Disease severity and mortality in Alzheimer's disease: an analysis using the U.S. National Alzheimer's Coordinating Center Uniform Data Set.

BACKGROUND: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. METHODS: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. RESULTS: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3-12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. CONCLUSIONS: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.

Modeling Manifest Huntington's Disease Prevalence Using Diagnosed Incidence and Survival Time.

INTRODUCTION: Understanding the epidemiology of Huntington's disease (HD) is key to assessing disease burden and the healthcare resources required to meet patients' needs. We aimed to develop and validate a model to estimate the diagnosed prevalence of manifest HD by the Shoulson-Fahn stage. METHODS: A literature review identified epidemiological data from Brazil, Canada, France, Germany, Italy, Spain, the UK, and the USA. Data on staging distribution at diagnosis, progression, and mortality were derived from Enroll-HD. Newly diagnosed patients with manifest HD were simulated by applying annual diagnosed incidence rates to the total population in each country, each year from 1950 onwards. The number of diagnosed prevalent patients from the previous year who remained in each stage was estimated in line with the probability of death or progression. Diagnosed prevalence in 2020 was estimated as the sum of simulated patients, from all the incident cohorts, still alive. RESULTS: The model estimates that in 2020, there were 66,787 individuals diagnosed with HD in the 8 included countries, of whom 62-63% were in Shoulson-Fahn stages 1 and 2 (with less severely limited functional capacity than those in stages 3-5). Diagnosed prevalence is estimated to be 8.2-9.0 per 100,000 in the USA, Canada, and the 5 included European countries and 3.5 per 100,000 in Brazil. CONCLUSION: The modeled estimates generally accord with the previously published data. This analysis contributes to better understanding of the epidemiology of HD and highlights areas of uncertainty.

A novel approach for measuring the burden of uncomplicated Plasmodium falciparum malaria: application to data from Zambia.

Measurement of malaria burden is fraught with complexity, due to the natural history of the disease, delays in seeking treatment or failure of case management. Attempts to establish an appropriate case definition for a malaria episode has often resulted in ambiguities and challenges because of poor information about treatment seeking, patterns of infection, recurrence of fever and asymptomatic infection. While the primary reason for treating malaria is to reduce disease burden, the effects of treatment are generally ignored in estimates of the burden of malaria morbidity, which are usually presented in terms of numbers of clinical cases or episodes, with the main data sources being reports from health facilities and parasite prevalence surveys. The use of burden estimates that do not consider effects of treatment, leads to under-estimation of the impact of improvements in case management. Official estimates of burden very likely massively underestimate the impact of the roll-out of ACT as first-line therapy across Africa. This paper proposes a novel approach for estimating burden of disease based on the point prevalence of malaria attributable disease, or equivalently, the days with malaria fever in unit time. The technique makes use of data available from standard community surveys, analyses of fever patterns in malaria therapy patients, and data on recall bias. Application of this approach to data from Zambia for 2009-2010 gave an estimate of 2.6 (95% credible interval: 1.5-3.7) malaria attributable fever days per child-year. The estimates of recall bias, and of the numbers of days with illness contributing to single illness recalls, could be applied more generally. To obtain valid estimates of the overall malaria burden using these methods, there remains a need for surveys to include the whole range of ages of hosts in the population and for data on seasonality patterns in confirmed case series.

Modelling the cost-effectiveness of mass screening and treatment for reducing Plasmodium falciparum malaria burden.

BACKGROUND: Past experience and modelling suggest that, in most cases, mass treatment strategies are not likely to succeed in interrupting Plasmodium falciparum malaria transmission. However, this does not preclude their use to reduce disease burden. Mass screening and treatment (MSAT) is preferred to mass drug administration (MDA), as the latter involves massive over-use of drugs. This paper reports simulations of the incremental cost-effectiveness of well-conducted MSAT campaigns as a strategy for P. falciparum malaria disease-burden reduction in settings with varying receptivity (ability of the combined vector population in a setting to transmit disease) and access to case management. METHODS: MSAT incremental cost-effectiveness ratios (ICERs) were estimated in different sub-Saharan African settings using simulation models of the dynamics of malaria and a literature-based MSAT cost estimate. Imported infections were simulated at a rate of two per 1,000 population per annum. These estimates were compared to the ICERs of scaling up case management or insecticide-treated net (ITN) coverage in each baseline health system, in the absence of MSAT. RESULTS: MSAT averted most episodes, and resulted in the lowest ICERs, in settings with a moderate level of disease burden. At a low pre-intervention entomological inoculation rate (EIR) of two infectious bites per adult per annum (IBPAPA) MSAT was never more cost-effective than scaling up ITNs or case management coverage. However, at pre-intervention entomological inoculation rates (EIRs) of 20 and 50 IBPAPA and ITN coverage levels of 40 or 60%, respectively, the ICER of MSAT was similar to that of scaling up ITN coverage further. CONCLUSIONS: In all the transmission settings considered, achieving a minimal level of ITN coverage is a "best buy". At low transmission, MSAT probably is not worth considering. Instead, MSAT may be suitable at medium to high levels of transmission and at moderate ITN coverage. If undertaken as a burden-reducing intervention, MSAT should be continued indefinitely and should complement, not replace, case management and vector control interventions.

Can we depend on case management to prevent re-establishment of P. falciparum malaria, after local interruption of transmission?

Recent declines in malaria burden in many parts of the world have prompted consideration of how interruption of Plasmodium falciparum transmission could be maintained, if achieved, and notably whether large-scale vector control could be replaced with surveillance. This information is essential for elimination feasibility assessments and planning. The risk of re-establishment of transmission depends mainly on vectorial capacity (receptivity), likely to rebound once vector control is removed, the rate of importation of infections (vulnerability), the capacity to detect and treat infections and the level of immunity in infected individuals. Timely detection and removal of new infections is likely to be critical to prevent re-establishment of transmission. We assess, through mathematical modeling and simulation, which levels of case detection and treatment (case management) are required to prevent re-establishment of transmission of P. falciparum after local interruption of transmission has been achieved, in settings with varying receptivity and vulnerability. We find that, even at rather low levels of receptivity, case management alone cannot reliably prevent re-establishment of P. falciparum malaria transmission in the face of medium to high importation rates. Thus, if vector control is to be discontinued, preventing the importations by controlling transmission in source areas will generally be necessary for preventing reintroduction in such settings, and cannot be substituted by very high levels of case management coverage.

Estimated global resources needed to attain international malaria control goals.

OBJECTIVE: To provide the international community with an estimate of the amount of financial resources needed to scale up malaria control to reach international goals, including allocations by country, year and intervention as well as an indication of the current funding gap. METHODS: A costing model was used to estimate the total costs of scaling up a set of widely recommended interventions, supporting services and programme strengthening activities in each of the 81 most heavily affected malaria-endemic countries. Two scenarios were evaluated, using different assumptions about the effect of interventions on the needs for diagnosis and treatment. Current health expenditures and funding for malaria control were compared to estimated needs. FINDINGS: A total of US$ 38 to 45 billion will be required from 2006 to 2015. The average cost during this period is US$ 3.8 to 4.5 billion per year. The average costs for Africa are US$ 1.7 billion and US$ 2.2 billion per year in the optimistic and pessimistic scenarios, respectively; outside Africa, the corresponding costs are US$ 2.1 billion and US$ 2.4 billion. CONCLUSION: While these estimates should not be used as a template for country-level planning, they provide an indication of the scale and scope of resources required and can help donors to collaborate towards meeting a global benchmark and targeting funding to countries in greatest need. The analysis highlights the need for much greater resources to achieve the goals and targets for malaria control set by the international community.