Rate (FDR) adjustment are applied to control the error rate across genes. The method is applied to a microarray experiment with four treatment groups (three microarrays in each group) and 16,998 genes. Simulation studies are conducted to investigate the performance of the SAM method and the BH-FDR procedure with regard to controlling the FDR, and to investigate the effect of small-variance genes on the FDR in the SAM procedure.

Modelling multisera data: the estimation of new joint and conditional epidemiological parameters.

Testing humans for infectious diseases is often done by assessing the presence or absence of disease-specific antibodies in serum samples. For feasibility and economical reasons, these sera are often tested for more than one antigen. Studying diseases with similar transmission routes can govern new insights for disease dynamics. We use flexible marginal and conditional models to model multisera data on the Varicella-Zoster virus and the Parvo B19-virus in Belgium. Next form the derivation of the age-dependent marginal force of infection (FOI), we introduce new epidemiological parameters: the age-dependent joint and conditional FOI. These parameters allow us to study the association among the occurrence and acquisition of both infections. Furthermore, we show how to test for association and whether the infection-specific age-dependent FOI curves are proportional and consequently whether separable mixing in the population holds.

Estimating the impact of vaccination using age-time-dependent incidence rates of hepatitis B.

The objective of this study was to model the age-time-dependent incidence of hepatitis B while estimating the impact of vaccination. While stochastic models/time-series have been used before to model hepatitis B cases in the absence of knowledge on the number of susceptibles, this paper proposed using a method that fits into the generalized additive model framework. Generalized additive models with penalized regression splines are used to exploit the underlying continuity of both age and time in a flexible non-parametric way. Based on a unique case notification dataset, we have shown that the implemented immunization programme in Bulgaria resulted in a significant decrease in incidence for infants in their first year of life with 82% (79-84%). Moreover, we have shown that conditional on an assumed baseline susceptibility percentage, a smooth force-of-infection profile can be obtained from which two local maxima were observed at ages 9 and 24 years.

Parvovirus B19 infection in five European countries: seroepidemiology, force of infection and maternal risk of infection.

We conducted a seroprevalence survey in Belgium, Finland, England & Wales, Italy and Poland on 13 449 serum samples broadly representative in terms of geography and age. Samples were tested for the presence of immunoglobulin G antibody using an enzyme immunoassay. The age-specific risk of infection was estimated using parametric and non-parametric statistical modelling. The age-specific risk in all five countries was highest in children aged 7-9 years and lower in adults. The average proportion of women of child-bearing age susceptible to parvovirus B19 infection and the risk of a pregnant women acquiring B19 infection during pregnancy was estimated to be 26% and 0.61% in Belgium, 38% and 0.69% in England & Wales, 43.5% and 1.24% in Finland, 39.9% and 0.92% in Italy and 36.8% and 1.58% in Poland, respectively. Our study indicates substantial epidemiological differences in Europe regarding parvovirus B19 infection.

Evidence for a substantial role of sharing of injecting paraphernalia other than syringes/needles to the spread of hepatitis C among injecting drug users.

In industrialized countries, transmission of hepatitis C occurs primarily through injecting drug use. Transmission of hepatitis C in injecting drug users is mainly associated with the sharing of contaminated syringes/needles, although evidence for risk of hepatitis C infection through sharing of other injecting paraphernalia is increasing. In this paper, the independent effects of sharing paraphernalia other than syringes/needles have been estimated. The prevalence and force of infection were modelled using three serological data sets from drug users in three centres in Belgium as a function of the sharing behaviour. It was found that sharing of materials other than syringes/needles indeed seemed to contribute substantially to the spread of hepatitis C among injecting drug users.

Social mixing patterns for transmission models of close contact infections: exploring self-evaluation and diary-based data collection through a web-based interface.

Although mixing patterns are crucial in dynamic transmission models of close contact infections, they are largely estimated by intuition. Using a convenience sample (n=73), we tested self-evaluation and prospective diary surveys with a web-based interface, in order to obtain social contact data. The number of recorded contacts was significantly (P<0.01) greater on workdays (18.1) vs. weekend days (12.3) for conversations, and vice versa for touching (5.4 and 7.2 respectively). Mixing was highly assortative with age for both (adults contacting other adults vs. 0- to 5-year-olds, odds ratio 8.9-10.8). Respondents shared a closed environment significantly more often with >20 other adults than with >20 children. The difference in number of contacts per day was non-significant between self-evaluation and diary (P=0.619 for conversations, P=0.125 for touching). We conclude that self-evaluation could yield similar results to diary surveys for general or very recent mixing information. More detailed data could be collected by diary, at little effort to respondents.

Seroepidemiology of diphtheria and pertussis in Luxembourg in 2000.

A large serosurvey was carried out in Luxembourg in 2000-2001, to determine the population immunity against a number of vaccine-preventable infections including diphtheria and pertussis. Immunity to diphtheria and pertussis was assessed using an in-house neutralization assay and a commercial ELISA test respectively. Mean pertussis antibody activity decreased from 4 to 8 years of age, reflecting the effects of waning of vaccine-induced immunity. Mean pertussis antibody activity increased during adolescence due to infection in previously vaccinated individuals and levelled out after approximately 20 years of age. For adults>25 years age, a statistically significant 30% difference in mean antibody activity between men and women was observed. The proportion of seronegatives for diphtheria among children and adolescents aged<20 years was 2.5% reflecting the high vaccination coverage. The proportion seronegative for diphtheria tended to increase with age such that 42% of individuals aged>40 years were seronegative. Our study supports the recently introduced acellular pertussis vaccine booster at 6 years to reduce pertussis transmission in school-aged children and adolescents.

Modelling age-dependent force of infection from prevalence data using fractional polynomials.

The force of infection is one of the primary epidemiological parameters of infectious diseases. For many infectious diseases it is assumed that the force of infection is age-dependent. Although the force of infection can be estimated directly from a follow up study, it is much more common to have cross-sectional seroprevalence data from which the prevalence and the force of infection can be estimated. In this paper, we propose to model the force of infection within the framework of fractional polynomials. We discuss several parametric examples from the literature and show that all of these examples can be expressed as special cases of fractional polynomial models. We illustrate the method on five seroprevalence samples, two of Hepatitis A, and one of Rubella, Mumps and Varicella.

Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia.

BACKGROUND & AIMS: Categorization of functional dyspepsia into subgroups is based on expert opinion according to (dominant) symptoms or on underlying pathophysiological mechanisms. We used an evidence-based approach to the determination of subtypes of functional dyspepsia. METHODS: Consecutive functional dyspepsia patients were recruited from a tertiary referral center. The following were performed: (1) exploratory (EFA) and confirmatory factor analysis (CFA) of symptom patterns in a large group of patients with functional dyspepsia; (2) external validation of these factors by the determination of their association pattern with physio- and psychopathological mechanisms, and with health-related quality of life and sickness behavior; and (3) cluster analysis of their distribution in this population. RESULTS: Both EFA and CFA do not support the existence of functional dyspepsia as a homogeneous (unidimensional) condition. A 4-factor model is found to be valid, with differential distribution within the patient population according to cluster analysis. Factor 1 is characterized by nausea, vomiting, early satiety, and weight loss and factor 2 by postprandial fullness and bloating. Both factor 1 and 2 are associated with delayed emptying, but only factor 1 is associated with younger age, female sex, and sickness behavior. Factor 3 is characterized by pain symptoms and associated with gastric hypersensitivity and several psychosocial dimensions including medically unexplained symptoms and health-related quality of life dimensions. Factor 4, characterized by belching, is also associated with hypersensitivity, but is unrelated to psychosocial dimensions. CONCLUSIONS: In a tertiary care population, functional dyspepsia is a heterogeneous condition characterized by 4 major dimensions differentially associated with psychopathological and physiopathological mechanisms.

Hepatitis B in St Petersburg, Russia (1994-1999): incidence, prevalence and force of infection.

Hepatitis B (HB) is thought to be an expanding health problem in Russia. The incidence of infection was estimated from mandatorily reported HB cases in St Petersburg. The two-sided t-test for independent samples and the LOESS (locally-weighted regression) smoother were used to compare the age at infection for symptomatic, asymptomatic and chronic infections, by gender. The force of infection was estimated from seroprevalence data (907 sera taken in 1999) using a newly developed nonparametric method based on local polynomials, as well as an earlier method based on isotonic regression and kernel smoothers. With the local polynomial method, pointwise confidence intervals (95%) were constructed by bootstrapping. On average, men contracted HB infection at a significantly younger age than women (in 1999, 21.8 vs 22.7 years, respectively). The overall male to female ratio was 1.92. In 1999 the overall incidence almost doubled compared with the preceding years and tripled among the age groups with highest incidence (15-29-year olds: 85% of cases in 1999). The incidence increase was associated with a lower average age at infection (24.1 years in 1994 vs 22.1 years in 1999). The age and gender-specific force of infection estimates generally confirmed the incidence estimates and emphasized the usefulness of local polynomials to do this. Hence HB transmission in St Petersburg occurs mainly in young adults. The dramatic increase of infections in 1999 was probably due to injecting drug use. Without intervention, HB virus is expected to continue to spread rapidly with a greater proportion of female infections caused by sexual transmission. These trends may also provide an indication for HIV transmission.