ANOVA kernels and RKHS of zero mean functions for model-based sensitivity analysis

Given a reproducing kernel Hilbert space (H,〈.,.〉)(H,〈.,.〉) of real-valued functions and a suitable measure μμ over the source space D⊂RD⊂R, we decompose HH as the sum of a subspace of centered functions for μμ and its orthogonal in HH. This decomposition leads to a special case of ANOVA kernels, for which the functional ANOVA representation of the best predictor can be elegantly derived, either in an interpolation or regularization framework. The proposed kernels appear to be particularly convenient for analyzing the effect of each (group of) variable(s) and computing sensitivity indices without recursivity.

Lake surface temperatures in a changing climate: a global sensitivity analysis

We estimate the effects of climatic changes, as predicted by six climate models, on lake surface temperatures on a global scale, using the lake surface equilibrium temperature as a proxy. We evaluate interactions between different forcing variables, the sensitivity of lake surface temperatures to these variables, as well as differences between climate zones. Lake surface equilibrium temperatures are predicted to increase by 70 to 85 % of the increase in air temperatures. On average, air temperature is the main driver for changes in lake surface temperatures, and its effect is reduced by ~10 % by changes in other meteorological variables. However, the contribution of these other variables to the variance is ~40 % of that of air temperature, and their effects can be important at specific locations. The warming increases the importance of longwave radiation and evaporation for the lake surface heat balance compared to shortwave radiation and convective heat fluxes. We discuss the consequences of our findings for the design and evaluation of different types of studies on climate change effects on lakes.

Defining and measuring urban regions: A sensitivity analysis

This paper evaluates the impact of alternative city boundary definitions on economic performance. First we discuss the theoretical background and motivate the empirical work. Then we present the methodological concept of the sensitivity analysis, which will be applied to a variety of data of Zurich and Bern (the financial and the administrative centres of Switzerland) in order to see how the values of different indicators vary depending on the definition adopted. Finally we will show whether the empirical patterns found are statistically significant. The analysis shows, that the delimitation of a city or city region indeed matters.

Metformin and the risk of head and neck cancer: a case-control analysis

AIMS Metformin use has been associated with a decreased risk of some cancers, although data on head and neck cancer (HNC) are scarce. We explored the relation between the use of antidiabetic drugs and the risk of HNC. METHODS We conducted a case-control analysis in the UK-based Clinical Practice Research Datalink (CPRD) of people with incident HNC between 1995 and 2013 below the age of 90 years. Six controls per case were matched on age, sex, calendar time, general practice and number of years of active history in the CPRD prior to the index date. Other potential confounders including body mass index (BMI), smoking, alcohol consumption and comorbidities were also evaluated. The final analyses were adjusted for BMI, smoking and diabetes mellitus (or diabetes duration in a sensitivity analysis). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Use of metformin was neither associated with a statistically significant altered risk of HNC overall (1-29 prescriptions: adjusted OR 0.87, 95% CI 0.61-1.24 and ≥ 30 prescriptions adjusted OR 0.80, 95% CI 0.53-1.22), nor was long-term use of sulphonylureas (adjusted OR 0.87, 95% CI 0.59-1.30), or any insulin use (adjusted OR 0.92, 95% CI 0.63-1.35). However, we found a (statistically non-significant) decreased risk of laryngeal cancer associated with long-term metformin use (adjusted OR 0.41, 95% CI 0.17-1.03). CONCLUSIONS In this population-based study, the use of antidiabetic drugs was not associated with a materially altered risk of HNC. Our data suggest a protective effect of long-term metformin use for laryngeal cancer.

Endoscopic and Open Release Similarly Safe for the Treatment of Carpal Tunnel Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND The Endoscopic Release of Carpal Tunnel Syndrome (ECTR) is a minimal invasive approach for the treatment of Carpal Tunnel Syndrome. There is scepticism regarding the safety of this technique, based on the assumption that this is a rather "blind" procedure and on the high number of severe complications that have been reported in the literature. PURPOSE To evaluate whether there is evidence supporting a higher risk after ECTR in comparison to the conventional open release. METHODS We searched MEDLINE (January 1966 to November 2013), EMBASE (January 1980 to November 2013), the Cochrane Neuromuscular Disease Group Specialized Register (November 2013) and CENTRAL (2013, issue 11 in The Cochrane Library). We hand-searched reference lists of included studies. We included all randomized or quasi-randomized controlled trials (e.g. study using alternation, date of birth, or case record number) that compare any ECTR with any OCTR technique. Safety was assessed by the incidence of major, minor and total number of complications, recurrences, and re-operations.The total time needed before return to work or to return to daily activities was also assessed. We synthesized data using a random-effects meta-analysis in STATA. We conducted a sensitivity analysis for rare events using binomial likelihood. We judged the conclusiveness of meta-analysis calculating the conditional power of meta-analysis. CONCLUSIONS ECTR is associated with less time off work or with daily activities. The assessment of major complications, reoperations and recurrence of symptoms does not favor either of the interventions. There is an uncertain advantage of ECTR with respect to total minor complications (more transient paresthesia but fewer skin-related complications). Future studies are unlikely to alter these findings because of the rarity of the outcome. The effect of a learning curve might be responsible for reduced recurrences and reoperations with ECTR in studies that are more recent, although formal statistical analysis failed to provide evidence for such an association. LEVEL OF EVIDENCE I.

Transmission dynamics of Chlamydia trachomatis affect the impact of screening programmes

To assess the impact of screening programmes in reducing the prevalence of Chlamydia trachomatis, mathematical and computational models are used as a guideline for decision support. Unfortunately, large uncertainties exist about the parameters that determine the transmission dynamics of C. trachomatis. Here, we use a SEIRS (susceptible-exposed-infected-recovered-susceptible) model to critically analyze the turnover of C. trachomatis in a population and the impact of a screening programme. We perform a sensitivity analysis on the most important steps during an infection with C. trachomatis. Varying the fraction of the infections becoming symptomatic as well as the duration of the symptomatic period within the range of previously used parameter estimates has little effect on the transmission dynamics. However, uncertainties in the duration of temporary immunity and the asymptomatic period can result in large differences in the predicted impact of a screening programme. We therefore analyze previously published data on the persistence of asymptomatic C. trachomatis infection in women and estimate the mean duration of the asymptomatic period to be longer than anticipated so far, namely 433 days (95% CI: 420-447 days). Our study shows that a longer duration of the asymptomatic period results in a more pronounced impact of a screening programme. However, due to the slower turnover of the infection, a substantial reduction in prevalence can only be achieved after screening for several years or decades.

Deglaciation records of 17O-excess in East Antarctica: reliable reconstruction of oceanic relative humidity from coastal sites

We measured δ17O and δ18O in two Antarctic ice cores at EPICA Dome C (EDC) and TALDICE (TD), respectively and computed 17O-excess with respect to VSMOW. The comparison of our 17O-excess data with the previous record obtained at Vostok (Landais et al., 2008) revealed differences up to 35 ppm in 17O-excess mean level and evolution for the three sites. Our data showed that the large increase depicted at Vostok (20 ppm) during the last deglaciation, is a regional and not a general pattern in the temporal distribution of 17O-excess in East Antarctica. The EDC data display an increase of 13 ppm, whereas the TD data show no significant variation from the Last Glacial Maximum (LGM) to the Early Holocene (EH). Lagrangian moisture source diagnostic revealed very different source regions for Vostok and EDC compared to TD. These findings combined with the results of a sensitivity analysis, using a Rayleigh-type isotopic model, suggest that relative humidity (RH) at the oceanic source region (OSR) are a determining factor for the spatial differences of 17O-excess in East Antarctica. However, 17O-excess in remote sites of continental Antarctica (e.g. Vostok) may be highly sensitive to local effects. Hence, we consider 17O-excess in coastal East Antarctic ice cores (TD) to be more reliable as a proxy for RH at the OSR.

Effects of drilling and stress release on hydraulic properties and porewater chemistry of crystalline rocks

The experimental verification of matrix diffusion in crystalline rocks largely relies on indirect methods performed in the laboratory. Such methods are prone to perturbations of the rock samples by collection and preparation and therefore the laboratory-derived transport properties and fluid composition might not represent in situ conditions. We investigated the effects induced by the drilling process and natural rock stress release by mass balance considerations and sensitivity analysis of analytical out-diffusion data obtained from originally saturated, large-sized drillcore material from two locations drilled using traced drilling fluid. For in situ stress-released drillcores of quartz-monzodiorite composition from the Aspo HRL, Sweden, tracer mass balance considerations and 1D and 2D diffusion modelling consistently indicated a contamination of <1% of the original pore water. This chemically disturbed zone extends to a maximum of 0.1 mm into the drillcore (61.8 mm x 180.1 mm) corresponding to about 0.66% of the total pore volume (0.77 vol.%). In contrast, the combined effects of stress release and the drilling process, which have influenced granodioritic drillcore material from 560 m below surface at Forsmark. Sweden, resulted in a maximum contamination of the derived porewater Cl(-) concentration of about 8%. The mechanically disturbed zone with modified diffusion properties covers the outermost similar to 6 mm of the drillcore (50 mm x 189 mm), whereas the chemically disturbed zone extends to a maximum of 0.3 mm based on mass balance considerations, and to 0.15 mm to 0.2 mm into the drillcore based on fitting the observed tracer data. This corresponds to a maximum of 2.4% of the total pore volume (0.62 vol.%) being affected by the drilling-fluid contamination. The proportion of rock volume affected initially by drilling fluid or subsequently with experiment water during the laboratory diffusion and re-saturation experiments depends on the size of the drillcore material and will become larger the smaller the sample used for the experiment. The results are further in support of matrix diffusion taking place in the undisturbed matrix of crystalline rocks at least in the cm range.

Resurgence of HIV infection among men who have sex with men in Switzerland: mathematical modelling study

Background New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. Methodology/Principal Findings The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995–1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. Conclusions/Significance The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions.

Deglaciation records of 17O-excess in East Antarctica: reliable reconstruction of oceanic normalized relative humidity from coastal sites

We measured δ17O and δ18O in two Antarctic ice cores at EPICA Dome C (EDC) and TALDICE (TD), respectively, and computed 17O-excess with respect to VSMOW. The comparison of our 17O-excess data with the previous record obtained at Vostok (Landais et al., 2008a) revealed differences up to 35 ppm in 17O-excess mean level and evolution for the three sites. Our data show that the large increase depicted at Vostok (20 ppm) during the last deglaciation is a regional and not a general pattern in the temporal distribution of 17O-excess in East Antarctica. The EDC data display an increase of 12 ppm, whereas the TD data show no significant variation from the Last Glacial Maximum (LGM) to the Early Holocene (EH). A Lagrangian moisture source diagnostic revealed very different source regions for Vostok and EDC compared to TD. These findings combined with the results of a sensitivity analysis, using a Rayleigh-type isotopic model, suggest that normalized relative humidity (RHn) at the oceanic source region (OSR) is a determining factor for the spatial differences of 17O-excess in East Antarctica. However, 17O-excess in remote sites of continental Antarctica (e.g. Vostok) may be highly sensitive to local effects. Hence, we consider 17O-excess in coastal East Antarctic ice cores (TD) to be more reliable as a proxy for RHn at the OSR.

Simulating the impact of four control strategies on the population dynamics of Neospora caninum infection in Swiss dairy cattle

A dynamic deterministic simulation model was developed to assess the impact of different putative control strategies on the seroprevalence of Neospora caninum in female Swiss dairy cattle. The model structure comprised compartments of "susceptible" and "infected" animals (SI-model) and the cattle population was divided into 12 age classes. A reference model (Model 1) was developed to simulate the current (status quo) situation (present seroprevalence in Switzerland 12%), taking into account available demographic and seroprevalence data of Switzerland. Model 1 was modified to represent four putative control strategies: testing and culling of seropositive animals (Model 2), discontinued breeding with offspring from seropositive cows (Model 3), chemotherapeutic treatment of calves from seropositive cows (Model 4), and vaccination of susceptible and infected animals (Model 5). Models 2-4 considered different sub-scenarios with regard to the frequency of diagnostic testing. Multivariable Monte Carlo sensitivity analysis was used to assess the impact of uncertainty in input parameters. A policy of annual testing and culling of all seropositive cattle in the population reduced the seroprevalence effectively and rapidly from 12% to <1% in the first year of simulation. The control strategies with discontinued breeding with offspring from all seropositive cows, chemotherapy of calves and vaccination of all cattle reduced the prevalence more slowly than culling but were still very effective (reduction of prevalence below 2% within 11, 23 and 3 years of simulation, respectively). However, sensitivity analyses revealed that the effectiveness of these strategies depended strongly on the quality of the input parameters used, such as the horizontal and vertical transmission factors, the sensitivity of the diagnostic test and the efficacy of medication and vaccination. Finally, all models confirmed that it was not possible to completely eradicate N. caninum as long as the horizontal transmission process was not interrupted.

Healthcare and patient costs of a proactive chlamydia screening programme: the Chlamydia Screening Studies project

BACKGROUND AND OBJECTIVE: Most economic evaluations of chlamydia screening do not include costs incurred by patients. The objective of this study was to estimate both the health service and private costs of patients who participated in proactive chlamydia screening, using mailed home-collected specimens as part of the Chlamydia Screening Studies project. METHODS: Data were collected on the administrative costs of the screening study, laboratory time and motion studies and patient-cost questionnaire surveys were conducted. The cost for each screening invitation and for each accepted offer was estimated. One-way sensitivity analysis was conducted to explore the effects of variations in patient costs and the number of patients accepting the screening offer. RESULTS: The time and costs of processing urine specimens and vulvo-vaginal swabs from women using two nucleic acid amplification tests were similar. The total cost per screening invitation was 20.37 pounds (95% CI 18.94 pounds to 24.83). This included the National Health Service cost per individual screening invitation 13.55 pounds (95% CI 13.15 pounds to 14.33) and average patient costs of 6.82 pounds (95% CI 5.48 pounds to 10.22). Administrative costs accounted for 50% of the overall cost. CONCLUSIONS: The cost of proactive chlamydia screening is comparable to those of opportunistic screening. Results from this study, which is the first to collect private patient costs associated with a chlamydia screening programme, could be used to inform future policy recommendations and provide unique primary cost data for economic evaluations.

Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor

OBJECTIVE: This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. METHODS: We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was conducted to determine the robustness of the results. RESULTS: Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356,000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. CONCLUSION: The study suggests that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will most likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher than for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice.

Evaluation of a new commercial enzyme-linked immunosorbent assay for the detection of porcine antibodies against Trichinella spp

Trichinellosis is a zoonotic disease that is caused by the nematode Trichinella spp. Both European Union regulations and guidelines from the World Organization for Animal Health foresee the possibility of conducting serological surveillance for Trichinella spp. A newly developed commercial enzyme-linked immunosorbent assay (ELISA) was evaluated against 2 existing diagnostic techniques: an in-house ELISA and an in-house Western blot. A total of 875 Trichinella larva-negative samples of pigs and 93 Trichinella larva-positive samples of both naturally and experimentally infected pigs were included in the study. Bayesian modeling techniques were used to correct for the absence of a perfect reference test. The sensitivity and specificity of the commercial ELISA was 97.1-97.8% and 99.5-99.8%, respectively. Sensitivity analysis demonstrated high stability in the models. In a serological surveillance system, ELISA-positive samples should be tested by a confirmatory test. The Western blot is a suitable test for this purpose. With the use of the results of the models, the sensitivity and specificity of a test protocol in both ELISA and Western blot were 95.9% and 99.9%, respectively. The high sensitivity and specificity were achieved with a lower limit of detection than that of the routine artificial digestion test, suggesting that serological surveillance is a valuable alternative in surveillance for Trichinella spp. in pig production.

Validation of a Western Blot for the detection of anti-Trichinella spp. antibodies in domestic pigs

Trichinellosis is a zoonotic disease in humans caused by Trichinella spp. According to international regulations and guidelines, serological surveillance can be used to demonstrate the absence of Trichinella spp. in a defined domestic pig population. Most enzyme-linked immunosorbent assay (ELISA) tests presently available do not yield 100% specificity, and therefore, a complementary test is needed to confirm the diagnosis of any initial ELISA seropositivity. The goal of the present study was to evaluate the sensitivity and specificity of a Western Blot assay based on somatic Trichinella spiralis muscle stage (L1) antigen using Bayesian modeling techniques. A total of 295 meat juice and serum samples from pigs negative for Trichinella larvae by artificial digestion, including 74 potentially cross-reactive sera of pigs with other nematode infections, and 93 meat juice samples from pigs infected with Trichinella larvae were included in the study. The diagnostic sensitivity and specificity of the Western Blot were ranged from 95.8% to 96.0% and from 99.5% to 99.6%, respectively. A sensitivity analysis showed that the model outcomes were hardly influenced by changes in the prior distributions, providing a high confidence in the outcomes of the models. This validation study demonstrated that the Western Blot is a suitable method to confirm samples that reacted positively in an initial ELISA.