The time trade-off (TTO) is widely used in population-based surveys to estimate health-state valuations. Typically, respondents may characterize states as being better than or worse than dead. However, worse-than-dead responses can produce strongly negative mean values, so various analytic transformations of these responses have been suggested. The episodic random utility model (eRUM), operationalized using a linear regression estimator, was proposed as an alternative to these transformations, in part because of its theoretical appeal. We analyzed the eRUM estimator's mathematical properties and found that it violates monotonicity under certain patterns of survey responses, such that improvement in some individual valuations would imply a lower overall valuation for a given health state. Consequently, it is possible that orderings of alternative strategies based on eRUM valuations could lead a decision-maker to choose a strictly dominated strategy. Re-analyzing data from a large population-based EQ-5D valuation survey in the United Kingdom, we found 27% of all TTO responses (63% of all worse-than-dead responses) met the conditions for violation of monotonicity, and 74% of all respondents had at least one such response. These results present some challenge to the use of the eRUM estimator in generating health-state valuations for population health measurement and economic evaluation.

The time trade-off (TTO) is widely used in population-based surveys to estimate health-state valuations. Typically, respondents may characterize states as being better than or worse than dead. However, worse-than-dead responses can produce stro... (more »)

BACKGROUND: Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries. METHODS AND FINDINGS: Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%-96% across regions) and lowest for nephropathy (15%-26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17-32 d across region) and heart failure (16-31 d) and lowest for nephropathy (12-23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively. CONCLUSIONS: Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems.

BACKGROUND: Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention an... (more »)

BACKGROUND: A 26-valent Group A Streptococcus (GAS) vaccine candidate has been developed that may provide protection against pharyngitis, invasive disease and rheumatic fever. However, recommendations for the use of a new vaccine must be informed by a range of considerations, including parents' preferences for different relevant health outcomes. Our objectives were to: (1) describe parent preferences for GAS disease and vaccination using willingness-to-pay (WTP) and time trade-off (TTO) methods; and (2) understand how parents' implied WTP for a quality-adjusted life year (QALY) gained might vary depending on the particular health outcome considered (e.g. averted GAS disease vs. vaccine adverse events). METHODS: Telephone interviews were conducted with parents of children diagnosed with GAS pharyngitis at 2 pediatric practice sites in the Boston metropolitan area. WTP and TTO (trading parental longevity for child's health) questions for 2 vaccine and 4 disease-associated health states were asked using a randomly selected opening bid, followed by a 2nd bid and a final open-ended question about the amount willing to pay or trade. Descriptive analyses included medians and interquartile ranges for WTP and TTO estimates. The Wilcoxon signed-rank test was used to assess differences in WTP/QALY values for vaccine adverse events vs. disease states. RESULTS: Of 119 respondents, 100 (84%) and 96 (81%) provided a complete set of responses for WTP and TTO questions, respectively. The median WTP and discounted (at 3% per year) TTO values to avoid each health state were as follows: local reaction, $30, 0.12 days; systemic reaction, $50, 0.22 days; impetigo, $75, 1.25 days; strep throat, $75, 2.5 days; septic arthritis, $1,000, 6.6 days; and toxic shock syndrome, $3,000, 31.0 days. The median WTP/QALY was significantly higher for vaccine adverse events (approximately $60,000/QALY) compared to disease states ($18,000 to $36,000/QALY). CONCLUSIONS: Parents strongly prefer to prevent GAS disease in children compared to vaccine adverse events. However, implied WTP/QALY ratios were higher for the prevention of vaccine adverse events. Regret for errors of commission vs. omission may differ and should be considered by vaccine policymakers.

BACKGROUND: A 26-valent Group A Streptococcus (GAS) vaccine candidate has been developed that may provide protection against pharyngitis, invasive disease and rheumatic fever. However, recommendations for the use of a new vaccine must be inform... (more »)

BACKGROUND: Previous estimates of the global burden of disease for children have not included much information from China, leading to a large gap in data. We identified the main causes of deaths in neonates (<1 month), postneonatal infants (1-11 months), and children (<5 years) in China using information that was available to the public. METHODS: The Child Health Epidemiology Reference Group in collaboration with colleagues from Peking University systematically searched Chinese databases that were available to the public. Information was obtained from the Chinese Ministry of Health and Bureau of Statistics websites, Chinese National Knowledge Infrastructure database, and Chinese Health Statistics yearbooks for 1990-2008. We also obtained information from 206 high-quality community-based longitudinal studies of different causes of deaths in children (<5 years) that were written in the Chinese language. A statistical model was developed to estimate the total number of deaths in children according to provinces, age groups, and main causes. FINDINGS: During 1990-2008, the mortality rates in neonates, postneonatal infants, and children were reduced by 70% (from 34.0 to 10.2 per 1000 livebirths), 72% (from 53.5 to 14.9 per 1000 livebirths), and 71% (from 64.6 to 18.5 per 1000 livebirths), respectively, meeting the targets set in the Millennium Development Goal 4. The leading causes of deaths in 2008 were pneumonia, birth asphyxia, and preterm birth complications, each accounting for 15-17% of all deaths. Congenital abnormalities and accidents increased in importance during this period, contributing to 11% and 10% of child deaths, respectively. Sudden infant death syndrome contributed to 5% of deaths in children. INTERPRETATION: Publically available Chinese databases contain much important information that has been underused in the estimation of global and regional burden of disease. On the basis of trends, preterm birth complications are expected to become the leading cause of child mortality in China, whereas deaths from congenital abnormalities, accidents, and sudden infant death syndrome are predicted to continue increasing in importance in the long term. FUNDING: Bill & Melinda Gates Foundation

BACKGROUND: Previous estimates of the global burden of disease for children have not included much information from China, leading to a large gap in data. We identified the main causes of deaths in neonates (<1 month), postneonatal infants (... (more »)

Motivated by observed discrepancies between 2 published studies on the cost-effectiveness of rotavirus vaccination in Vietnam, the authors' objectives were to illustrate a specific, systematic approach to assessing model (structure and process) uncertainty and to quantify explicitly the contributions of different sources of variation in the outputs of different studies that share the same research question. On the basis of a series of working definitions of key model elements, the authors developed 5 alternative computer simulation (state-transition) models of rotavirus disease. They examined how epidemiological outcomes and cost-effectiveness ratios associated with rotavirus vaccination would change as elements of model structure and modeling process were progressively modified. They also explicitly decomposed the relative contributions of different modeling elements to differences in the cost-effectiveness results between the 2 previous analyses motivating the present study. The findings suggest that within the category of a static, deterministic, aggregate-level model, different choices in model structure and process lead to relatively modest differences in the estimated cost-effectiveness of rotavirus vaccination, but that intermediate epidemiologic outcomes vary more substantially depending on the choice of model structure. The authors caution against generalizing the quantitative results in this study beyond the present example but suggest that the approach presented here may serve as a template for other examinations of model uncertainty. As new research questions arise after the introduction of rotavirus vaccination programs, a reevaluation of model uncertainty is likely to be needed.

Motivated by observed discrepancies between 2 published studies on the cost-effectiveness of rotavirus vaccination in Vietnam, the authors' objectives were to illustrate a specific, systematic approach to assessing model (structure and process)... (more »)

Objective The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptations made in EPP 2009, the latest version of this tool, as new issues have arisen in the global response, in particular the global expansion of antiretroviral therapy (ART). Results By December 2008 over 4 million people globally were receiving ART, substantially improving their survival. EPP 2009 required modifications to correctly adjust for the effects of ART on incidence and the resulting increases in HIV prevalence in populations with high ART coverage. Because changing incidence is a better indicator of program impact, the 2009 series of UNAIDS tools also focuses on calculating incidence alongside prevalence. Other changes made in EPP 2009 include: an improved procedure, incremental mixture importance sampling, for efficiently generating more accurate uncertainty estimates; provisions to vary the urban/rural population ratios in generalised epidemics over time; introduction of a modified epidemic model that accommodates behaviour change in low incidence settings; and improved procedures for calibrating models. This paper describes these changes in detail, and discusses anticipated future changes in the next version of EPP.

Objective The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptati... (more »)

BACKGROUND: This study characterizes the historical relationship between coverage of measles containing vaccines (MCV) and mortality in children under 5 years, with a view toward ongoing global efforts to reduce child mortality.

METHODOLOGY/PRINCIPAL FINDINGS: Using country-level, longitudinal panel data, from 44 countries over the period 1960-2005, we analyzed the relationship between MCV coverage and measles mortality with (1) logistic regressions for no measles deaths in a country-year, and (2) linear regressions for the logarithm of the measles death rate. All regressions allowed a flexible, non-linear relationship between coverage and mortality. Covariates included birth rate, death rates from other causes, percent living in urban areas, population density, per-capita GDP, use of the two-dose MCV, year, and mortality coding system. Regressions used lagged covariates, country fixed effects, and robust standard errors clustered by country. The likelihood of no measles deaths increased nonlinearly with higher MCV coverage (ORs: 13.8 [1.6-122.7] for 80-89% to 40.7 [3.2-517.6] for ≥95%), compared to pre-vaccination risk levels. Measles death rates declined nonlinearly with higher MCV coverage, with benefits accruing more slowly above 90% coverage. Compared to no coverage, predicted average reductions in death rates were -79% at 70% coverage, -93% at 90%, and -95% at 95%.

CONCLUSIONS/SIGNIFICANCE: 40 years of experience with MCV vaccination suggests that extremely high levels of vaccination coverage are needed to produce sharp reductions in measles deaths. Achieving sustainable benefits likely requires a combination of extended vaccine programs and supplementary vaccine efforts.

BACKGROUND: This study characterizes the historical relationship between coverage of measles containing vaccines (MCV) and mortality in children under 5 years, with a view toward ongoing global efforts to reduce child mortali... (more »)

The time trade-off (TTO) is widely used in population-based surveys to estimate health-state valuations. Typically, respondents may characterize states as being better than or worse than dead. However, worse-than-dead responses can produce strongly negative mean values, so various analytic transformations of these responses have been suggested. The episodic random utility model (eRUM), operationalized using a linear regression estimator, was proposed as an alternative to these transformations, in part because of its theoretical appeal. We analyzed the eRUM estimator's mathematical properties and found that it violates monotonicity under certain patterns of survey responses, such that improvement in some individual valuations would imply a lower overall valuation for a given health state. Consequently, it is possible that orderings of alternative strategies based on eRUM valuations could lead a decision-maker to choose a strictly dominated strategy. Re-analyzing data from a large population-based EQ-5D valuation survey in the United Kingdom, we found 27% of all TTO responses (63% of all worse-than-dead responses) met the conditions for violation of monotonicity, and 74% of all respondents had at least one such response. These results present some challenge to the use of the eRUM estimator in generating health-state valuations for population health measurement and economic evaluation.

The time trade-off (TTO) is widely used in population-based surveys to estimate health-state valuations. Typically, respondents may characterize states as being better than or worse than dead. However, worse-than-dead responses can produce stro... (more »)

OBJECTIVE: UNAIDS and country analysts use a simple infectious disease model, embedded in the Estimation and Projection Package (EPP), to generate annual updates on the global HIV/AIDS epidemic. Our objective was to develop modifications to the current model that improve fit to recently observed prevalence trends across countries.

METHODS: Our proposed alternative to the current EPP approach simplifies the model structure and explicitly models changes in average infection risk over time, operationalised using penalised B-splines in a Bayesian framework. We also present an alternative approach to initiating the epidemic that improves standardisation and efficiency, and add an informative prior distribution for changes in infection risk beyond the last data point that enhances the plausibility of short-term extrapolations.

RESULTS: The spline-based model produces better fits than the current model to observed prevalence trends in settings that have recently experienced levelling or rising prevalence following a steep decline, such as Uganda and urban Rwanda. The model also predicts a deceleration of the decline in prevalence for countries with recent experience of steady declines, such as Kenya and Zimbabwe. Estimates and projections from our alternative model are comparable to those from the current model where the latter performs well.

CONCLUSIONS: A more flexible epidemiological model that accommodates changing infection risk over time can provide better estimates and short-term projections of HIV/AIDS incidence, prevalence and mortality than the current EPP model. The alternative model specification can be incorporated easily into existing analytical tools that are used to produce updates on the global HIV/AIDS epidemic.

OBJECTIVE: UNAIDS and country analysts use a simple infectious disease model, embedded in the Estimation and Projection Package (EPP), to generate annual updates on the global HIV/AIDS epidemic. Our objective was to develop m... (more »)

BACKGROUND: Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.

METHODS AND FINDINGS: A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24-26, 27-29, and 30-33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24-26, 27-29, and 30-33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.

CONCLUSIONS: Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis. Please see later in the article for the Editors' Summary.

BACKGROUND: Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed cho... (more »)

As global efforts proceed to scale up the delivery of antiretroviral therapy (ART) to HIV-infected persons in most urgent need, it is essential to understand the potential impact of treatment expansion on the transmission of new HIV infections. In this study, we use a series of simple mathematical models to explore the direction and magnitude of treatment effects on the sexual transmission of HIV. By defining the circumstances under which ART can reduce the number of new infections transmitted by treated patients, we provide critical benchmarks to aid in prioritizing efforts to maximize the population health impact of treatment and in evaluating the performance of different treatment programmes. We find that, based on the best currently available evidence of possible treatment effects on patient infectiousness, survival and behavior, the potential remains for either positive or negative changes in overall transmission. In relation to the total number of expected secondary infections caused by each infected person, however, these net treatment effects are relatively modest, particularly if treatment is initiated at advanced stages of the disease. This finding implies that treatment alone should not be expected to alter the population-level incidence of new infections dramatically, in the absence of changes in other factors including possible behavioral responses among uninfected persons and among infected persons who are not yet treatment candidates.

As global efforts proceed to scale up the delivery of antiretroviral therapy (ART) to HIV-infected persons in most urgent need, it is essential to understand the potential impact of treatment expansion on the transmission of new HIV infections. In... (more »)

Explicit priority setting presents Mexico with the opportunity to match the pressure and complexity of an advancing epidemiological transition with evidence-based policies driven by a fundamental concern for how to make the best use of scarce resources to improve population health. The Mexican priority-setting experience describes how standardised analytical approaches to decision making, mainly burden of disease and cost-effectiveness analyses, combine with other criteria--eg, being responsive to the legitimate non-health expectations of patients and ensuring fair financing across households--to design and implement a set of three differentiated health intervention packages. This process is a key element of a wider set of reform components aimed at extending health insurance, especially to the poor. The most relevant policy implications include lessons on the use of available and proven analytical tools to set national health priorities, the usefulness of priority-setting results to guide long-term capacity development, the importance of favouring an institutionalised approach to cost-effectiveness analysis, and the need for local technical capacity strengthening as an essential step to balance health-maximising arguments and other non-health criteria in a transparent and systematic process.

Explicit priority setting presents Mexico with the opportunity to match the pressure and complexity of an advancing epidemiological transition with evidence-based policies driven by a fundamental concern for how to make... (more »)

BACKGROUND: Development of new, effective, and affordable tuberculosis (TB) therapies has been identified as a critical priority for global TB control. As new candidates emerge from the global TB drug pipeline, the potential impacts of novel, shorter regimens on TB incidence and mortality have not yet been examined. METHODS AND FINDINGS: We used a mathematical model of TB to evaluate the expected benefits of shortening the duration of effective chemotherapy for active pulmonary TB. First, we considered general relationships between treatment duration and TB dynamics. Next, as a specific example, we calibrated the model to reflect the current situation in the South-East Asia region. We found that even with continued and rapid progress in scaling up the World Health Organization's DOTS strategy of directly observed, short-course chemotherapy, the benefits of reducing treatment duration would be substantial. Compared to a baseline of continuing DOTS coverage at current levels, and with currently available tools, a 2-mo regimen introduced by 2012 could prevent around 20% (range 13%-28%) of new cases and 25% (range 19%-29%) of TB deaths in South-East Asia between 2012 and 2030. If effective treatment with existing drugs expands rapidly, overall incremental benefits of shorter regimens would be lower, but would remain considerable (13% [range 8%-19%] and 19% [range 15%-23%] reductions in incidence and mortality, respectively, between 2012 and 2030). A ten-year delay in the introduction of new drugs would erase nearly three-fourths of the total expected benefits in this region through 2030. CONCLUSIONS: The introduction of new, shorter treatment regimens could dramatically accelerate the reductions in TB incidence and mortality that are expected under current regimens-with up to 2- or 3-fold increases in rates of decline if shorter regimens are accompanied by enhanced case detection. Continued progress in reducing the global TB burden will require a balanced approach to pursuing new technologies while promoting wider implementation of proven strategies.

BACKGROUND: Development of new, effective, and affordable tuberculosis (TB) therapies has been identified as a critical priority for global TB control. As new candidates emerge from the global TB drug pipeline, the potential impacts of novel, s... (more »)

To assess the costs and health effects of a range of interventions for preventing the spread of HIV and for treating people with HIV/AIDS in the context of the millennium development goal for combating HIV/AIDS.

DESIGN:

Cost effectiveness analysis based on an epidemiological model.

SETTING:

Analyses undertaken for two regions classified using the WHO epidemiological grouping-Afr-E, countries in sub-Saharan Africa with very high adult and high child mortality, and Sear-D, countries in South East Asia with high adult and high child mortality.

DATA SOURCES:

Biological and behavioural parameters from clinical and observational studies and population based surveys. Intervention effects and resource inputs based on published reports, expert opinion, and the WHO-CHOICE database.

MAIN OUTCOME MEASURES:

Costs per disability adjusted life year (DALY) averted in 2000 international dollars (Int dollars).

RESULTS:

In both regions interventions focused on mass media, education and treatment of sexually transmitted infections for female sex workers, and treatment of sexually transmitted infections in the general population cost < Int150 dollars per DALY averted. Voluntary counselling and testing costs < Int350 dollars per DALY averted in both regions, while prevention of mother to child transmission costs < Int50 dollars per DALY averted in Afr-E but around Int850 dollars per DALY in Sear-D. School based education strategies and various antiretroviral treatment strategies cost between Int500 dollars and Int5000 dollars per DALY averted.

CONCLUSIONS:

Reducing HIV transmission could be done most efficiently through mass media campaigns, interventions for sex workers and treatment of sexually transmitted infections where resources are most scarce. However, prevention of mother to child transmission, voluntary counselling and testing, and school based education would yield further health gains at higher budget levels and would be regarded as cost effective or highly cost effective based on standard international benchmarks. Antiretroviral therapy is at least as cost effective in improving population health as some of these interventions.

To assess the costs and health effects of a range of interventions for preventing the spread of HIV and for treating people with HIV/AIDS in the context of the millennium development goal for combating HIV/AIDS.

DESIGN:

Cost effectiv... (more »)