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1.  Packaging Health Services When Resources Are Limited: The Example of a Cervical Cancer Screening Visit 
PLoS Medicine  2006;3(11):e434.
Background
Increasing evidence supporting the value of screening women for cervical cancer once in their lifetime, coupled with mounting interest in scaling up successful screening demonstration projects, present challenges to public health decision makers seeking to take full advantage of the single-visit opportunity to provide additional services. We present an analytic framework for packaging multiple interventions during a single point of contact, explicitly taking into account a budget and scarce human resources, constraints acknowledged as significant obstacles for provision of health services in poor countries.
Methods and Findings
We developed a binary integer programming (IP) model capable of identifying an optimal package of health services to be provided during a single visit for a particular target population. Inputs to the IP model are derived using state-transition models, which compute lifetime costs and health benefits associated with each intervention. In a simplified example of a single lifetime cervical cancer screening visit, we identified packages of interventions among six diseases that maximized disability-adjusted life years (DALYs) averted subject to budget and human resource constraints in four resource-poor regions. Data were obtained from regional reports and surveys from the World Health Organization, international databases, the published literature, and expert opinion. With only a budget constraint, interventions for depression and iron deficiency anemia were packaged with cervical cancer screening, while the more costly breast cancer and cardiovascular disease interventions were not. Including personnel constraints resulted in shifting of interventions included in the package, not only across diseases but also between low- and high-intensity intervention options within diseases.
Conclusions
The results of our example suggest several key themes: Packaging other interventions during a one-time visit has the potential to increase health gains; the shortage of personnel represents a real-world constraint that can impact the optimal package of services; and the shortage of different types of personnel may influence the contents of the package of services. Our methods provide a general framework to enhance a decision maker's ability to simultaneously consider costs, benefits, and important nonmonetary constraints. We encourage analysts working on real-world problems to shift from considering costs and benefits of interventions for a single disease to exploring what synergies might be achievable by thinking across disease burdens.
Jane Kim and colleagues analyzed the possible ways that multiple health interventions might be packaged together during a single visit, taking into account scarce financial and human resources.
Editors' Summary
Background.
Public health decision makers in developed and developing countries are exploring the idea of providing packages of health checks at specific times during a person's lifetime to detect and/or prevent life-threatening diseases such as diabetes, heart problems, and some cancers. Bundling together tests for different diseases has advantages for both health-care systems and patients. It can save time and money for both parties and, by associating health checks with life events such as childbirth, it can take advantage of a valuable opportunity to check on the overall health of individuals who may otherwise rarely visit a doctor. But money and other resources (for example, nurses to measure blood pressure) are always limited, even in wealthy countries, so decision makers have to assess the likely costs and benefits of packages of interventions before putting them into action.
Why Was This Study Done?
Recent evidence suggests that women in developing countries would benefit from a once-in-a-lifetime screen for cervical cancer, a leading cause of cancer death for this population. If such a screening strategy for cervical cancer were introduced, it might provide a good opportunity to offer women other health checks, but it is unclear which interventions should be packaged together. In this study, the researchers have developed an analytic framework to identify an optimal package of health services to offer to women attending a clinic for their lifetime cervical cancer screen. Their model takes into account monetary limitations and possible shortages in trained personnel to do the health checks, and balances these constraints against the likely health benefits for the women.
What Did the Researchers Do and Find?
The researchers developed a “mathematical programming” model to identify an optimal package of health services to be provided during a single visit. They then used their model to estimate the average costs and health outcomes per woman of various combinations of health interventions for 35- to 40-year-old women living in four regions of the world with high adult death rates. The researchers chose breast cancer, cardiovascular disease, depression, anemia caused by iron deficiency, and sexually transmitted diseases as health conditions to be checked in addition to cervical cancer during the single visit. They considered two ways—one cheap in terms of money and people; the other more expensive but often more effective—of checking for or dealing with each potential health problem. When they set a realistic budgetary constraint (based on the annual health budget of the poorest countries and a single health check per woman in the two decades following her reproductive years), the optimal health package generated by the model for all four regions included cervical cancer screening done by testing for human papillomavirus (an effective but complex test), treatment for depression, and screening or treatment for anemia. When a 50% shortage in general (for example, nurses) and specialized (for example, doctors) personnel time was also included, the health benefits of the package were maximized by using a simpler test for cervical cancer and by treating anemia but not depression; this freed up resources in some regions to screen for breast cancer or cardiovascular disease.
What Do These Findings Mean?
The model described by the researchers provides a way to explore the potential advantages of delivering a package of health interventions to individuals in a single visit. Like all mathematical models, its conclusions rely heavily on the data used in its construction. Indeed, the researchers stress that, because they did not have full data on the effectiveness of each intervention and made many other assumptions, their results on their own cannot be used to make policy decisions. Nevertheless, their results clearly show that the packaging of multiple health services during a single visit has great potential to maximize health gains, provided the right interventions are chosen. Most importantly, their analysis shows that in the real world the shortage of personnel, which has been ignored in previous analyses even though it is a major problem in many developing countries, will affect which health conditions and specific interventions should be bundled together to provide the greatest impact on public health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030434.g001.
The World Health Organization has information on choosing cost-effective health interventions and on human resources for health
The American Cancer Society offers patient information on cervical cancer
The Alliance for Cervical Cancer Prevention includes information about cervical cancer prevention programs in developing countries
doi:10.1371/journal.pmed.0030434
PMCID: PMC1635742  PMID: 17105337
2.  Optimization of PSA Screening Policies: a Comparison of the Patient and Societal Perspectives 
Medical Decision Making  2011;32(2):337-349.
Objective
To estimate the benefit of PSA-based screening for prostate cancer from the patient and societal perspectives.
Method
A partially observable Markov decision process (POMDP) model was used to optimize PSA screening decisions. We considered age-specific prostate cancer incidence rates and the mortality rates from prostate cancer and competing causes. Our model trades off the potential benefit of early detection with the cost of screening and loss of patient quality of life due to screening and treatment. PSA testing and biopsy decisions are made based on the patient’s probability of having prostate cancer. Probabilities are inferred based on the patient’s complete PSA history using Bayesian updating.
Data Sources
The results of all PSA tests and biopsies done in Olmsted County, Minnesota from 1993 to 2005 (11,872 men and 50,589 PSA test results).
Perspective and Outcome Measures
Patients’ perspective: maximize expected quality-adjusted life years (QALYs); societal perspective: maximize the expected monetary value based on societal willingness to pay for QALYs and the cost of PSA testing, prostate biopsies and treatment.
Results
From the patient perspective the optimal policy recommends stopping PSA testing and biopsy at age 76. From the societal perspective the stopping age is 71. The expected incremental benefit of optimal screening over the traditional guideline of annual PSA screening with threshold 4.0 ng/mL for biopsy is estimated to be 0.165 QALYs per person from the patient perspective, and 0.161 QALYs per person from the societal perspective. PSA screening based on traditional guidelines is found to be worse than no screening at all.
Conclusions
PSA testing done with traditional guidelines underperforms and therefore underestimates the potential benefit of screening. Optimal screening guidelines differ significantly depending on the perspective of the decision maker.
doi:10.1177/0272989X11416513
PMCID: PMC3288242  PMID: 21933990
3.  Opportunity Cost for Early Treatment of Chagas Disease in Mexico 
Background
Given current neglect for Chagas disease in public health programs in Mexico, future healthcare and economic development policies will need a more robust model to analyze costs and impacts of timely clinical attention of infected populations.
Methodology/Principal Findings
A Markov decision model was constructed to simulate the natural history of a Chagas disease cohort in Mexico and to project the associated short and long-term clinical outcomes and corresponding costs. The lifetime cost for a timely diagnosed and treated Chagas disease patient is US$ 10,160, while the cost for an undiagnosed individual is US$ 11,877. The cost of a diagnosed and treated case increases 24-fold from early acute to indeterminate stage. The major cost component for lifetime cost was working days lost, between 44% and 75%, depending on the program scenario for timely diagnosis and treatment.
Conclusions/Significance
In the long term, it is cheaper to diagnose and treat chagasic patients early, instead of doing nothing. This finding by itself argues for the need to shift current policy, in order to prioritize and attend this neglected disease for the benefit of social and economic development, which implies including treatment drugs in the national formularies. Present results are even more relevant, if one considers that timely diagnosis and treatment can arrest clinical progression and enhance a chronic patient's quality of life.
Author Summary
Chagas disease is caused by the flagellated protozoan parasite Trypanosoma cruzi, vectored in Mexico in both rural and urban areas via one of 18 triatomine bug species. Despite ample morbidity and mortality evidence, however, health policy managers in Mexico have continued to neglect prevention, control and clinical attention for the disease. A computer simulation Markov model was programmed and fed with information from published evidence and an expert panel. The lifetime cost for a timely diagnosed and treated Chagas disease patient is US$ 10,160, while the cost for an undiagnosed individual is US$ 11,877. The cost of a diagnosed and treated case increases 24-fold from early acute to indeterminate stage. The major cost component for lifetime cost was working days lost, between 44% and 75%, depending on the program scenario for timely diagnosis and treatment. Timely medical attention for infected individuals is cheaper than doing nothing, especially if life and labor costs are included. The evidence provided, essential for decision-making, should be used to develop disease-specific prevention, control and patient clinical diagnosis and treatment policies for Chagas disease in Mexico.
doi:10.1371/journal.pntd.0002776
PMCID: PMC3990484  PMID: 24743112
4.  Decision Theoretic Analysis of Improving Epidemic Detection 
The potentially catastrophic impact of an epidemic specially those due to bioterrorist attack, makes developing effective detection methods essential for public health. Current detection methods trade off reliability of alarms for early detection of outbreaks. The performance of these methods can be improved by disease-specific modeling techniques that take into account the potential costs and effects of an attack to provide optimal warnings and the cost and effectiveness of interventions. We study this optimization problem in the framework of sequential decision making under uncertainty. Our approach relies on estimating the future benefit of true alarms and the costs of false alarms. Using these quantities it identifies optimal decisions regarding the credibility of outputs from a traditional detection method at each point in time. The key contribution of this paper is to apply Partially Observable Markov Decision Processes (POMDPs) on outbreak detection methods for improving alarm function in the case of anthrax. We present empirical evidence illustrating that at a fixed specificity, the performance of detection methods with respect to sensitivity and timeliness is improved significantly by utilizing POMDPs in detection of anthrax attacks.
PMCID: PMC2655796  PMID: 18693857
5.  The development of an adaptive upper-limb stroke rehabilitation robotic system 
Background
Stroke is the primary cause of adult disability. To support this large population in recovery, robotic technologies are being developed to assist in the delivery of rehabilitation. This paper presents an automated system for a rehabilitation robotic device that guides stroke patients through an upper-limb reaching task. The system uses a decision theoretic model (a partially observable Markov decision process, or POMDP) as its primary engine for decision making. The POMDP allows the system to automatically modify exercise parameters to account for the specific needs and abilities of different individuals, and to use these parameters to take appropriate decisions about stroke rehabilitation exercises.
Methods
The performance of the system was evaluated by comparing the decisions made by the system with those of a human therapist. A single patient participant was paired up with a therapist participant for the duration of the study, for a total of six sessions. Each session was an hour long and occurred three times a week for two weeks. During each session, three steps were followed: (A) after the system made a decision, the therapist either agreed or disagreed with the decision made; (B) the researcher had the device execute the decision made by the therapist; (C) the patient then performed the reaching exercise. These parts were repeated in the order of A-B-C until the end of the session. Qualitative and quantitative question were asked at the end of each session and at the completion of the study for both participants.
Results
Overall, the therapist agreed with the system decisions approximately 65% of the time. In general, the therapist thought the system decisions were believable and could envision this system being used in both a clinical and home setting. The patient was satisfied with the system and would use this system as his/her primary method of rehabilitation.
Conclusions
The data collected in this study can only be used to provide insight into the performance of the system since the sample size was limited. The next stage for this project is to test the system with a larger sample size to obtain significant results.
doi:10.1186/1743-0003-8-33
PMCID: PMC3152889  PMID: 21679457
6.  Modeling treatment of ischemic heart disease with partially observable Markov decision processes. 
Diagnosis of a disease and its treatment are not separate, one-shot activities. Instead they are very often dependent and interleaved over time, mostly due to uncertainty about the underlying disease, uncertainty associated with the response of a patient to the treatment and varying cost of different diagnostic (investigative) and treatment procedures. The framework of Partially observable Markov decision processes (POMDPs) developed and used in operations research, control theory and artificial intelligence communities is particularly suitable for modeling such a complex decision process. In the paper, we show how the POMDP framework could be used to model and solve the problem of the management of patients with ischemic heart disease, and point out modeling advantages of the framework over standard decision formalisms.
PMCID: PMC2232362  PMID: 9929277
7.  Cost-Effectiveness of Interventions to Promote Physical Activity: A Modelling Study 
PLoS Medicine  2009;6(7):e1000110.
Linda Cobiac and colleagues model the costs and health outcomes associated with interventions to improve physical activity in the population, and identify specific interventions that are likely to be cost-saving.
Background
Physical inactivity is a key risk factor for chronic disease, but a growing number of people are not achieving the recommended levels of physical activity necessary for good health. Australians are no exception; despite Australia's image as a sporting nation, with success at the elite level, the majority of Australians do not get enough physical activity. There are many options for intervention, from individually tailored advice, such as counselling from a general practitioner, to population-wide approaches, such as mass media campaigns, but the most cost-effective mix of interventions is unknown. In this study we evaluate the cost-effectiveness of interventions to promote physical activity.
Methods and Findings
From evidence of intervention efficacy in the physical activity literature and evaluation of the health sector costs of intervention and disease treatment, we model the cost impacts and health outcomes of six physical activity interventions, over the lifetime of the Australian population. We then determine cost-effectiveness of each intervention against current practice for physical activity intervention in Australia and derive the optimal pathway for implementation. Based on current evidence of intervention effectiveness, the intervention programs that encourage use of pedometers (Dominant) and mass media-based community campaigns (Dominant) are the most cost-effective strategies to implement and are very likely to be cost-saving. The internet-based intervention program (AUS$3,000/DALY), the GP physical activity prescription program (AUS$12,000/DALY), and the program to encourage more active transport (AUS$20,000/DALY), although less likely to be cost-saving, have a high probability of being under a AUS$50,000 per DALY threshold. GP referral to an exercise physiologist (AUS$79,000/DALY) is the least cost-effective option if high time and travel costs for patients in screening and consulting an exercise physiologist are considered.
Conclusions
Intervention to promote physical activity is recommended as a public health measure. Despite substantial variability in the quantity and quality of evidence on intervention effectiveness, and uncertainty about the long-term sustainability of behavioural changes, it is highly likely that as a package, all six interventions could lead to substantial improvement in population health at a cost saving to the health sector.
Please see later in the article for Editors' Summary
Editors' Summary
Background
The human body needs regular physical activity throughout life to stay healthy. Physical activity—any bodily movement produced by skeletal muscles that uses energy—helps to maintain a healthy body weight and to prevent or delay heart disease, stroke, type 2 diabetes, colon cancer, and breast cancer. In addition, physically active people feel better and live longer than physically inactive people. For an adult, 30 minutes of moderate physical activity—walking briskly, gardening, swimming, or cycling—at least five times a week is sufficient to promote and maintain health. But at least 60% of the world's population does not do even this modest amount of physical activity. The daily lives of people in both developed and developing countries are becoming increasingly sedentary. People are sitting at desks all day instead of doing manual labor; they are driving to work in cars instead of walking or cycling; and they are participating less in physical activities during their leisure time.
Why Was This Study Done?
In many countries, the chronic diseases that are associated with physical inactivity are now a major public-health problem; globally, physical inactivity causes 1.9 million deaths per year. Clearly, something has to be done about this situation. Luckily, there is no shortage of interventions designed to promote physical activity, ranging from individual counseling from general practitioners to mass-media campaigns. But which intervention or package of interventions will produce the optimal population health benefits relative to cost? Although some studies have examined the cost-effectiveness of individual interventions, different settings for analysis and use of different methods and assumptions make it difficult to compare results and identify which intervention approaches should be give priority by policy makers. Furthermore, little is known about the cost-effectiveness of packages of interventions. In this study, the researchers investigate the cost-effectiveness in Australia (where physical inactivity contributes to 10% of deaths) of a package of interventions designed to promote physical activity in adults using a standardized approach (ACE-Prevention) to the assessment of the cost-effectiveness of health-care interventions.
What Did the Researchers Do and Find?
The researchers selected six interventions for their study: general practitioner “prescription” of physical activity; general practitioner referral to an exercise physiologist; a mass-media campaign to promote physical activity; the TravelSmart car use reduction program; a campaign to encourage the use of pedometers to increase physical activity; and an internet-based program. Using published data on the effects of physical activity on the amount of illness and death caused by breast and colon cancer, heart disease, stroke, and type 2 diabetes and on the effectiveness of each intervention, the researchers calculated the health outcomes of each intervention in disability-adjusted life years (DALY; a year of healthy life lost because of premature death or disability) averted over the lifetime of the Australian population. They also calculated the costs associated with each intervention offset by the costs associated with the five conditions listed above. These analyses showed that the pedometer program and the mass-media campaign were likely to be the most cost-effective interventions. These interventions were also most likely to be cost-saving. Referral to an exercise physiologist was the least cost-effective intervention. The other three interventions, though unlikely to be cost-saving, were likely to be cost-effective. Finally, a package of all six interventions would be cost-effective and would avert 61,000 DALYs, a third of what could be achieved if every Australian did 30 minutes of physical activity five times a week.
What Do These Findings Mean?
As in all modeling studies, these findings depend on the quality of the data and on the assumptions included by the researchers in their calculations. Unfortunately, there was substantial variability in the quantity and quality of evidence on the effectiveness of each intervention and uncertainty about the long-term effects of each intervention. Nevertheless, the findings presented in this study suggest that the assessment of the cost-effectiveness of a combination of interventions designed to promote physical activity might provide policy makers with some guidance about the best way to reduce the burden of disease caused by physical inactivity. More specifically, for Australia, these findings suggest that the package of the six interventions considered here is likely to provide a cost-effective way to substantially improve the health of the nation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000110.
The World Health Organization provides information about physical activity and health (in several languages); it also provides an explanation of DALYs
The US Centers for Disease Control and Prevention provides information on physical activity for different age groups and for health professionals
The UK National Health Service information source Choices also explains the benefits of regular physical activity
MedlinePlus has links to other resources about exercise and physical fitness (in English and Spanish)
The University of Queensland Web site has more information on ACE-Prevention (Assessing Cost-Effectiveness Prevention)
doi:10.1371/journal.pmed.1000110
PMCID: PMC2700960  PMID: 19597537
8.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Background
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
Conclusions
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
Background
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000098.
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
9.  Serological Testing Versus Other Strategies for Diagnosis of Active Tuberculosis in India: A Cost-Effectiveness Analysis 
PLoS Medicine  2011;8(8):e1001074.
This cost-effectiveness study shows that sputum smear microscopy is the most cost-effective test for active tuberculosis (TB) in India, and liquid culture plus microscopy is more cost-effective for TB diagnosis than serological tests.
Background
Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown.
Methods and Findings
Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive.
If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses.
Conclusions
In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 2 million people develop tuberculosis in India—a fifth of the global incidence of this highly contagious bacterial infection. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs although it can also infect other organs. The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Diagnostic tests for tuberculosis include sputum smear microscopy (microscopic analysis of mucus brought up from the lungs by coughing), culture (growth) of M. tuberculosis from sputum samples in liquid media (using, for example, a commercial product called the mycobacteria growth indicator tube or MGIT), and nucleic acid amplification tests (which detect the bacterium's genome in patient samples) such as the Xpert MTB/RIF system. Tuberculosis can usually be cured by taking several powerful antibiotics daily for at least 6 months.
Why Was This Study Done?
In India, as elsewhere, undiagnosed and misdiagnosed tuberculosis drives the tuberculosis epidemic by increasing the transmission of M. tuberculosis. Unfortunately, sputum smear microscopy, the current mainstay of tuberculosis diagnosis worldwide, detects only half of tuberculosis cases, mycobacterial culture can take weeks to provide a diagnosis, and rapid techniques such as nucleic acid amplification require infrastructure that is often not available in developing countries. Consequently, in India and other developing countries, serological tests are widely used for the diagnosis of tuberculosis. Serological tests detect antibodies against M. tuberculosis in the blood (antibodies are proteins made by the immune system in response to infections). Serological tests are fast and simple to perform, but they are not recommended for clinical use, and the available evidence suggests that they do not diagnose tuberculosis accurately. Even so, and in the absence of information about the cost and impact (cost-effectiveness) of serological testing, about 1.5 million serological tests for tuberculosis are conducted every year in India at a cost of more than US$15 million. Here, the researchers analyze the cost-effectiveness of serological tests compared to other diagnostic tests from the perspective of tuberculosis control in India.
What Did the Researchers Do and Find?
The researchers used “decision analysis” to estimate the cost-effectiveness of sputum smear microscopy, microscopy plus liquid culture using the MGIT system, and serological testing using the widely used anda-tb ELISA commercial test in a hypothetical group of 1.5 million people suspected of having tuberculosis. Decision analysis formally assesses the decision-making process by using models that evaluate outcomes under different scenarios. By feeding data on the costs and accuracy of different diagnostic tests into their decision-analysis model, the researchers estimate that, over a year, serology would generate 14,000 more tuberculosis diagnoses than sputum microscopy. However, it would also generate 121,000 more false-positive diagnoses and 32,000 more tuberculosis transmissions to other people (secondary transmissions), and avert 102,000 fewer disability-adjusted life years (DALYs; a DALY is a year of healthy life lost because of premature death or disability) at four times the incremental cost of sputum microscopy. MGIT culture added to sputum smear microscopy would avert 130,000 DALYs at an incremental cost of US$213 per DALY averted. Finally, sensitivity analyses (reruns of the decision-analysis model using different values for test costs and accuracy) identified no scenario in which serology was either less costly or more effective than sputum smear microscopy alone or in which serology plus sputum microscopy was more cost-effective than MGIT culture plus sputum microscopy.
What Do These Findings Mean?
These findings identify sputum smear microscopy as the most cost-effective existing diagnostic test for tuberculosis in India. Moreover, they suggest that in areas where high-quality microscopy is available, resources are sufficient, and infrastructure to effectively use culture exists, the addition of MGIT culture to sputum smear microscopy would be more cost-effective than the addition of serology. Importantly, these findings suggest that, if used as an initial test for tuberculosis in India, serology would result in more DALYs, more secondary infections, and more false-positive diagnoses than sputum smear microscopy while increasing per-patient costs to the Indian tuberculosis control sector. Given these findings and the results of a recent updated systematic review on the accuracy of serological tests, the World Health Organization's Strategic and Technical Advisory Group for Tuberculosis recently advised against the use of currently available serological tests for the diagnosis of tuberculosis. The WHO negative policy against serological tests must now be implemented in India.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001074.
Details of the recent systematic review of serological tests for tuberculosis diagnosis are available in a PLoS Medicine Research Article by Steingart et al.
The World Health Organization provides information on all aspects of tuberculosis, including tuberculosis diagnostics and the Stop TB Partnership (some information is in several languages); its Strategic and Technical Advisory Group for Tuberculosis recommendations on tuberculosis diagnosis are available
The Evidence-based TB Diagnosis Web site by the Stop TB Partnership's New Diagnostics Working Group provides evidence syntheses on various TB tests, along with guidelines, resources, and training materials
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the diagnosis of tuberculosis disease
The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001074
PMCID: PMC3153451  PMID: 21857810
10.  Online Planning Algorithms for POMDPs 
Partially Observable Markov Decision Processes (POMDPs) provide a rich framework for sequential decision-making under uncertainty in stochastic domains. However, solving a POMDP is often intractable except for small problems due to their complexity. Here, we focus on online approaches that alleviate the computational complexity by computing good local policies at each decision step during the execution. Online algorithms generally consist of a lookahead search to find the best action to execute at each time step in an environment. Our objectives here are to survey the various existing online POMDP methods, analyze their properties and discuss their advantages and disadvantages; and to thoroughly evaluate these online approaches in different environments under various metrics (return, error bound reduction, lower bound improvement). Our experimental results indicate that state-of-the-art online heuristic search methods can handle large POMDP domains efficiently.
PMCID: PMC2748358  PMID: 19777080
11.  Reward Optimization in the Primate Brain: A Probabilistic Model of Decision Making under Uncertainty 
PLoS ONE  2013;8(1):e53344.
A key problem in neuroscience is understanding how the brain makes decisions under uncertainty. Important insights have been gained using tasks such as the random dots motion discrimination task in which the subject makes decisions based on noisy stimuli. A descriptive model known as the drift diffusion model has previously been used to explain psychometric and reaction time data from such tasks but to fully explain the data, one is forced to make ad-hoc assumptions such as a time-dependent collapsing decision boundary. We show that such assumptions are unnecessary when decision making is viewed within the framework of partially observable Markov decision processes (POMDPs). We propose an alternative model for decision making based on POMDPs. We show that the motion discrimination task reduces to the problems of (1) computing beliefs (posterior distributions) over the unknown direction and motion strength from noisy observations in a Bayesian manner, and (2) selecting actions based on these beliefs to maximize the expected sum of future rewards. The resulting optimal policy (belief-to-action mapping) is shown to be equivalent to a collapsing decision threshold that governs the switch from evidence accumulation to a discrimination decision. We show that the model accounts for both accuracy and reaction time as a function of stimulus strength as well as different speed-accuracy conditions in the random dots task.
doi:10.1371/journal.pone.0053344
PMCID: PMC3551910  PMID: 23349707
12.  Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis 
PLoS Medicine  2010;7(10):e1000350.
Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit.
Background
The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada.
Methods and Findings
A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children would annually save society US$65.6 million (US$49.1–US$81.1) and health care payers US$61.1 million (US$46.2–US$76.3). In Canada the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations annually. Its routine administration would annually save society CDN$1.72 million (CDN$1.15–CDN$1.89) and the health care system CDN$1.18 million (CDN$0.88–CDN$1.41).
Conclusions
In countries where intravenous rehydration is often employed, the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings compared to a no-ondansetron policy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Although many episodes of gastroenteritis in children are mild and can be managed with oral fluids, including oral rehydration therapy (ORT), some cases are severe enough to require hospital admission for intravenous fluids. Administration of an antiemetic (a drug that reduces nausea and sickness) can be clinically effective, especially ondansetron, (a drug that belongs to a class of drugs known as selective serotonin receptor antagonists), which is safer than other antiemetics, such as promethazine and prochlorperazine, and in which there is good evidence to support its effectiveness in improving the success of ORT in children with gastroenteritis. Furthermore, studies have shown that administration of ondansetron decreases the risk of further vomiting, and hence the need for intravenous rehydration, and immediate hospital admission. However, despite the proven clinical benefits of ondansetron, clinical practice guidelines continue to recommend against the use of antiemetics in gastroenteritis because the evidence of cost savings is not yet clear. Last year, the UK's National Institute for Health and Clinical Excellence recommended that such a cost analysis should be a key research priority in pediatric gastroenteritis.
Why Was This Study Done?
This study—which is an economic analysis—was conducted in response to the various calls for the need to demonstrate the cost effectiveness of ondansetron in the management of pediatric gastroenteritis.
What Did the Researchers Do and Find?
The researchers analysed the costs of the administration of oral ondansetron in both the US and Canada, if routinely given to children with gastroenteritis-induced vomiting and dehydration in the emergency department setting. In addition, the researchers calculated the incremental cost of ondansetron per quality-adjusted life-year (QALY) gained from a health care perspective, compared to a regimen without ondansetron administration. The authors conducted a particular type of statistical analysis, known as decision tree analysis, to compare the two treatment options—administering ondansetron and not administering ondansetron in addition to ORT, with the clinical outcomes (further vomiting, intravenous rehydration, and hospitalization) determined on the basis of the documented efficacy of ondansetron. In addition, the researchers conducted their analyses from both the societal perspective (which included all costs, both direct—the resources required to produce a service; and indirect—productivity costs) and the health care payer's perspective. The US and Canada use similar medical resources, management programs, and treatment guidelines, but as prices differ dramatically (for example, the cost of hospitalization in the US is 8-fold higher than that in Canada), the researchers conducted a separate analysis for each country.
On the basis of data from the US, the researchers found that the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations every year with an annual saving of US$65.6 million to society and US$61.1 million to payers of health care costs if this drug was given routinely. When using Canadian data, the researchers found that the administration of ondansetron to eligible children would prevent 4,065 intravenous insertions and 1,003 hospitalizations every year, with an annual saving of CDN$1.72 million to society and CDN$1.18 million to payers of health care costs if this drug was given routinely.
What Do These Findings Mean?
The results of this study show that the emergency department administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis results in significant monetary savings from both societal and health care perspectives compared to a policy that does not include ondansetron administration. Furthermore, the societal savings are probably an underestimate because in their model, the researchers assumed that only 10% of children with gastroenteritis presenting to an emergency department would meet eligibility criteria (in reality, this proportion would likely be higher). In addition, the researchers did not include estimates for ondansetron administration in the clinic or private office setting, as although such use is common, no estimates of eligibility and efficacy were available.
Therefore, in addition to being clinically beneficial, the administration of oral ondansetron to children with dehydration and vomiting secondary to gastroenteritis is also economically advantageous.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000350.
Patient UK and the US National Institutes of Health provide information for patients on ondansetron
Patient UK provides information on gastroenteritis in children
BBC Health also provides general information on gastroenteritis
The Centers for Disease Control and Prevention contains a report on managing acute gastroenteritis among children
doi:10.1371/journal.pmed.1000350
PMCID: PMC2953527  PMID: 20967234
13.  Screening of the hearing of newborns - Update 
Introduction
Permanent congenital bilateral hearing loss (CHL) of moderate or greater degree (≥40 dB HL) is a rare disease, with a prevalence of about 1 to 3 per 1000 births. However, it is one of the most frequent congenital diseases. Reliance on physician observation and parental recognition has not been successful in the past in detecting significant hearing loss in the first year of life. With this strategy significant hearing losses have been detected in the second year of life. With two objective technologies based on physiologic response to sound, otoacoustic emissions (OAE) and auditory brainstem response (ABR) hearing screening in the first days of life is made possible.
Objectives
The objective of this health technology assessment report is to update the evaluation on clinical effectiveness and cost-effectiveness of newborn hearing screening programs. Universal newborn hearing screening (UHNS) (i), selective screening of high risk newborns (ii), and the absence of a systematic screening program are compared for age at identification and age at hearing aid fitting of children with hearing loss. Secondly the potential benefits of early intervention are analysed. Costs and cost-effectiveness of newborn hearing screening programs are determined. This report is intended to make a contribution to the decision making whether and under which conditions a newborn hearing screening program should be reimbursed by the statutory sickness funds in Germany.
Methods
This health technology assessment report updates a former health technology assessment (Kunze et al. 2004 [1]). A systematic review of the literature was conducted, based on a documented search and selection of the literature using predefined inclusion and exclusion criteria and a documented extraction and appraisal of the included studies. To assess the cost-effectiveness of the different screening strategies in Germany the decision analytic Markov state model which had been developed in our former health technology assessment report was updated.
Results
Universal newborn hearing screening programs are able to substantially reduce the age at identification and the age at intervention of children with CHL to six months of age in the German health care setting. High coverage rates, low fail rates and - if tracking systems are implemented – high follow-up-rates to diagnostic evaluation for test positives were achieved. New publications on potential benefits of early intervention could not be retrieved. For a final assessment of cost-effectiveness of newborn hearing screening evidence based long-term data are lacking. Decision analytic models with lifelong time horizon assuming that early detection results in improved language abilities and lower educational costs and higher life time productivity showed a potential of UNHS for long term cost savings compared to selective screening and no screening. For the short-term cost-effectiveness with a time horizon up to diagnostic evaluation more evidence based data are available. The average costs per case diagnosed range from 16,000 EURO to 33,600 EURO in Germany and hence are comparable to the cost of other implemented newborn screening programs. Empirical data for cost of selective screening in the German health care setting are lacking. Our decision analytic model shows that selective screening is more cost-effective but detects only 50% of all cases of congenital hearing loss.
Discussion
There is good evidence that UNHS-Programs with appropriate quality management can reduce the age at start of intervention below six months. Up to now there is no indication of considerable negative consequences of screening for children with false positive test results and their parents. However, it is more difficult to prove the efficacy of early intervention to improve long-term outcomes. Randomized clinical trials of the efficacy of early intervention for children with CHL hearing losses are inappropriate because of ethical reasons. Prospective cohort studies with long-term outcomes of rare diseases are costly, take a long time and simultaneously substantial benefits of early intervention for language development seem likely.
Conclusions
A UNHS-Program should be implemented in Germany and be reimbursed by the statutory sickness funds. To achieve high coverage and because of better conditions for obtaining low false positive rates UNHS should be performed in hospital after birth. For outpatient deliveries additionally screening measures in an outpatient setting must be provided.
PMCID: PMC3011344  PMID: 21289971
14.  Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico 
PLoS Medicine  2010;7(12):e1000379.
Joshua Salomon and colleagues performed a cost-effectiveness analysis using health and economic outcomes following preterm birth in Mexico and showed that neonatal intensive care provided high value for the money in this setting.
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
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (the period during which a baby develops in its mother). In developed countries and some middle-income countries such as Mexico, improvements in the care of newborn babies (neonatal intensive care) mean that more preterm babies survive now than in the past. Nevertheless, preterm birth is still a major cause of infant death worldwide that challenges attainment of Target 5 of Millennium Development Goal 4—the reduction of the global under-five mortality rate by two-thirds of the 1990 rate by 2015 (the Millennium Development Goals, which were agreed by world leaders in 2000, aim to reduce world poverty). Furthermore, many preterm babies who survive have long-term health problems and disabilities such as cerebral palsy, deafness, or learning difficulties. The severity of these disabilities and their long-term costs to families and to society depend on the baby's degree of prematurity.
Why Was This Study Done?
Mexico recently reformed its health system in an effort to improve access to care, particularly for the poorest sections of its population, and to improve the quality of its health care. The central component of this health care reform is the System of Social Protection of Health (SSPH). The SSPH contains a family health insurance program—Seguro Popular—that aims to provide the 50 million uninsured people living in Mexico with free access to an explicit set of health care interventions. As with any insurance program, decisions have to be made about which interventions Seguro Poplar should cover. Should neonatal intensive care be covered, for example? Do the benefits of this intervention (increased survival of babies) outweigh the costs of neonatal care and of long-term care for survivors with disabilities? In other words, is neonatal intensive care cost-effective? In this study, the researchers investigate this question by estimating the clinical benefits, costs, and cost-effectiveness of neonatal intensive care in Mexico.
What Did the Researchers Do and Find?
The researchers built a decision analytic model, a mathematical model that combines evidence on the outcomes and costs of alternative treatments to help inform decisions about health care policy. They gathered data about the health outcomes of preterm births in Mexico from registers of births and deaths and from hospital discharge databases, and estimated the costs of neonatal intensive care and long-term care for disabled survivors using data from the Mexican Ministry of Health and the World Health Organization. They then applied their model, which estimates changes in parameters such as life expectancy, lifetime costs, disability-adjusted life years (DALYs; one DALY represents the loss of a year of healthy life), and incremental cost-effectiveness ratios (ICERs; the additional cost expended for each DALY averted) for neonatal intensive care compared to no intensive care, to a group of 2 million infants. Neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestation prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs at incremental costs of US$11,000, US$10,000, and US$3000, respectively, compared to no intensive care. The ICERs of neonatal intensive care for babies born at these times were US$1200, US$700, and US$300 per DALY averted, respectively.
What Do These Findings Mean?
Interventions with ICERs of less than a country's per capita gross domestic product (GDP) are highly cost-effective; those with ICERs of 1–3 times the per capita GDP are potentially cost-effective. Mexico's per capita GDP in 2005 was approximately US$8,200. Thus, neonatal intensive care could provide exceptional value for money in Mexico (and maybe in other middle-income countries), even for very premature babies. The accuracy of these findings inevitably depends on the assumptions used to build the decision analytic model and on the accuracy of the data fed into it, but the findings were little changed by a wide range of alterations that the researchers made to the model. Importantly, however, this cost-effectiveness analysis focuses on health and economic consequences of different intervention choices, and does not capture all aspects of well-being. Decisions regarding neonatal intensive care will need to be based on a full consideration of all relevant factors, including ethical issues, and cost-effectiveness analyses should continue to be updated as new data emerge on health outcomes and costs associated with neonatal intensive care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000379.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies (in English and Spanish)
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
A PLoS Medicine Policy Forum by Núria Homedes and Antonio Ugalde discusses health care reforms in Mexico
doi:10.1371/journal.pmed.1000379
PMCID: PMC3001895  PMID: 21179496
15.  Male Circumcision at Different Ages in Rwanda: A Cost-Effectiveness Study 
PLoS Medicine  2010;7(1):e1000211.
Agnes Binagwaho and colleagues predict that circumcision of newborn boys would be effective and cost-saving as a long-term strategy to prevent HIV in Rwanda.
Background
There is strong evidence showing that male circumcision (MC) reduces HIV infection and other sexually transmitted infections (STIs). In Rwanda, where adult HIV prevalence is 3%, MC is not a traditional practice. The Rwanda National AIDS Commission modelled cost and effects of MC at different ages to inform policy and programmatic decisions in relation to introducing MC. This study was necessary because the MC debate in Southern Africa has focused primarily on MC for adults. Further, this is the first time, to our knowledge, that a cost-effectiveness study on MC has been carried out in a country where HIV prevalence is below 5%.
Methods and Findings
A cost-effectiveness model was developed and applied to three hypothetical cohorts in Rwanda: newborns, adolescents, and adult men. Effectiveness was defined as the number of HIV infections averted, and was calculated as the product of the number of people susceptible to HIV infection in the cohort, the HIV incidence rate at different ages, and the protective effect of MC; discounted back to the year of circumcision and summed over the life expectancy of the circumcised person. Direct costs were based on interviews with experienced health care providers to determine inputs involved in the procedure (from consumables to staff time) and related prices. Other costs included training, patient counselling, treatment of adverse events, and promotion campaigns, and they were adjusted for the averted lifetime cost of health care (antiretroviral therapy [ART], opportunistic infection [OI], laboratory tests). One-way sensitivity analysis was performed by varying the main inputs of the model, and thresholds were calculated at which each intervention is no longer cost-saving and at which an intervention costs more than one gross domestic product (GDP) per capita per life-year gained. Results: Neonatal MC is less expensive than adolescent and adult MC (US$15 instead of US$59 per procedure) and is cost-saving (the cost-effectiveness ratio is negative), even though savings from infant circumcision will be realized later in time. The cost per infection averted is US$3,932 for adolescent MC and US$4,949 for adult MC. Results for infant MC appear robust. Infant MC remains highly cost-effective across a reasonable range of variation in the base case scenario. Adolescent MC is highly cost-effective for the base case scenario but this high cost-effectiveness is not robust to small changes in the input variables. Adult MC is neither cost-saving nor highly cost-effective when considering only the direct benefit for the circumcised man.
Conclusions
The study suggests that Rwanda should be simultaneously scaling up circumcision across a broad range of age groups, with high priority to the very young. Infant MC can be integrated into existing health services (i.e., neonatal visits and vaccination sessions) and over time has better potential than adolescent and adult circumcision to achieve the very high coverage of the population required for maximal reduction of HIV incidence. In the presence of infant MC, adolescent and adult MC would evolve into a “catch-up” campaign that would be needed at the start of the program but would eventually become superfluous.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981 and more than 31 million people (22 million in sub-Saharan Africa alone) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. There is no cure for HIV/AIDS and no vaccine against HIV infection. Consequently, prevention of HIV transmission is extremely important. HIV is most often spread through unprotected sex with an infected partner. Individuals can reduce their risk of HIV infection, therefore, by abstaining from sex, by having one or a few sexual partners, and by always using a male or female condom. In addition, male circumcision—the removal of the foreskin, the loose fold of skin that covers the head of penis—can halve HIV transmission rates to men resulting from sex with women. Thus, as part of its HIV prevention strategy, the World Health Organization (WHO) recommends that male circumcision programs be scaled up in countries where there is a generalized HIV epidemic and where few men are circumcised.
Why Was This Study Done?
One such country is Rwanda. Here, 3% of the adult population is infected with HIV but only 15% of men are circumcised—worldwide, about 30% of men are circumcised. Demand for circumcision is increasing in Rwanda but, before policy makers introduce a country-wide male circumcision program, they need to identify the most cost-effective way to increase circumcision rates. In particular, they need to decide the age at which circumcision should be offered. Circumcision soon after birth (neonatal circumcision) is quick and simple and rarely causes any complications. Circumcision of adolescents and adults is more complex and has a higher complication rate. Although several studies have investigated the cost-effectiveness (the balance between the clinical and financial costs of a medical intervention and its benefits) of circumcision in adult men, little is known about its cost-effectiveness in newborn boys. In this study, which is one of several studies on male circumcision being organized by the National AIDS Control Commission in Rwanda, the researchers model the cost-effectiveness of circumcision at different ages.
What Did the Researchers Do and Find?
The researchers developed a simple cost-effectiveness model and applied it to three hypothetical groups of Rwandans: newborn boys, adolescent boys, and adult men. For their model, the researchers calculated the effectiveness of male circumcision (the number of HIV infections averted) by estimating the reduction in the annual number of new HIV infections over time. They obtained estimates of the costs of circumcision (including the costs of consumables, staff time, and treatment of complications) from health care providers and adjusted these costs for the money saved through not needing to treat HIV in males in whom circumcision prevented infection. Using their model, the researchers estimate that each neonatal male circumcision would cost US$15 whereas each adolescent or adult male circumcision would cost US$59. Neonatal male circumcision, they report, would be cost-saving. That is, over a lifetime, neonatal male circumcision would save more money than it costs. Finally, using the WHO definition of cost-effectiveness (for a cost-effective intervention, the additional cost incurred to gain one year of life must be less than a country's per capita gross domestic product), the researchers estimate that, although adolescent circumcision would be highly cost-effective, circumcision of adult men would only be potentially cost-effective (but would likely prove cost-effective if the additional infections that would occur from men to their partners without a circumcision program were also taken into account).
What Do These Findings Mean?
As with all modeling studies, the accuracy of these findings depends on the many assumptions included in the model. However, the findings suggest that male circumcision for infants for the prevention of HIV infection later in life is highly cost-effective and likely to be cost-saving and that circumcision for adolescents is cost-effective. The researchers suggest, therefore, that policy makers in Rwanda and in countries with similar HIV infection and circumcision rates should scale up male circumcision programs across all age groups, with high priority being given to the very young. If infants are routinely circumcised, they suggest, circumcision of adolescent and adult males would become a “catch-up” campaign that would be needed at the start of the program but that would become superfluous over time. Such an approach would represent a switch from managing the HIV epidemic as an emergency towards focusing on sustainable, long-term solutions to this major public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000211.
This study is further discussed in a PLoS Medicine Perspective by Seth Kalichman
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information is available from the Joint United Nations Programme on HIV/AIDS (UNAIDS) on HIV infection and AIDS and on male circumcision in relation to HIV and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa, and on circumcision and HIV (some information in English and Spanish)
More information about male circumcision is available from the Clearinghouse on Male Circumcision
The National AIDS Control Commission of Rwanda provides detailed information about HIV/AIDS in Rwanda (in English and French)
doi:10.1371/journal.pmed.1000211
PMCID: PMC2808207  PMID: 20098721
16.  Personalized Prediction of Lifetime Benefits with Statin Therapy for Asymptomatic Individuals: A Modeling Study 
PLoS Medicine  2012;9(12):e1001361.
In a modeling study conducted by Myriam Hunink and colleagues, a population-based cohort from Rotterdam is used to predict the possible lifetime benefits of statin therapy, on a personalized basis.
Background
Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks.
Methods and Findings
A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk.
Conclusions
We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cardiovascular disease (CVD) affects the heart and/or the blood vessels and is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Established risk factors for CVD include smoking, high blood pressure, obesity, and high blood levels of a fat called low-density lipoprotein (“bad cholesterol”). Because many of these risk factors can be modified by lifestyle changes and by drugs, CVD can be prevented. Thus, physicians can assess a healthy individual's risk of developing CVD using a CVD prediction model (equations that take into account the CVD risk factors to which the individual is exposed) and can then recommend lifestyle changes and medications to reduce that individual's CVD risk.
Why Was This Study Done?
Current guidelines recommend that asymptomatic (healthy) individuals whose likely CVD risk is high should be encouraged to take statins—cholesterol-lowering drugs—as a preventative measure. Statins help to prevent CVD in healthy people with a high predicted risk of CVD, but, like all medicines, they have some unwanted side effects, so it is important that physicians can communicate both the benefits and drawbacks of statins to their patients in a way that allows them to make an informed decision about taking these drugs. Telling a patient that statins will reduce his or her short-term risk of CVD is not always helpful—patients really need to know the potential lifetime benefits of statin therapy. That is, they need to know how much longer they might live if they take statins. Here, the researchers use a mathematical model to predict the personalized lifetime benefits (increased total and CVD-free life expectancy) of statin therapy for individuals without a history of CVD.
What Did the Researchers Do and Find?
The researchers used the Rotterdam Ischemic Heart Disease & Stroke Computer Simulation (RISC) model, which simulates the life courses of individuals through six health states, from well through to CVD or non-CVD death, to estimate lifetime outcomes with and without statin therapy in a population of healthy elderly individuals. They then used these outcomes and information on baseline risk factors to develop a web-based calculator suitable for personalized prediction of the lifetime benefits of statins in routine clinical practice. The model estimated that statin therapy increases average life expectancy in the study population by 0.3 years and average CVD-free life expectancy by 0.7 years. The gains in total and CVD-free life expectancy associated with statin therapy increased with blood pressure, unfavorable cholesterol levels, and body mass index (an indicator of body fat) but decreased with age. Notably, the web-based calculator predicted that some individuals with a low ten-year CVD risk might achieve a similar or larger gain in CVD-free life expectancy with statin therapy than some individuals with a high ten-year risk. So, for example, both a 55-year-old non-smoking woman with a ten-year CVD mortality risk of 2% (a two in a hundred chance of dying of CVD within ten years) and a 65-year-old male smoker with a ten-year CVD mortality risk of 15% might both gain one year of CVD-free life expectancy with statin therapy.
What Do These Findings Mean?
These findings suggest that statin therapy can lead on average to small gains in total life expectancy and slightly larger gains in CVD-free life expectancy among healthy individuals, and show that life expectancy benefits can be predicted using an individual's risk factor profile. The accuracy and generalizability of these findings is limited by the assumptions included in the model (in particular, the model did not allow for the known side effects of statin therapy) and by the data fed into it—importantly, the risk prediction model needs to be validated using an independent dataset. If future research confirms the findings of this study, the researchers' web-based calculator could provide complementary information to the currently recommended ten-year CVD mortality risk assessment. Whether communication of personalized outcomes will ultimately result in better clinical outcomes remains to be seen, however, because patients may be less likely to choose statin therapy when provided with more information about its likely benefits.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001361.
The web-based calculator for personalized prediction of lifetime benefits with statin therapy is available (after agreement to software license)
The American Heart Association provides information about many types of cardiovascular disease for patients, carers, and professionals, including information about drug therapy for cholesterol and a heart attack risk calculator
The UK National Health Service Choices website provides information about cardiovascular disease and about statins
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy; information is also available on statins, including personal stories about deciding to take statins
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
The European Society of Cardiology's cardiovascular disease risk assessment model (SCORE) is available
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, stroke, and statins (in English and Spanish)
doi:10.1371/journal.pmed.1001361
PMCID: PMC3531501  PMID: 23300388
17.  Which States Matter? An Application of an Intelligent Discretization Method to Solve a Continuous POMDP in Conservation Biology 
PLoS ONE  2012;7(2):e28993.
When managing populations of threatened species, conservation managers seek to make the best conservation decisions to avoid extinction. Making the best decision is difficult because the true population size and the effects of management are uncertain. Managers must allocate limited resources between actively protecting the species and monitoring. Resources spent on monitoring reduce expenditure on management that could be used to directly improve species persistence. However monitoring may prevent sub-optimal management actions being taken as a result of observation error. Partially observable Markov decision processes (POMDPs) can optimize management for populations with partial detectability, but the solution methods can only be applied when there are few discrete states. We use the Continuous U-Tree (CU-Tree) algorithm to discretely represent a continuous state space by using only the states that are necessary to maintain an optimal management policy. We exploit the compact discretization created by CU-Tree to solve a POMDP on the original continuous state space. We apply our method to a population of sea otters and explore the trade-off between allocating resources to management and monitoring. We show that accurately discovering the population size is less important than management for the long term survival of our otter population.
doi:10.1371/journal.pone.0028993
PMCID: PMC3281817  PMID: 22363398
18.  The cost-utility of open prostatectomy compared with active surveillance in early localised prostate cancer 
Background
There is an on-going debate about whether to perform surgery on early stage localised prostate cancer and risk the common long term side effects such as urinary incontinence and erectile dysfunction. Alternatively these patients could be closely monitored and treated only in case of disease progression (active surveillance). The aim of this paper is to develop a decision-analytic model comparing the cost-utility of active surveillance (AS) and radical prostatectomy (PE) for a cohort of 65 year old men with newly diagnosed low risk prostate cancer.
Methods
A Markov model comparing PE and AS over a lifetime horizon was programmed in TreeAge from a German societal perspective. Comparative disease specific mortality was obtained from the Scandinavian Prostate Cancer Group trial. Direct costs were identified via national treatment guidelines and expert interviews covering in-patient, out-patient, medication, aids and remedies as well as out of pocket payments. Utility values were used as factor weights for age specific quality of life values of the German population. Uncertainty was assessed deterministically and probabilistically.
Results
With quality adjustment, AS was the dominant strategy compared with initial treatment. In the base case, it was associated with an additional 0.04 quality adjusted life years (7.60 QALYs vs. 7.56 QALYs) and a cost reduction of €6,883 per patient (2011 prices). Considering only life-years gained, PE was more effective with an incremental cost-effectiveness ratio of €96,420/life year gained. Sensitivity analysis showed that the probability of developing metastases under AS and utility weights under AS are a major sources of uncertainty. A Monte Carlo simulation revealed that AS was more likely to be cost-effective even under very high willingness to pay thresholds.
Conclusion
AS is likely to be a cost-saving treatment strategy for some patients with early stage localised prostate cancer. However, cost-effectiveness is dependent on patients’ valuation of health states. Better predictability of tumour progression and modified reimbursement practice would support widespread use of AS in the context of the German health care system. More research is necessary in order to reliably quantify the health benefits compared with initial treatment and account for patient preferences.
doi:10.1186/1472-6963-14-163
PMCID: PMC4022451  PMID: 24721557
Economic evaluation; Cost-utility analysis; Cost-effectiveness; Prostate cancer; Active surveillance; Decision analysis; Early evaluation
19.  Cost Effectiveness of Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in Ireland 
Background
Romiplostim, a thrombopoietin receptor agonist (TPOra), is a second-line medical treatment option for adults with chronic immune thrombocytopenia (ITP). Clinical trials have shown that romiplostim increases platelet counts, while reducing the risk of bleeding and, in turn, the need for costly rescue medications.
Aims
The objective of this study was to assess the cost effectiveness of romiplostim in the treatment of adult ITP in Ireland, in comparison with eltrombopag and the medical standard of care (SoC).
Methods
A lifetime treatment-sequence cost-utility Markov model with embedded decision tree was developed from an Irish healthcare perspective to compare romiplostim with eltrombopag and SoC. The model was driven by platelet response (platelet count ≥50 × 109/L), which determined effectiveness and progression along the treatment pathway, need for rescue therapy (e.g. intravenous immunoglobulin [IVIg] and steroids) and risk of bleeding. Probability of response, mean treatment duration, average time to initial response and utilities were derived from clinical trials and other published evidence. Treatment sequences and healthcare utilization practice were validated by Irish clinical experts. Costs were assessed in € for 2011 and included drug acquisition costs and costs associated with monitoring patients and management of bleeding, as available from published Irish reimbursement lists and other relevant sources. Deterministic and probabilistic sensitivity analyses were conducted.
Results
Romiplostim treatment resulted in an average of 20.2 fewer administrations of rescue medication (IVIg or intravenous steroids) over a patient lifetime than eltrombopag, and 29.3 fewer rescue medication administrations than SoC. Romiplostim was dominant, with cost savings of €13,258 and €22,673 and gains of 0.76 and 1.17 quality-adjusted life-years (QALYs), compared with eltrombopag and SoC, respectively. Romiplostim remained cost effective throughout a variety of potential scenarios, including short-term TPOra treatment duration (1 year). One-way sensitivity analysis showed that the model was most sensitive to variation in the cost of IVIg and use of romiplostim and IVIg. Probabilistic sensitivity analysis showed that romiplostim was likely to be cost effective in over 90 % of cases compared with eltrombopag, and 96 % compared with SoC at a willingness-to-pay threshold of €30,000 per QALY.
Conclusions
Use of romiplostim in the ITP treatment pathway, compared with eltrombopag or SoC, is likely to be cost effective in Ireland. Romiplostim improves clinical outcomes by increasing platelet counts, reducing bleeding events and the use of IVIg and steroids, resulting in both cost savings and additional QALYs when compared with current treatment practices.
Electronic supplementary material
The online version of this article (doi:10.1007/s40258-013-0044-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s40258-013-0044-y
PMCID: PMC3824633  PMID: 23857462
20.  Optimal Management of High-Risk T1G3 Bladder Cancer: A Decision Analysis 
PLoS Medicine  2007;4(9):e284.
Background
Controversy exists about the most appropriate treatment for high-risk superficial (stage T1; grade G3) bladder cancer. Immediate cystectomy offers the best chance for survival but may be associated with an impaired quality of life compared with conservative therapy. We estimated life expectancy (LE) and quality-adjusted life expectancy (QALE) for both of these treatments for men and women of different ages and comorbidity levels.
Methods and Findings
We evaluated two treatment strategies for high-risk, T1G3 bladder cancer using a decision-analytic Markov model: (1) Immediate cystectomy with neobladder creation versus (2) conservative management with intravesical bacillus Calmette-Guérin (BCG) and delayed cystectomy in individuals with resistant or progressive disease. Probabilities and utilities were derived from published literature where available, and otherwise from expert opinion. Extensive sensitivity analyses were conducted to identify variables most likely to influence the decision. Structural sensitivity analyses modifying the base case definition and the triggers for cystectomy in the conservative therapy arm were also explored. Probabilistic sensitivity analysis was used to assess the joint uncertainty of all variables simultaneously and the uncertainty in the base case results. External validation of model outputs was performed by comparing model-predicted survival rates with independent published literature. The mean LE of a 60-y-old male was 14.3 y for immediate cystectomy and 13.6 y with conservative management. With the addition of utilities, the immediate cystectomy strategy yielded a mean QALE of 12.32 y and remained preferred over conservative therapy by 0.35 y. Worsening patient comorbidity diminished the benefit of early cystectomy but altered the LE-based preferred treatment only for patients over age 70 y and the QALE-based preferred treatment for patients over age 65 y. Sensitivity analyses revealed that patients over the age of 70 y or those strongly averse to loss of sexual function, gastrointestinal dysfunction, or life without a bladder have a higher QALE with conservative therapy. The results of structural or probabilistic sensitivity analyses did not change the preferred treatment option. Model-predicted overall and disease-specific survival rates were similar to those reported in published studies, suggesting external validity.
Conclusions
Our model is, to our knowledge, the first of its kind in bladder cancer, and demonstrated that younger patients with high-risk T1G3 bladder had a higher LE and QALE with immediate cystectomy. The decision to pursue immediate cystectomy versus conservative therapy should be based on discussions that consider patient age, comorbid status, and an individual's preference for particular postcystectomy health states. Patients over the age of 70 y or those who place high value on sexual function, gastrointestinal function, or bladder preservation may benefit from a more conservative initial therapeutic approach.
Using a Markov model, Shabbir Alibhai and colleagues develop a decision analysis comparing cystectomy with conservative treatment for high-risk superficial bladder cancer depending on patient age, comorbid conditions, and preferences.
Editors' Summary
Background.
Every year, about 67,000 people in the US develop bladder cancer. Like all cancers, bladder cancer arises when a single cell begins to grow faster than normal, loses its characteristic shape, and moves into surrounding tissues. Most bladder cancers develop from cells that line the bladder (“transitional” cells) and most are detected before they spread out of this lining. These superficial or T1 stage cancers can be removed by transurethral resection of bladder tumor (TURBT). The urologist (a specialist who treats urinary tract problems) passes a small telescope into the bladder through the urethra (the tube through which urine leaves the body) and removes the tumor. If the tumor cells look normal under a microscope (so-called normal histology), the cancer is unlikely to return; if they have lost their normal appearance, the tumor is given a “G3” histological grade, which indicates a high risk of recurrence.
Why Was This Study Done?
The best treatment for T1G3 bladder cancer remains controversial. Some urologists recommend immediate radical cystectomy— surgical removal of the bladder, the urethra, and other nearby organs. This treatment often provides a complete cure but can cause serious short-term health problems and affects long-term quality of life. Patients often develop sexual dysfunction or intestinal (gut) problems and sometimes find it hard to live with a reconstructed bladder. The other recommended treatment is immunotherapy with bacillus Calmette-Guérin (BCG, bacteria that are also used to vaccinate against tuberculosis). Long-term survival is not always as good with this conservative treatment but it is less likely than surgery to cause short-term illness or to reduce quality of life. In this study, the researchers have used decision analysis (a systematic evaluation of the important factors affecting a decision) to determine whether immediate cystectomy or conservative therapy is the optimal treatment for patients with T1G3 bladder cancer. Decision analysis allowed the researchers to account for quality-of-life factors while comparing the health benefits of each treatment for T1G3 bladder cancer.
What Did the Researchers Do and Find?
Using a decision analysis model called a Markov model, the researchers calculated the months of life gained, and the quality of life expected to result, from each of the two treatments. To estimate the life expectancy (LE) associated with each treatment, the researchers incorporated the published probabilities of various outcomes of each treatment into their model. To estimate quality-adjusted life expectancy (QALE, the number of years of good quality life), they incorporated “utilities,” measures of relative satisfaction with outcomes. (A utility of 1 represents perfect health; death is assigned a value of 0, and outcomes considered less than ideal, but better than death, fall in between). For a sexually potent 60-year-old man with bladder cancer but no other illnesses, the average LE predicted by the model was nearly eight months longer with immediate cystectomy than with conservative treatment (both LEs predicted by this model matched those seen in clinical trials); the average QALE with cystectomy was 4.2 months longer than with conservative treatment. Having additional diseases decreased the benefit of immediate cystectomy but the treatment still gave a longer LE until the patient reached 70 years old, when conservative treatment became better. For QALE, this change in optimal treatment appeared at age 65. Finally, conservative treatment gave a higher QALE than immediate cystectomy for patients concerned about preserving sexual function or averse to living with intestinal problems or a reconstructed bladder.
What Do These Findings Mean?
As with all mathematical models, these results depend on the assumptions included in the model. In particular, because published probability and utility values are not available for some of the possible outcomes of the two treatments, the LE and QALE calculations could be inaccurate. Also, assigning numerical ratings to life experiences is generally something of a simplification, which could affect the reliability of the QALE (but not the LE) results. Nevertheless, these findings provide useful guidance for urologists trying to balance the benefits of immediate cystectomy or conservative treatment against the potential short-term and long-term effects of these treatments on patients' quality of life. Specifically, the results indicate that decisions on treatment for T1G3 bladder cancer should be based on a consideration of the patient's age and any coexisting disease coupled with detailed discussions with the patient about their attitudes regarding the possible health-related effects of cystectomy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040284.
MedlinePlus encyclopedia page on bladder cancer (in English and Spanish)
Information for patients and professionals from the US National Cancer Institute on bladder cancer (in English and Spanish)
Information for patients on bladder cancer from the UK charity Cancerbackup
Online course on Decision Analysis in Health Care from George Mason University
doi:10.1371/journal.pmed.0040284
PMCID: PMC1989749  PMID: 17896857
21.  Laparoscopic fundoplication compared with medical management for gastro-oesophageal reflux disease: cost effectiveness study 
Objective To describe the long term costs, health benefits, and cost effectiveness of laparoscopic surgery compared with those of continued medical management for patients with gastro-oesophageal reflux disease (GORD).
Design We estimated resource use and costs for the first year on the basis of data from the REFLUX trial. A Markov model was used to extrapolate cost and health benefit over a lifetime using data collected in the REFLUX trial and other sources.
Participants The model compared laparoscopic surgery and continued proton pump inhibitors in male patients aged 45 and stable on GORD medication.
Intervention Laparoscopic surgery versus continued medical management.
Main outcome measures We estimated quality adjusted life years and GORD related costs to the health service over a lifetime. Sensitivity analyses considered other plausible scenarios, in particular size and duration of treatment effect and the GORD symptoms of patients in whom surgery is unsuccessful.
Main results The base case model indicated that surgery is likely to be considered cost effective on average with an incremental cost effectiveness ratio of £2648 (€3110; US$4385) per quality adjusted life year and that the probability that surgery is cost effective is 0.94 at a threshold incremental cost effectiveness ratio of £20 000. The results were sensitive to some assumptions within the extrapolation modelling.
Conclusion Surgery seems to be more cost effective on average than medical management in many of the scenarios examined in this study. Surgery might not be cost effective if the treatment effect does not persist over the long term, if patients who return to medical management have poor health related quality of life, or if proton pump inhibitors were cheaper. Further follow-up of patients from the REFLUX trial may be valuable.
Trial registration ISRCTN15517081.
doi:10.1136/bmj.b2576
PMCID: PMC2714673  PMID: 19654097
22.  Cost-Effectiveness of Providing Full Drug Coverage to Increase Medication Adherence in Post–Myocardial Infarction Medicare Beneficiaries 
Circulation  2008;117(10):1261-1268.
Background
Effective therapies for the secondary prevention of coronary heart disease–related events are significantly underused, and attempts to improve adherence have often yielded disappointing results. Elimination of patient out-of-pocket costs may be an effective strategy to enhance medication use. We sought to estimate the incremental cost-effectiveness of providing full coverage for aspirin, β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins (combination pharmacotherapy) to individuals enrolled in the Medicare drug benefit program after acute myocardial infarction.
Methods and Results
We created a Markov cost-effectiveness model to estimate the incremental cost-effectiveness of providing Medicare beneficiaries with full coverage for combination pharmacotherapy compared with current coverage under the Medicare Part D program. Our analysis was conducted from the societal perspective and considered a lifetime time horizon. In a sensitivity analysis, we repeated our analysis from the perspective of Medicare. In the model, post–myocardial infarction Medicare beneficiaries who received usual prescription drug coverage under the Part D program lived an average of 8.21 quality-adjusted life-years after their initial event, incurring coronary heart disease–related medical costs of $114 000. Those who received prescription drug coverage without deductibles or copayments lived an average of 8.56 quality-adjusted life-years and incurred $111 600 in coronary heart disease–related costs. Compared with current prescription drug coverage, full coverage for post–myocardial infarction secondary prevention therapies would result in greater functional life expectancy (0.35 quality-adjusted life-year) and less resource use ($2500). From the perspective of Medicare, full drug coverage was highly cost-effective ($7182/quality-adjusted life-year) but not cost saving.
Conclusions
Our analysis suggests that providing full coverage for combination therapy to post–myocardial infarction Medicare beneficiaries would save both lives and money from the societal perspective.
doi:10.1161/CIRCULATIONAHA.107.735605
PMCID: PMC2722033  PMID: 18285564
cost-benefit analysis; drugs; epidemiology; insurance; myocardial infarction; prevention
23.  Reinforcement Learning with Limited Reinforcement: Using Bayes Risk for Active Learning in POMDPs 
Partially Observable Markov Decision Processes (POMDPs) have succeeded in planning domains that require balancing actions that increase an agent's knowledge and actions that increase an agent's reward. Unfortunately, most POMDPs are defined with a large number of parameters which are difficult to specify only from domain knowledge. In this paper, we present an approximation approach that allows us to treat the POMDP model parameters as additional hidden state in a “model-uncertainty” POMDP. Coupled with model-directed queries, our planner actively learns good policies. We demonstrate our approach on several POMDP problems.
doi:10.1901/jaba.2008.301-256
PMCID: PMC2868199  PMID: 20467572
24.  Screen or not to screen for peripheral arterial disease: guidance from a decision model 
BMC Public Health  2014;14:89.
Background
Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling.
Methods
A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters.
Results
For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant.
Conclusion
This decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or clopidogrel in the identified patients is a cost-effective strategy. Implementation of targeted PAD screening and subsequent treatment in primary care practices and in public health programs is likely to improve the societal health and to save health care costs by reducing catastrophic cardiovascular events.
doi:10.1186/1471-2458-14-89
PMCID: PMC3912926  PMID: 24476213
Cost-effectiveness; Peripheral arterial disease; Ankle brachial index; Decision model
25.  Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(9):e1001316.
David Boulware and colleagues assess the cost effectiveness of different treatment strategies in low- and middle-income countries for cryptococcal meningitis, one of the most common opportunistic infections of people with HIV.
Background
Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.
Methods and Findings:
We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.
Conclusions
Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Cryptococcal meningitis, a fungal infection of the membranes around the brain and spinal cord, affects about a million people every year (most of them living in sub-Saharan Africa and Southeast Asia) and kills about 640,000 people annually. People become infected with Cryptococcus neoformans, the fungus that causes cryptococcal meningitis and which is found in soil and dirt, by breathing it in. In healthy individuals, infection rarely causes disease. But in people living with AIDS, whose immune system has been damaged by HIV infection, and in people whose immune system is compromised for other reasons, the fungus can invade and damage many organs, including the brain. Cryptococcal meningitis, the symptoms of which include fever, stiff neck, headache, and vomiting, is diagnosed by looking for the fungus in fluid taken from the spinal cord in a procedure called a lumbar puncture. Cryptococcal meningitis is treated with antifungal drugs such as amphotericin, fluconazole, and flucytosine (induction therapy); recurrence of the infection is prevented by taking fluconazole daily for life or until the immune system recovers.
Why Was This Study Done?
The World Health Organization (WHO) recommends a 14-day regimen of intravenous (injected) amphotericin and oral flucytosine or fluconazole for induction therapy of cryptococcal meningitis. Unfortunately, this regimen is impractical in many resource-limited settings because of the cost of the drugs and hospital care and the need for intensive monitoring—amphotericin is extremely toxic. Consequently, high-dose fluconazole monotherapy is the usual treatment for cryptococcal meningitis in resource-limited countries, although this regimen is much less effective. Another regimen that has improved survival in trials is flucytosine with fluconazole for two weeks. However, flucytosine is very expensive and is not licensed in most sub-Saharan African countries. Stakeholders in developing countries badly need guidance, therefore, on which induction treatment for cryptococcal meningitis they should recommend to optimize outcomes in their particular countries. In this cost-effectiveness analysis (a study that compares the costs and health effects of different interventions), the researchers use costs in Uganda to estimate the survival, cost, and cost per benefit associated with various induction treatments for cryptococcal meningitis in HIV-infected patients.
What Did the Researchers Do and Find?
The researchers calculated the overall cost of six induction treatments using 2012 healthcare costs in Uganda for medications, supplies, and hospital care, and average laboratory costs for monitoring treatment from three African countries. They used data from published trials of cryptococcal meningitis treatment in resource-limited areas to estimate ten-week and one-year survival, life expectancy, and quality-adjusted life years (QALYs, the number of years of life added by an intervention, adjusted for the quality of life) for each intervention. Finally, they calculated the cost-effectiveness ratio (cost per QALY gained) and the incremental cost effectiveness ratio (ICER, the additional cost of a treatment strategy compared to fluconazole monotherapy divided by the incremental improvement in QALYs) for each intervention. The estimated costs per person for each induction treatment strategy ranged from US$154 for 14 days of fluconazole monotherapy to US$467 for 14 days of amphotericin plus flucytosine. Estimated average one-year survival was lowest for fluconazole (40%) and highest for short-course (seven days) amphotericin plus 14 days of fluconazole (66%), similar to other amphotericin-based treatments. Cost-effectiveness ratios ranged from US$20 per QALY for short-course amphotericin plus fluconazole to US$44 per QALY for 14 days of amphotericin plus flucytosine. Short-course amphotericin plus fluconazole had the lowest ICER (US$15.11 per additional QALY over fluconazole monotherapy).
What Do These Findings Mean?
These findings suggest that, among the treatments investigated, a seven-day course of amphotericin with high-dose fluconazole for at least two weeks is the most cost-effective induction treatment for cryptococcal meningitis in Uganda. Although this result should be generalizable to other African countries, it needs to be treated with caution because very few trials have actually looked at the clinical effectiveness of this particular regimen. While short short-course amphotericin appears to be substantially more effective than fluconazole monotherapy, large-scale trials comparing short-course amphotericin regimens with more traditional 14-day regimens in resource-limited countries must be undertaken before short-course amphotericin-based treatments are adopted. Notably, however, if these trials confirm that survival with short-course amphotericin with fluconazole is about 30% better than with fluconazole alone, the researchers calculate that moving to short-course amphotericin could save about 150,000 lives every year in sub-Saharan Africa at a cost of US$220 per life saved.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001316.
This study is further discussed in a PLOS Medicine Perspective by Andrew Farlow
Preventcrypto.org provides a clearinghouse for updated guidelines for cryptococcal diagnosis and treatment.
The US Centers for Disease Control and Prevention provides information on Cryptococcus neoformans and a training manual called the Cryptococcal Screening Program Training Manual for Healthcare Providers
NAM/aidsmap provides information about all aspects of infection with Cryptococcus neoformans, including a personal story about cryptococcal meningitis
AIDS InfoNet has a fact sheet on cryptococcal meningitis (in several languages)
The not-for-profit organization Project Inform, which provides information, inspiration, and advocacy for people with HIV/AIDS and hepatitis C (in English and Spanish), has a fact sheet on cryptococcal meningitis
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
doi:10.1371/journal.pmed.1001316
PMCID: PMC3463510  PMID: 23055838

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