Socioeconomic benefit to individuals of achieving 2020 targets for four neglected tropical diseases controlled/eliminated by innovative and intensified disease management: Human African trypanosomiasis, leprosy, visceral leishmaniasis, Chagas disease.

BACKGROUND: The control or elimination of neglected tropical diseases (NTDs) has targets defined by the WHO for 2020, reinforced by the 2012 London Declaration. We estimated the economic impact to individuals of meeting these targets for human African trypanosomiasis, leprosy, visceral leishmaniasis and Chagas disease, NTDs controlled or eliminated by innovative and intensified disease management (IDM). METHODS: A systematic literature review identified information on productivity loss and out-of-pocket payments (OPPs) related to these NTDs, which were combined with projections of the number of people suffering from each NTD, country and year for 2011-2020 and 2021-2030. The ideal scenario in which the WHO's 2020 targets are met was compared with a counterfactual scenario that assumed the situation of 1990 stayed unaltered. Economic benefit equaled the difference between the two scenarios. Values are reported in 2005 US$, purchasing power parity-adjusted, discounted at 3% per annum from 2010. Probabilistic sensitivity analyses were used to quantify the degree of uncertainty around the base-case impact estimate. RESULTS: The total global productivity gained for the four IDM-NTDs was I$ 23.1 (I$ 15.9 -I$ 34.0) billion in 2011-2020 and I$ 35.9 (I$ 25.0 -I$ 51.9) billion in 2021-2030 (2.5th and 97.5th percentiles in brackets), corresponding to US$ 10.7 billion (US$ 7.4 -US$ 15.7) and US$ 16.6 billion (US$ 11.6 -US$ 24.0). Reduction in OPPs was I$ 14 billion (US$ 6.7 billion) and I$ 18 billion (US$ 10.4 billion) for the same periods. CONCLUSIONS: We faced important limitations to our work, such as finding no OPPs for leprosy. We had to combine limited data from various sources, heterogeneous background, and of variable quality. Nevertheless, based on conservative assumptions and subsequent uncertainty analyses, we estimate that the benefits of achieving the targets are considerable. Under plausible scenarios, the economic benefits far exceed the necessary investments by endemic country governments and their development partners. Given the higher frequency of NTDs among the poorest households, these investments represent good value for money in the effort to improve well-being, distribute the world's prosperity more equitably and reduce inequity.

The Socioeconomic Benefit to Individuals of Achieving the 2020 Targets for Five Preventive Chemotherapy Neglected Tropical Diseases.

BACKGROUND: Lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminths (STH) and trachoma represent the five most prevalent neglected tropical diseases (NTDs). They can be controlled or eliminated by means of safe and cost-effective interventions delivered through programs of Mass Drug Administration (MDA)-also named Preventive Chemotherapy (PCT). The WHO defined targets for NTD control/elimination by 2020, reinforced by the 2012 London Declaration, which, if achieved, would result in dramatic health gains. We estimated the potential economic benefit of achieving these targets, focusing specifically on productivity and out-of-pocket payments. METHODS: Productivity loss was calculated by combining disease frequency with productivity loss from the disease, from the perspective of affected individuals. Productivity gain was calculated by deducting the total loss expected in the target achievement scenario from the loss in a counterfactual scenario where it was assumed the pre-intervention situation in 1990 regarding NTDs would continue unabated until 2030. Economic benefits from out-of-pocket payments (OPPs) were calculated similarly. Benefits are reported in 2005 US$ (purchasing power parity-adjusted and discounted at 3% per annum from 2010). Sensitivity analyses were used to assess the influence of changes in input parameters. RESULTS: The economic benefit from productivity gain was estimated to be I$251 billion in 2011-2020 and I$313 billion in 2021-2030, considerably greater than the total OPPs averted of I$0.72 billion and I$0.96 billion in the same periods. The net benefit is expected to be US$ 27.4 and US$ 42.8 for every dollar invested during the same periods. Impact varies between NTDs and regions, since it is determined by disease prevalence and extent of disease-related productivity loss. CONCLUSION: Achieving the PCT-NTD targets for 2020 will yield significant economic benefits to affected individuals. Despite large uncertainty, these benefits far exceed the investment required by governments and their development partners within all reasonable scenarios. Given the concentration of the NTDs among the poorest households, these investments represent good value for money in efforts to share the world's prosperity and reduce inequity.

Productivity Loss Related to Neglected Tropical Diseases Eligible for Preventive Chemotherapy: A Systematic Literature Review.

BACKGROUND: Neglected Tropical Diseases (NTDs) not only cause health and life expectancy loss, but can also lead to economic consequences including reduced ability to work. This article describes a systematic literature review of the effect on the economic productivity of individuals affected by one of the five worldwide most prevalent NTDs: lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths (ascariasis, trichuriasis, and hookworm infection) and trachoma. These diseases are eligible to preventive chemotherapy (PCT). METHODOLOGY/PRINCIPAL FINDINGS: Eleven bibliographic databases were searched using different names of all NTDs and various keywords relating to productivity. Additional references were identified through reference lists from relevant papers. Of the 5316 unique publications found in the database searches, thirteen papers were identified for lymphatic filariasis, ten for onchocerciasis, eleven for schistosomiasis, six for soil-transmitted helminths and three for trachoma. Besides the scarcity in publications reporting the degree of productivity loss, this review revealed large variation in the estimated productivity loss related to these NTDs. CONCLUSIONS: It is clear that productivity is affected by NTDs, although the actual impact depends on the type and severity of the NTD as well as on the context where the disease occurs. The largest impact on productivity loss of individuals affected by one of these diseases seems to be due to blindness from onchocerciasis and severe schistosomiasis manifestations; productivity loss due to trachoma-related blindness has never been studied directly. However, productivity loss at an individual level might differ from productivity loss at a population level because of differences in the prevalence of NTDs. Variation in estimated productivity loss between and within diseases is caused by differences in research methods and setting. Publications should provide enough information to enable readers to assess the quality and relevance of the study for their purposes.

Clinical Practice Variation Needs to be Considered in Cost-Effectiveness Analyses: A Case Study of Patients with a Recent Transient Ischemic Attack or Minor Ischemic Stroke.

BACKGROUND AND OBJECTIVE: The cost-effectiveness of clinical interventions is often assessed using current care as the comparator, with national guidelines as a proxy. However, this comparison is inadequate when clinical practice differs from guidelines, or when clinical practice differs between hospitals. We examined the degree of variation in the way patients with a recent transient ischemic attack (TIA) or minor ischemic stroke are assessed and used the results to illustrate the importance of investigating possible clinical practice variation, and the need to perform hospital-level cost-effectiveness analyses (CEAs) when variation exists. METHODS: Semi-structured interviews were conducted with 16 vascular neurologists in hospitals throughout the Netherlands. Questions were asked about the use of initial and confirmatory diagnostic imaging tests to assess carotid stenosis in patients with a recent TIA or minor ischemic stroke, criteria to perform confirmatory tests, and criteria for treatment. We also performed hospital-level CEAs to illustrate the consequences of the observed diagnostic strategies in which the diagnostic test costs, sensitivity and specified were varied according to the local hospital conditions. RESULTS: 56 % (9/16) of the emergency units and 63 % (10/16) of the outpatient clinics use the initial and confirmatory diagnostic tests to assess carotid stenosis in accordance with the national guidelines. Of the hospitals studied, only one uses the recommended criteria for use of a confirmatory test, 38 % (6/16) follow the guidelines for treatment. The most cost-effective diagnostic test strategy differs between hospitals. CONCLUSIONS: If important practice variation exists, hospital-level CEAs should be performed. These CEAs should include an assessment of the feasibility and costs of switching to a different strategy.

Which factors may determine the necessary and feasible type of effectiveness evidence? A mixed methods approach to develop an instrument to help coverage decision-makers.

OBJECTIVES: Reimbursement decisions require evidence of effectiveness and, in general, a blinded randomised controlled trial (RCT) is the preferred study design to provide it. However, there are situations where a cohort study, or even patient series, can be deemed acceptable. The aim of this study was to develop an instrument that first examines which study characteristics of a blinded RCT are necessary, and then, if particular characteristics are considered necessary, examines whether these characteristics are feasible. DESIGN: We retrospectively studied 22 interventions from 20 reimbursement reports concerning medical specialist care made by the Dutch National Health Care Institute (ZIN) to identify any factors that influenced the necessity and feasibility of blinded RCTs, and their constituent study characteristics, that is, blinding, randomisation and a control group. A literature review was performed to identify additional factors. Additional expertise was included by interviewing eight experts in epidemiology, medicine and ethics. The resulting instrument was called the FIT instrument (Feasible Information Trajectory), and was prospectively validated using three consecutive reimbursement reports. RESULTS: (Blinded) RCT evidence was lacking in 5 of 11 positive reimbursement decisions and 3 of 11 negative decisions. In the reimbursement reports, we found no empirical evidence supporting situations where a blinded RCT is unnecessary. The literature also revealed few arguments against the necessity of a blinded RCT. In contrast, many factors influencing the feasibility of randomisation, a control group and blinding, were found in the reimbursement reports and the literature; for example, when a patient population is too small or when an intervention is common practice, randomisation will be hindered. CONCLUSIONS: Policy regarding the necessity and feasibility of different types of evidence of effectiveness would benefit from systematic guidance. The FIT instrument has the potential to support transparent, reproducible and well-founded decisions on appropriate evidence of effectiveness in medical specialist care.

BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study.

PURPOSE: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS: Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION: Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition.

In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study(MRISC), a non-randomized prospective multicenter study,women with high familial risk or a genetic predisposition for breast cancer were screened once a year by mammography and MRI and every 6 months with a clinical breast examination (CBE). The false-negative MR examinations were subject of this study and were retrospectively reviewed by two experienced radiologists. From November 1999 until March 2006, 2,157 women were eligible for study analyses. Ninety-seven malignant breast tumors were detected, including 19 DCIS (20%). In 22 patients with a malignant lesion, the MRI was assessed as BI-RADS 1 or 2. One patient was excluded because the examinations were not available for review. Forty-three percent (9/21) of the false-negative MR cases concerned pure ductal carcinoma in situ (DCIS) or DCIS with invasive foci, in eight of them no enhancement was seen at the review. In six patients the features of malignancy were missed or misinterpreted.Small lesion size (n = 3), extensive diffuse contrast enhancement of the breast parenchyma (n = 2),and a technically inadequate examination (n = 1) were other causes of the missed diagnosis. A major part of the false-negative MR diagnoses concerned non-enhancing DCIS, underlining the necessity of screening not only with MRI but also with mammography. Improvement of MRI scanning protocols may increase the detection rate of DCIS. The missed and misinterpreted cases are reflecting the learning curve of a multicenter study.

Exploring the course of psychological distress around two successive control visits in women at hereditary risk of breast cancer.

In this article we determined the course of psychological distress during a breast cancer surveillance program in women at increased risk of developing hereditary breast cancer (BC). The sample comprised of 357 unaffected women (mean age 40.5 years) adhering to a surveillance programme (MRISC-study). Before and after two successive biannual surveillance appointments, the Impact of Event Scale (BC-specific distress) and the Hospital Anxiety and Depression Scale (general distress) were administered, totalling four measurement moments. In general, psychological distress remained within normal limits and decreased significantly after a surveillance appointment, except for breast cancer specific distress after the second appointment. Scheduled imaging examinations were not significantly related to distress. The course of BC specific distress differed significantly for risk over-estimators and for young (<40 years) excessive breast self examiners. The course of general distress differed significantly for women closely involved in a sister's BC-process. These more vulnerable subgroups may be in need of extra counselling and care.

The impact of having relatives affected with breast cancer on psychological distress in women at increased risk for hereditary breast cancer.

PURPOSE: Being at hereditary risk of breast cancer (BC) may lead to elevated levels of distress because of the impact of the BC-process in relatives. OBJECTIVE: Determine the association between psychological distress and BC in relatives. We studied: kind of kinship with the affected relative(s), degree of involvement with the relative's BC, time elapsed since the BC diagnosis of the relative, and loss of a relative as a consequence of BC. METHODS: The study cohort consisted of women at increased risk of developing BC, adhering to regular surveillance and participating in the Dutch MRISC-study. Two months prior to the surveillance appointment, demographics, general and BC specific distress and experience with BC in the family were assessed. RESULTS: 347 out of 351 participants (mean age 40 1/2) had at least one relative affected with BC. The following variables were significantly, positively related to BC specific distress: having at least one affected sister (n = 105; p < 0.04); close involvement in a sister's BC process (n = 94; p < 0.03); and a recent (less than three years ago) BC diagnosis in a sister (n = 30; p < 0.03). General distress did not show any significant associations with the experience of BC in the family. CONCLUSION: These findings show the impact of a BC diagnosis in a sister, particularly a recent diagnosis, on psychological distress. Women who have experienced BC in their sister may be in need of additional counselling or of more attention during the surveillance process.

Psychological distress in women at increased risk for breast cancer: the role of risk perception.

The magnetic resonance imaging screening (MRISC) study evaluates a surveillance programme for women with a hereditary risk for breast cancer. The psychological burden of surveillance in these women may depend on inaccurate risk perceptions. To examine differences in risk perceptions between three predefined risk categories and associations with psychological distress. BC-specific distress, general distress, and RP (cognitive and affective) were assessed, two months before a surveillance appointment. Cumulative lifetime risk (CLTR) of developing breast cancer was trichotomised into: (1) CLTR of 60-85% (mutation carriers), (2) CLTR of 30-50%, and (3) CLTR of 15-30%. In a total group of 351 women (mean age 40.5 years, range 21-63 years) the three risk categories significantly differed in their accuracy of assessing cognitive risk perceptions. In category 1, 60% had an accurate risk perceptions, in category 2, 43.7% and in category 3, 33.3%. Overestimators reported significantly more breast cancer-specific distress. After adding affective risk perception to the model, this effect disappeared. Affective risk perceptions showed significant associations with breast cancer-specific and general distress. Affective risk perception is a more important determinant for psychological distress than cognitive risk perception. This knowledge should be used during surveillance appointments in order to improve and individualise support for these women.

Mammography benefit in the Canadian National Breast Screening Study-2: a model evaluation.

The CNBSS-2 among women aged 50-59 did not show any significant difference in breast cancer mortality between a control arm screened annually by CBE and a study arm screened by CBE and mammography. Because of this design, the benefit of screening compared to no screening could not be evaluated. We therefore conducted a modeling effort to estimate the benefit of mammography or CBE compared to no screening. We incorporated demographic, epidemiologic and screening characteristics of the CNBSS-2 in MISCAN. Stage-specific sensitivities of CBE, with and without mammography, and breast cancer incidence rate in the trial were estimated by comparing observed trial data with model predictions. We predicted the number of breast cancer deaths for both study arms of the CNBSS-2 and in the absence of screening, assuming improvement in prognosis by early detection. We estimated a 24-29% higher breast cancer incidence rate in the CNBSS-2 than the average Canadian rate. Estimated sensitivity of CBE (control arm) varied from 0.29 to 0.48 for stage T1c and from 0.6 to 0.65 for stage T2+. Estimated sensitivity of CBE supplemented with mammography (study arm) varied from 0.5 to 0.79 for stage T1c and was 0.95 for stage T2+. Expected breast cancer mortality reduction by annual CBE screening is 20.5% compared to no screening. Estimated breast cancer mortality reduction by mammography screening compared to no screening for the CNBSS-2 fell within the range 13.6-34.1%. Enrolled women had above average risk. Screening sensitivity in both arms was high. A benefit of mammography screening is supported by our modeling of the CNBSS-2 results.