Context-Specific Estimation of Future Unrelated Medical Costs and Their Impact on Cost-Effectiveness Analyses.

OBJECTIVES: This study constructed and applied procedures for the estimation of unrelated future medical costs (UFMC) of women with breast cancer in Israel (as a case study) and examined the influence of including UFMC in cost-effectiveness analyses (CEAs). METHODS: Part I consisted of a retrospective cohort study based on patient-level claims data of both patients with breast cancer and matched controls during 14 years of follow-up. UFMC were estimated as (a) the annual average all-cause healthcare costs of the control subjects, and (b) as predicted values based on a generalized linear model (GLM) adjusted to patients' characteristics. Part II consisted of a CEA performed using a Markov simulation model comparing regimens of chemotherapy with/without trastuzumab, both excluding and including UFMC and for each of the UFMC estimates separately. All costs were adjusted to 2019 prices. Costs and QALYs were discounted at a yearly rate of 3%. RESULTS: The average annual healthcare costs in the control group were $2328 (± $5662). The corresponding incremental cost-effectiveness ratio (ICER) was $53,411/QALY and $55,903/QALY, when UFMC were excluded or included, respectively. Hence, trastuzumab was not considered cost-effective compared with a threshold of willingness-to-pay of $37,000 per QALY, regardless of the inclusion of UFMC. When UFMC were estimated on the basis of the prediction model, the ICERs were $37,968/QALY and $39,033/QALY, when UFMC were excluded or included, respectively. Thus, in this simulation, trastuzumab was not considered cost-effective, independent of the inclusion of UFMC. CONCLUSION: Our case study revealed that the inclusion of UFMC had modest effect on the ICERs, and thus did not alter the conclusion. Thus, we should estimate context-specific UFMC if they are expected to change the ICERs significantly, and transparently report the corresponding assumptions to uphold the integrity and reliability of the economic evaluation.

City-level SARS-CoV-2 sewage surveillance.

The COVID-19 pandemic created a global crisis impacting not only healthcare systems, but also economics and society. Therefore, it is important to find novel methods for monitoring disease activity. Recent data have indicated that fecal shedding of SARS-CoV-2 is common, and that viral RNA can be detected in wastewater. This suggests that wastewater monitoring is a potentially efficient tool for both epidemiological surveillance, and early warning for SARS-CoV-2 circulation at the population level. In this study we sampled an urban wastewater infrastructure in the city of Ashkelon (Ì´ 150,000 population), Israel, during the end of the first COVID-19 wave in May 2020 when the number of infections seemed to be waning. We were able to show varying presence of SARS-CoV-2 RNA in wastewater from several locations in the city during two sampling periods, before the resurgence was clinically apparent. This was expressed with a new index, Normalized Viral Load (NVL) which can be used in different area scales to define levels of virus activity such as red (high) or green (no), and to follow morbidity in the population at the tested area. The rise in viral load between the two sampling periods (one week apart) indicated an increase in morbidity that was evident two weeks to a month later in the population. Thus, this methodology may provide an early indication for SARS-CoV-2 infection outbreak in a population before an outbreak is clinically apparent.

Regressing SARS-CoV-2 Sewage Measurements Onto COVID-19 Burden in the Population: A Proof-of-Concept for Quantitative Environmental Surveillance.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus, a member of the coronavirus family of respiratory viruses that includes severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East respiratory syndrome (MERS). It has had an acute and dramatic impact on health care systems, economies, and societies of affected countries during the past 8 months. Widespread testing and tracing efforts are being employed in many countries in attempts to contain and mitigate this pandemic. Recent data has indicated that fecal shedding of SARS-CoV-2 is common and that the virus RNA can be detected in wastewater. This indicates that wastewater monitoring may provide a potentially efficient tool for the epidemiological surveillance of SARS-CoV-2 infection in large populations at relevant scales. In particular, this provides important means of (i) estimating the extent of outbreaks and their spatial distributions, based primarily on in-sewer measurements, (ii) managing the early-warning system quantitatively and efficiently, and (iii) verifying disease elimination. Here we report different virus concentration methods using polyethylene glycol (PEG), alum, or filtration techniques as well as different RNA extraction methodologies, providing important insights regarding the detection of SARS-CoV-2 RNA in sewage. Virus RNA particles were detected in wastewater in several geographic locations in Israel. In addition, a correlation of virus RNA concentration to morbidity was detected in Bnei-Barak city during April 2020. This study presents a proof of concept for the use of direct raw sewage-associated virus data, during the pandemic in the country as a potential epidemiological tool.

Development and Efficacy of an Electronic, Culturally Adapted Lifestyle Counseling Tool for Improving Diabetes-Related Dietary Knowledge: Randomized Controlled Trial Among Ethnic Minority Adults With Type 2 Diabetes Mellitus.

BACKGROUND: Ethnic minority populations exhibit disproportionately high rates of type 2 diabetes mellitus (T2DM). Electronic health tools have the potential to facilitate the cultural adaptation and tailoring of T2DM education to improve the knowledge and management of diabetes mellitus (DM). OBJECTIVE: This study aimed (1) to develop an adaptable Interactive Lifestyle Assessment, Counseling, and Education (I-ACE) software to support dietitian-delivered lifestyle counseling among low-socioeconomic status (SES) ethnic minority patients with T2DM and (2) to evaluate its effect on DM-related dietary knowledge and management compared with standard lifestyle advice (SLA) in a randomized controlled trial (RCT). METHODS: The I-ACE software, developed in consultation with clinical dieticians, incorporates evidence-based dietary and physical activity (PA) recommendations and educational materials. The features and behavioral change techniques include quantitative lifestyle (dietary intake and PA) assessment and simulation, individually tailored education and recommendations, motivational interviewing, and goal setting. For the unblinded pilot RCT, 50 overweight or obese Arab adults (aged 40-62 years) with poorly controlled T2DM were recruited from primary care clinics and randomly assigned to receive 4 in-person, dietician-delivered counseling sessions over 6 months using either (1) the I-ACE tool (experimental arm) or (2) the SLA methods (comparison arm). All outcome assessments were face-to-face. DM-related dietary knowledge (primary outcome) was measured at baseline, 3, 6, and 12 months. Lifestyle and other parameters were measured before, during, and after the intervention. Multiple linear regression and repeated measures linear mixed models were used to compare the changes in study outcomes and explore time trends in between-group and within-group changes. RESULTS: A total of 25 participants were enrolled in each arm, of whom 24 and 21 completed the final assessment of the primary outcome in the I-ACE and SLA arms, respectively. DM-related lifestyle knowledge increased more rapidly in the I-ACE arm than in the SLA arm (P value for study arm×time interaction=.02). Within the I-ACE arm, the mean (SE) differences in added sugar and dietary fiber intakes from baseline to 12 months were -2.6% (SE 1.0%) of total energy (P=.03) and 2.7 (SE 0.0) g/1000 kcal (P=.003), respectively. The odds of engaging in any leisure PA at 12 months tended to be higher in the I-ACE arm versus SLA arm, but did not reach statistical significance (odds ratio 2.8; 95% CI 0.7-11.6; P=.16). Both arms exhibited significant reductions in HbA1c (P value for change over time <.001). CONCLUSIONS: The use of the I-ACE software in a 6-month, 4-session dietician-delivered lifestyle counseling intervention improved the efficiency of lifestyle education, compared with SLA, among low-SES, ethnic minority patients with T2DM. This pilot trial provides justification for conducting a large-scale trial to evaluate its effectiveness and applicability in routine clinical care among ethnically diverse populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01858506; https://clinicaltrials.gov/ct2/show/NCT01858506.

Cost effectiveness and affordability of trastuzumab in sub-Saharan Africa for early stage HER2-positive breast cancer.

BACKGROUND: Breast cancer is the second most common cancer worldwide, the most common among women, and the most frequent cause of death among women in less developed regions. Trastuzumab is a humanized monoclonal antibody that downregulates the extracellular domain of the HER2 protein. Using trastuzumab to treat women with localized HER2-positive breast cancer has been shown to improve survival. The objective of this study is to explore the cost-effectiveness of adjuvant trastuzumab, from a societal perspective, in 11 African countries. In addition, we aimed to establish value-based prices for trastuzumab based on the gross domestic product per capita in each country. METHODS: We developed a Markov model in order to assess the costs and benefits associated with trastuzumab treatment over a lifetime horizon. A probabilistic sensitivity analysis was performed in order to estimate the impact of uncertainty of parameter-values on the results. Efficacy inputs were derived using clinical trial data from non-African countries. RESULTS: In the base case analysis, trastuzumab yielded a gain ranging from 0.92 LYs in Nigeria to 1.07 LYs in South Africa, and 0.9 QALYs in Nigeria to 1.02 QALYs in South Africa. The incremental cost ranged from 19,561 USD in Nigeria to 19,997 USD in Congo, and an incremental cost-effectiveness ratio ranging from 19,534 USD/QALY in South Africa to 21,697 USD/QALY in Nigeria. Using willingness to pay estimates based on World Health Organization recommendations, trastuzumab appear to not be cost-effective in all countries analyzed. Cost-effectiveness estimates were most sensitive to the discount rate, trastuzumab cost, and the hazard ratio. CONCLUSIONS: Trastuzumab does not appear to be cost effective in the African countries analyzed. In order for trastuzumab to be cost-effective, the costs of treatment would require significant discounts.

The Effects of Publicized Suicide Deaths on Subsequent Suicide Counts in Israel.

This study investigated associations between indiscriminate media reporting of suicides and later inflated suicide counts among Israel's general population between the years 2008 and 2012. Self-inflicted deaths that received post-suicide media exposure (referred to as "publicized suicides") were selected via Google news search-hit appraisals. Distributions of suicides were inspected and risk ratios (RRs) estimated by comparing population suicide rates 4 weeks before and 4 weeks after each publicized suicide ("reference" vs. "affected" periods, respectively). Poisson time series regression was employed to account also for secular trends and seasonality. A total of 2,119 people died by suicide, 13 of whom received noticeable media attention throughout the study. No meaningful impact following the 13 deaths on subsequent suicide counts during the observation window (affected vs. reference phase) was found. Poisson regression confirmed that suicide counts following publicized suicides were independent of media coverage. Given the pronounced search hits following the publicized suicides developing regulation practices that constrain indiscreet media reporting should officially be included as part of suicide prevention practices. Future research should focus on imitation suicide effects as a function of post-suicide media exposure, while including both risk and protective factors.

Modeling and analyzing respondent-driven sampling as a counting process.

Respondent-driven sampling (RDS) is an approach to sampling design and analysis which utilizes the networks of social relationships that connect members of the target population, using chain-referral. RDS sampling will typically oversample participants with many acquaintances. Naïve estimators, such as the sample average, will thus be biased towards the state of the most highly connected individuals. Current methodology cannot estimate population size from RDS, and promotes inverse probability weighted estimators for population parameters such as HIV prevalence. We propose to use the timing of recruitment, typically collected and discarded, in order to estimate the population size via a counting process model. Once population size and degree frequencies are made available, prevalence can be debiased in a post-stratified framework. We adapt methods developed for inference in epidemiology and software reliability to estimate the population size, degree counts and frequencies. A fundamental advantage of our approach is that it makes the assumptions of the sampling design explicit. This enables verification of the assumptions, maximum likelihood estimation, extension with covariates, and model selection. We develop large-sample theory, proving consistency and asymptotic normality. We further compare our estimators to other estimators in the RDS literature, through simulation and real-world data. In both cases, we find our estimators to outperform current methods. The likelihood problem in the model we present is separable, and thus efficiently solvable. We implement these estimators in an accompanying R package, chords, available on CRAN.

Estimation of polio infection prevalence from environmental surveillance data.

A major obstacle to eradicating polio is that poliovirus from endemic countries can be reintroduced to polio-free countries. Environmental surveillance (ES) can detect poliovirus from sewage or wastewaters samples, even in the absence of patients with paralysis. ES is underused, in part because its sensitivity is unknown. We used two unique data sets collected during a natural experiment provided by the 2013 polio outbreak in Israel: ES data from different locations and records of supplemental immunization with the live vaccine. Data from the intersecting population between the two data sets (covering more than 63,000 people) yielded a dose-dependent relationship between the number of poliovirus shedders and the amount of poliovirus in sewage. Using a mixed-effects linear regression analysis of these data, we developed several quantitative tools, such as (i) ascertainment of the number of infected individuals from ES data for application during future epidemics elsewhere, (ii) evaluation of the sensitivity of ES, and (iii) determination of the confidence level of the termination of poliovirus circulation after an outbreak. These results will be valuable in monitoring future outbreaks with ES, and this approach could be used to certify poliovirus elimination or to validate the need for more containment efforts.

Chromatic Multifocal Pupillometer for Objective Perimetry and Diagnosis of Patients with Retinitis Pigmentosa.

PURPOSE: To assess visual field (VF) defects and retinal function objectively in healthy participants and patients with retinitis pigmentosa (RP) using a chromatic multifocal pupillometer. DESIGN: Cross-sectional study. PARTICIPANTS: The right eyes of 16 healthy participants and 13 RP patients. METHODS: Pupil responses to red and blue light (peak, 485 and 625 nm, respectively) presented by 76 light-emitting diodes, 1.8-mm spot size at different locations of a 16.2° VF were recorded. Subjective VFs of RP patients were determined using chromatic dark-adapted Goldmann VFs (CDA-GVFs). Six healthy participants underwent 2 pupillometer examinations to determine test-retest reliability. MAIN OUTCOME MEASURES: Three parameters of pupil contraction were determined automatically: percentage of change of pupil size (PPC), maximum contraction velocity (MCV; in pixels per second), and latency of MCV (LMCV; in seconds). The fraction of functional VF was determined by CDA-GVF. RESULTS: In healthy participants, higher PPC and MCV were measured in response to blue compared with red light. The LMCV in response to blue light was relatively constant throughout the VF. Healthy participants demonstrated higher PPC and MCV and shorter LMCV in central compared with peripheral test points in response to red light. Test-retest correlation coefficients were 0.7 for PPC and 0.5 for MCV. In RP patients, test point in which the PPC and MCV were lower than 4 standard errors from the mean of healthy participants correlated with areas that were indicated as nonseeing by CDA-GVF. The mean absolute deviation in LMCV parameter in response to the red light between different test point was significantly higher in RP patients (range, 0.16-0.47) than in healthy participants (range, 0.02-0.16; P < 0.0001) and indicated its usefulness as a diagnostic tool with high sensitivity and specificity (area under the receiver operating characteristic curve (AUC), 0.97, Mann-Whitney-Wilcoxon analysis). Randomly reducing the number of test points to a total of 15 points did not significantly reduce the AUC in RP diagnosis based on this parameter. CONCLUSIONS: This study demonstrates the feasibility of using a chromatic multifocal pupillometer for objective diagnosis of RP and assessment of VF defects.

Impact of routine manual aspiration thrombectomy on outcomes of patients undergoing primary percutaneous coronary intervention for acute myocardial infarction: A meta-analysis.

BACKGROUND: The efficacy and safety of thrombectomy as an adjunct to primary percutaneous intervention (PCI) in the management of acute myocardial infarction (AMI) are debated. We performed a meta-analysis of randomized trials comparing primary PCI performed with versus without routine aspiration thrombectomy (AT). METHODS: A meta-analysis of randomized AT trials reporting clinical outcomes was done in accordance with the PRISMA guidelines. Trials reporting only non-clinical endpoints and those of technologies other than manual devices were excluded. The primary endpoint of this meta-analysis was mortality (either all-cause or cardiovascular). Secondary endpoints were reinfarction, stent thrombosis, and stroke. RESULTS: Seventeen randomized trials, involving 20,853 patients were included. Weighted mean follow-up was 9.3 ± 3.3 months. The rates of all-cause mortality (reported in 14 trials, n = 10,430) and cardiovascular mortality (reported in 6 trials, n = 11,810) did not differ significantly between patients treated with or without AT (4.6% vs. 5.3%, RR = 0.88 [95%CI = 0.75-1.04]; and, 3.0% vs. 3.7%, RR = 0.83 [95%CI = 0.68-1.01]; respectively). The rates of reinfarction and stent thrombosis were also similar in patients treated with versus those treated without AT (2.1% vs. 2.2%; RR = 0.96 [95%CI = 0.80-1.15]; and, 1.2% vs. 1.4%; RR = 0.84 [95%CI = 0.65-1.07], respectively). However, stroke rates were increased with AT (0.84% vs. 0.52%, RR = 1.56 [95%CI = 1.09-2.25]). CONCLUSIONS: Routine AT as an adjunct to primary PCI does not reduce the rates of death, reinfarction, or stent thrombosis, but is associated with increased stroke risk.

Emergence and size of the giant component in clustered random graphs with a given degree distribution.

Standard techniques for analyzing network models usually break down in the presence of clustering. Here we introduce a new analytic tool, the "free-excess degree" distribution, which extends the generating function framework, making it applicable for clustered networks (C>0). The methodology is general and provides a new expression for the threshold point at which the giant component emerges and shows that it scales as (1-C)(-1). In addition, the size of the giant component may be predicted even for more complicated scenarios such as the removal of a fixed fraction of nodes at random.