Regional policy has â in general â the intention to supporting the efforts of regions with development problems to overcome their current problems and to stimulate an increase in regional economic growth. If the regional policy measures by a jurisdiction are successful, there will be a tendency towards more economic convergence between the various regions within that jurisdiction, with the result of a higher degree of cohesion between these regions, than in a state without regional policy. There are many studies on evaluating the impact of different instruments of regional policy on cohesion. But there are only few investigations so far into the institutional framework of these instruments. One institutional aspect has become more and more relevant in public discussions during the last few years: In federations (e. g. in the EU), there is in general not only one jurisdiction responsible for regional policy, but two, three or even more levels of government; the responsibilities (or: competences) are fragmentated between these levels. The paper presents a theoretical analysis of the impact of the allocation of competences in the field of regional policy on the outcome (interregional cohesion) and on the costs (economic efficiency) of regional policy. The analysis is based on the Theory of Fiscal Federalism, including the Economic Theory of Intergovernmental Grants. All the possible more central or more decentral arrangements of regional policy are located between two polar cases: At one pole, we have an arrangement where only the central level of government (e. g. the EU level) is responsible for regional policy; neither any subcentral unit of government (e. g. at the member state level in the EU), nor the regions which are to be supported (the less developed regions) have any influence for deciding on the implementation of regional policy instruments, and only the central government has to finance regional policy with its own resources. At the other pole, we find an arrangement where only the subcentral units of government and the less developed regions themselves are deciding on regional policy and are responsible for financing. In connection with financing, different categories of grants in aid may be applied. In addition, the arrangements may differ from each other because of different institutions for controlling the activities of the lower levels. The main hypothesis is, that a more decentralized institutional arrangement is not in general more efficient and effective than a more centralized arrangement; but â as compared to the status quo in Europe â a more decentralized arrangement for some public responsibilities would lead to better results in the field of regional policy. Central questions to be answered are: Have subcentral governments (as compared to central units of government) a tendency for neglecting their subregions with development problems' What is the impact of information costs and asymmetrical information on the choice of the level of government for certain (sub-) responsibilities' To which degree is the central influence stimulating â or: paralyzing â the initiative of the regions which are to be supported?
District health systems, comprising primary health care and first referral hospitals, are key to the delivery of basic health services in developing countries. They should be prioritized in resource allocation and in the building of management and service capacity. The relegation in the World Health Report 2000 of primary health care to a 'second generation' reform--to be superseded by third generation reforms with a market orientation--flows from an analysis that is historically flawed and ideologically biased. Primary health care has struggled against economic crisis and adjustment and a neoliberal ideology often averse to its principles. To ascribe failures of primary health care to a weakness in policy design, when the political economy has starved it of resources, is to blame the victim. Improvement in the working and living conditions of health workers is a precondition for the effective delivery of public health services. A multidimensional programme of health worker rehabilitation should be developed as the foundation for health service recovery. District health systems can and should be financed (at least mainly) from public funds. Although in certain situations user fees have improved the quality and increased the utilization of primary care services, direct charges deter health care use by the poor and can result in further impoverishment. Direct user fees should be replaced progressively by increased public finance and, where possible, by prepayment schemes based on principles of social health insurance with public subsidization. Priority setting should be driven mainly by the objective to achieve equity in health and wellbeing outcomes. Cost effectiveness should enter into the selection of treatments for people (productive efficiency), but not into the selection of people for treatment (allocative efficiency). Decentralization is likely to be advantageous in most health systems, although the exact form(s) should be selected with care and implementation should be phased in after adequate preparation. The public health service should usually play the lead provider role in district health systems, but non-government providers can be contracted if needed. There is little or no evidence to support proactive privatization, marketization or provider competition. Democratization of political and popular involvement in health enhances the benefits of decentralization and community participation. Integrated district health systems are the means by which specific health programmes can best be delivered in the context of overall health care needs. International assistance should address communicable disease control priorities in ways that strengthen local health systems and do not undermine them. The Global Fund to Fight AIDS, Tuberculosis and Malaria should not repeat the mistakes of the mass campaigns of past decades. In particular, it should not set programme targets that are driven by an international agenda and which are achievable only at the cost of an adverse impact on sustainable health systems. Above all the targets must not retard the development of the district health systems so badly needed by the rural poor.
Open access
Healthcare Policy and Management
Health Systems, Economic Evaluations, Quality of Life
The current need and enthusiasm for health reforms open an important arena for deeper analysis of the policy process with a view to understanding the political determinants of reforms and strengthening implementation. The studies described in this thesis analyse positions of different actors in the reform process, their actions in support or opposition of the process, and their impact on the health sector reform process. Globally and especially in developing countries health sector reforms have been implemented over long periods. Although there have been improvements in health, the remaining burden of disease in many countries is still very high. Reasons for the high burden of disease have been classified into lack of resources and poor organizational and managerial capacity. Good stewardship was needed to facilitate improvement in the performance of health systems. Stakeholdersâ alignment and support was one of the most important components of good stewardship. However, stakeholder analysis had not been a common undertaking in developing countries despite the reforms that were being implemented in most of them. It was the aim of this study to answer the question: What has been the role and importance of stakeholders in supporting or opposing the health sector reform process? The study was conducted in Tanzania as one of the poorest countries in Africa, using the decentralization of the Expanded Programme on Immunization (EPI) as a case reference. The study units were the Ministry of Health Headquarters, Medical Stores Department, Expanded Programme on Immunization, national archives, regions and districts. At district level the study units were District Council, Council Health Management Team, EPI managers at regional and district levels, ward and village authorities, health facility, facility providers and households. Qualitative and quantitative methods were used to collect data from January 2000 to June 2002. Relevant data collection instruments were prepared and pre-tested. The qualitative data collection methods included document review, \nin-depth interviews, key informants interviews and observations. Quantitative \nmethods involved retrieval of secondary data, health facility survey and \nhousehold surveys. Regular discussions with key informants and data \ncollectors were held to verify the findings. Qualitative data was analysed \nmanually. Quantitative data was captured and analysed using Epi Info version \n6.1 and STATA version 6.0. The study involved answering five main questions. The first question was: Do \nreforms learn from history? Analysis of the waves of health reforms prior to \nthe current reforms from 1926 was done to answer the question. The main \nstakeholders in the reforms were the political party in power, the government \nand donors who supported the reforms each time. Each wave of health sector \nreforms provided information on health provision, financing and resource \ngeneration. Due to the political contexts, information on failures of health \nfinancing did not provide lessons for succeeding reforms of the health sector. \nStakeholdersâ political interests opposed lessons that did not match the \npolitical ideology at the time i.e. free public services versus privatization and \npaying for social services. Lessons from previous health reforms were \nselective, and did not consider health-financing needs among others. The \nongoing health reforms needed to use information from all functional aspects \nof the health system to provide lessons for improving the health system. The second question was: Who were the stakeholders in the current health \nreforms and what were their interests and reactions? The main stakeholders \nwere donors, and the government. The two had a very high support for the \nreforms evidenced by their participation in problem identification, justification, \nreform design, planning and implementation. The health sector reforms thus \nhad high political support at central level. In the implementation process, \nissues that triggered stakeholdersâ reaction included sectoral versus local \ngovernment decentralization. Another issue was the donor modality in \nfinancing the health sector and need for adopting new financial management \nsystems. Among the donors there was hesitancy to join the common financing \nmodalities that included a Sector Wide Approach (SWAp) and Basket \n Funding. As a result, there was delay in the process in order to reach better \nconsensus. \nThe third question was: What was the impact of stakeholders in the process of \nreforming a vertical programme like EPI? Health Sector Reforms in EPI \nincluded integration of generic functions, for example, vaccine procurement to \nmedical stores department. Qualitative and quantitative data was collected \nand analysed from the Ministry of Health, EPI management unit. This again \nrevealed that EPI reforms were well supported by the government and donors \ncentrally. EPI managers at both district and regional levels opposed some of \nthe EPI reforms. They argued that coverage was falling due to the reforms. \nHowever, there was no concrete evidence relating reforms in the EPI \nprogramme and falling coverage. The primary aim of certain actors was to \nmake sure that they continued receiving extra income from EPI functions. One \nof the effects of stakeholdersâ reaction was reversal of reforms (recentralization) \nand return to the status quo. The fourth question was: What was the immediate reaction of stakeholders to \ndecentralization at district level and how might it have affected performance of \nEPI functions and the challenges? The immediate reaction of stakeholders \nwas reduced cooperation between the Council Health Management Team \n(CHMT) and the District Council who were politically supreme in the district. \nWithin the Council Health Management Team there was inadequate \ncommunication, which led to poor teamwork. The result of this was reduced \nsupervisory visits to peripheral health facilities. The EPI coverage in the study \ndistrict was 52.8 per cent, which was well below the previous national average \n(80 per cent). A logistic regression model for EPI service quality variables on \nchildren between 12 months and 23 months who had completed vaccination \nwas applied. Certain EPI quality of service variables predicted significant \nchanges in the odds ratio for completing vaccination. It was then suggested \nthat strategies were needed to improve management skills among the CHMT \nand District Council members. Also there was a need of hastening the \nprocess of increasing remuneration and motivation of peripheral health \nworkers. The fifth and final question was: What was the interest of the stakeholders \nand prospects of increasing EPI coverage at district level? Decentralization \nand integration of EPI functions were among the reforms at district level. The \nanalysis revealed that active stakeholders at district level were the Ministry of \nHealth, CHMT, EPI managers at district and regional levels and facility \nproviders. The Ministry of Health opposed integration of EPI at district level by \nissuing the directive that DCCOs and MCHCOs (EPI manager at district level) \nshould resume their tasks. However, the CHMT had no option but to comply. \nThis action reversed some of the health reforms at district level. Analysis of \nthe importance the community attached to EPI, using willingness to pay for \nEPI cold chain kerosene, was done. The support was low (48.7 per cent). EPI \nservice quality variables were significantly negatively associated with odds \nratio for willingness to pay for EPI input. Simulation with Policy Maker \ncomputer software predicted that an increased number of stakeholders \nthrough community participation would significantly improve the current low \nlevel of EPI coverage. It was then proposed to do a similar analysis in other \nvertical programmes and implement on a trial basis the results of the \nsimulation. \nIn conclusion, stakeholders were found to be active and influential in the \nhealth sectors of developing countries like Tanzania but poorly considered in \nimplementation of reforms. Stakeholders are important since some strongly \nsupport while others oppose the reforms. The reaction of stakeholders is \nevident through deployment or non-deployment of information depending on \ninterest and context. This would result in poor management leading to \ninefficiency in resource use, which would then be followed by poor quality of \nservices, poor support by communities and consequently poor utilization of \nhealth services. It is suggested that stakeholder analysis be conducted in \nother vertical programmes in the process of integration. Promotion of \nstakeholder analysis and also Policy Maker as a tool to manage stakeholders \nwill facilitate the management of reforms in the health sector.
Torsten Eymann, Stefan Sackmann, GĂźnter MĂźller, Ingo Pippow
The mobile and increasingly ubiquitous use of information technology leads to more dynamic, constantly self-reconfiguring networks. Their services are available anytime and anywhere; as software agents, they can make local, context-aware decisions. F. A. von Hayek developed a theory for economic coordination based on individual decision making. This paper presents the explanation concepts of economic self-organization as at least one option for the design of decentralized coordination of information systems consisting of autonomous software agents with limited information processing capacity and incomplete information. Experiments using a multi-agent system show that a targeted change of this basic rule set directly influences the behavior of the individual elements and indirectly the behavior of the overall system.
Philipp Obreiter, Birgitta KĂśnigâRies, Michael Klein
In the context of mobile and wireless devices, an information system is no longer a centralized component storing all the relevant data nor is it a decentralized component governed by a common authority. Rather, the information spread across huge numbers of autonomous mobile and wireless devices owned by independent organizations and individuals can be regarded as a highly dynamic, virtual information system. For this vision to become reality, the autonomous devices involved need to be motivated to cooperate. This cooperation needs to occur not only on the application layer, but, depending on the network architecture, also on the lower layers from the link layer on upwards. In this report, we investigate on which protocol layers cooperation is needed and what constitutes uncooperative behavior. We then identify necessary properties of incentive schemes that encourage cooperation and discourage uncooperative behavior. In this context, we examine remuneration types that are a major constituent of incentive schemes. Finally, using the example of ad hoc networks, the most challenging technical basis of a wireless information system, we compare existing incentive schemes to these characteristics.
This paper assesses the impact on local government budget of the rearrangement of central-local fiscal relationship under proposal in Japan, or the so-called Trinity Reform, where it is proposed that some of the tax base be handed from the central to the local governments, in conjunction with drastic cut in both transfer of the tax revenue and a collection of subsidies. The tool used for this objective is the Nagoya City University Econometric Model (NCUEi 2003) whose core system has been duly modified to simulate proposals, and also to investigate the performance of the local economy under the strain of declining and aging population. The object case taken up in this paper is Nagoya City.The model is characterized by the market adjustment of the regional total demandsupply balance, where the age distribution of the population is incorporated so as to assess the impact of the demographic change both on the total demand and productive capacity. The forecast and simulations show that while the abovementioned Reform generates persistent unfavorable impact to the local government, the dominant negative impact comes from the demographic change, in terms of the primary balance of Nagoya City. Unless proper measures are to be taken, the simulations indicate, the local government's fiscal soundness will hardly be maintained under the two major pressures, one from the fiscal decentralization as represented in the subsidy cut-cum-tax base transfer and the other from the demographic change. The simulation of the abovementioned reform reveals that it definitely worsens the primary balance of the locality, and implies that practically an additional transfer of consumption tax must accompany this reform, even for one of the most favorable localities like Nagoya where its major industrial sectors, or the automobile-industry-led industries in this case, are steadily growing. The implication will be obvious for localities where economy is less favorable.
Theoretical computer science has found fertile ground in many areas of mathematics. The approach has been to consider classical problems through the prism of computational complexity, where the number of basic computational steps taken to solve a problem is the crucial qualitative parameter. This new approach has led to a sequence of advances, in setting and solving new mathematical challenges as well as in harnessing discrete mathematics to the task of solving real-world problems. In this talk, I will survey the development of modern cryptography -- the mathematics behind secret communications and protocols -- in this light. I will describe the complexity theoretic foundations underlying the cryptographic tasks of encryption, pseudo-randomness number generators and functions, zero knowledge interactive proofs, and multi-party secure protocols. I will attempt to highlight the paradigms and proof techniques which unify these foundations, and which have made their way into the mainstream of complexity theory.
The introduction of user-payment for health services is frequently followed by concern about the impact on equity of access for poor people. Decentralizing governments often try to remedy the created inequities by putting in place safety nets in the form of exemptions and waivers in the user-fee systems. However, where user payments merely operate as local government strategies for health financing, without national policy they are likely to be self-defeating, as local governments are frequently more interested in raising revenue to meet recurrent costs of devolved services than in promoting equity. Thus guidelines put in place by the central government to operationalize safety nets are seen by local governments as being contradictory to this goal, and are thus ignored or altered to suit the district revenue aims. This study was carried out to investigate the context and the constraints in implementing exemption schemes. Data were collected in two selected administrative districts of Uganda (Mbarara and Mukono). Qualitative approaches to data collection were adopted, namely focus group discussions and key informant interviews with policy-makers, health administrators, service providers and community members. These methods were combined with document review. We found little evidence of safety-net guidelines initiated by decentralized/local governments, since district local governments had little motivation to extend exemptions, waivers or credits. The conclusion is that safety nets such as waivers and exemptions will only be effective if they are backed by a national health financing policy, they reconcile the often competing demands of local government revenue needs, and are strictly enforced and supervised by both the local and central governments. The implications of the findings for remedying the tension between the needs for cost recovery and for attainment of equity goals through exemption policies for the poor and indigent are discussed.
Decentralization is commonly championed as a means for achieving equity. To date, however, there has been little discussion of the mechanisms underlying this relationship, and several of the few empirical investigations that have addressed the topic have found the converse; that decentralization has exacerbated inequalities. This article examines the performance and equity in financing of the Honduras Ministry of Health's (MOH) decentralized user fee system. The MOH of Honduras established a national user fee policy in 1989. It provided a framework of rules and regulations and decentralized administration of the system to the regional offices. A survey conducted under the auspices of this study provided detailed information about the structures and operations of MOH user fee systems. The survey revealed that the systems vary markedly by region, creating horizontal inequities, and that they have numerous other shortcomings. The average price of a consultation is low, US dollars 0.16, and revenues have consistently equalled just 2% of MOH expenditures. The systems' administrative costs are equal to 67% of their revenues. Eliminating the user fee systems in all but the national and regional hospitals would actually save money and/or enable the MOH to provide more care. Average consultation prices are highest in health posts, intermediate in centres and lowest in the national hospitals, thereby encouraging the inappropriate use of the MOH's pyramidal referral system and fostering MOH inefficiency. Fee levels and exemption practices are horizontally and vertically inequitable. The likelihood of paying for an ambulatory visit is highest at a health post, 89%, and lowest at a hospital, 49%. Individuals from the poorest one-fifth of households are the most likely to have to pay for care. Honduras' experience demonstrates that a decentralized user fee system is not necessarily equitable, and that, more generally, the gains that can be realized from decentralizing user fee systems are not automatic. They must be anticipated, planned for and cultivated by a well-designed and well-implemented initiative that is not a single, one-time event, but rather a dynamic, on-going enterprise.
Most economists agree that new investments in highways at this point in time in the United States have little impact on overall growth in output. New highways play a more important role in shifting economic activities among places, drawing jobs from other locations into the highway corridors, a phenomenon known as negative spillovers. The objective of this dissertation is two-fold, to examine the proposal to decentralize highway finance, which aims to solve the financial responsibility mismatch problem that stems from economic spillovers of highways, and to test the hypothesis of economic spillovers of highway investment at the metropolitan level. First, to better understand how spillovers influence the highway investment decision, the theoretical framework from the interjurisdictional tax competition literature is borrowed to model governments' investment behaviors. Numerical simulations show that decentralized local governments, which independently maximize output in their own jurisdiction, may engage in wasteful investments in highways with the presence of spillovers. Second, to shed more light on the spatial detail of economic spillovers, empirical tests of the spillover hypothesis are conducted at the metropolitan level, with census tracts as the unit of observation. The results of the quasi-experiment reveal census tract employment growth patterns that confirm the existence of negative spillovers caused by the opening of the Interstate 105 in 1993. The benefiting area, which grew substantially after the highway was opened, is limited to a long narrow corridor around the highway, while nearby locations outside the corridor experienced slow growth relative to the rest of the metropolitan area after controlling for various factors. Together, these results suggest that although negative spillovers are present at the metropolitan level, decentralizing highway finance may not be an effective policy to deal with the financial responsibility mismatch problem. Highway finance should remain centralized within metropolitan areas, and regional governing bodies should pay special attention to the distributional impact of highway projects.
Vertical fiscal imbalance, decentralized responsibility of spending with centralized financing, creates a common pool problem with spending pressure towards central funds. A model of decentralized government spending under vertical fiscal imbalance is developed, and the importance of national political characteristics for internalization of costs and spending level is investigated in an econometric analysis of Norway during 1880â1990. We argue that in a parliamentary democracy, the internalization of costs is influenced by the party fragmentation of parliament. This is confirmed by the econometric analysis using a Herfindahl index as a measure of fragmentation and political strength.
Over the last 15 yr, genes responsible for hundreds of inherited human diseases have been identified, enabling clinical diagnosis and the potential for therapeutic intervention. Until very recently, however, success has been limited to so-called monogenic disorders, diseases in which mutation of a single gene is both necessary and sufficient to cause disease in any given individual. Because such mutations are strictly co-inherited with disease, it is possible to use linkage analysis to identify their chromosomal location by analyzing which of a genome-wide set of markers segregates with disease in families. Genes contained within such linked regions become positional âcandidatesâ and are next examined for mutations in affected individuals. For any such candidate gene, proof of causality typically depends on two additional lines of evidence. First, the putative causal changes should be found only in affected individuals. Second, one hopes for a âsmoking gunââthat the disease-associated mutations are obviously deleterious to protein function (due to truncation or deletion of a coding region or alteration of a highly conserved residue). Success is typically declared when these criteria are all satisfied: the putative disease gene 1) is located in a chromosomal region that co-segregates with disease in affected families, 2) contains multiple independent mutations that are perfectly associated with disease status in the families, and 3) whose characteristics obviously alter protein function. Most common diseases are strongly influenced by inheritance, but, to date, relatively few genes have been identified that are responsible for familial clustering of these diseases. Success has been elusive because common diseases are almost all complex disorders, where multiple genes and environmental factors collaborate to cause disease. Because no single gene segregates tightly with disease, it has proven very difficult to confidently localize putative disease genes to chromosomal locations. For this reason, optimistic gene hunters have leapt directly to the latter stage of examining candidate genes for mutations that show association to disease. Typically, however, these candidate genes are based on a biological hypothesis, rather than chromosomal position relative to a linkage study. Association studies can, in theory, succeed where linkage fails, because association can offer much greater statistical power (1), thus providing a rationale for circumventing linkage analysis. But several problems bedevil such association studies. First, it is expected that the causal mutations are neither necessary nor sufficient to cause disease. That is, some people will have the mutation but not disease, and others will have disease without a causal mutation of that gene. Because of this imperfect correlation, association studies must compare the frequencies of a putative causal mutation in individuals with disease and in appropriate controls. If the mutation is found at a statistically significant higher frequency in affected individuals, the mutation is said to be associated with disease. However, determining appropriate thresholds of significance is challenging because the a priori likelihood that any given candidate gene plays a role in disease is unknown, but certainly low (in following up a solid linkage peak, one at least begins with the knowledge that one or more genes in the region is responsible for the disease). In addition, these more subtle genetic risk factors need not be premature stop codons or protein truncation mutants. Rather, they may be innocuous to the scientistâs eye and yet cause disease by altering the in vivo regulation, expression, stability, activity, or interactions of the encoded protein. Because of these and other difficulties (see, for example, Ref. 2), it is important that association studies be performed and scrutinized carefully, especially when different investigators reach different conclusions as to whether mutations or genetic variation in a gene is associated with disease. Here, we discuss the relevant points in light of a report in this issue questioning the relationship of mutations in the MC4R gene and severe obesity (3). Most association studies have focused on a common genetic variation: by convention, common genetic variants (or polymorphisms) are those for which two or more alleles each exist in 1% or more of the population at large. There are many practical advantages to studying common variants. Because they are present at high frequency, common variants can be discovered in any modest sized group of individuals. This facilitates cataloging of common variants. Over the last 3 yr, millions of common human sequence variants have been identified and placed in databases (4). Moreover, because strong correlations are typically observed between neighboring variants (linkage disequilibrium), most common variations in the genome can be tested for a role in disease using a subset of carefully chosen âtagâ single nucleotide polymorphisms (see Ref. 5 and references therein). Finally, testing common variants for association to disease is technically straightforward. The frequencies of each variant can be accurately estimated in modest sized collections of patients with and without the disease. Of course, there is no reason to presume that the mutations responsible for common diseases will themselves be common. Certainly, many rare monogenic disorders are due to a heterogeneous collection of variants that are individually very rare. In thinking about the allele spectrum of common diseases, it is important to consider both the overall characteristics of human genetic variation and the particular evolutionary features of each disease (6). The characteristic features of human genetic variation have been well described (see Ref. 4 and references therein). Numerically, rare variants outnumber common variants, but the vast majority of variant alleles in the population (heterozygosity) are attributable to the small number of common variants. Thus, for disease phenotypes that had a neutral effect on human evolutionary fitness, the spectrum of alleles causing disease should resemble this overall patternâmost of the genetic burden of disease in the population will be due to common variants. In contrast, where disease was disadvantageous from an evolutionary perspective (e.g. diseases that are lethal in childhood), rare variants will predominate, because variants that lower reproductive fitness generally do not drift up to high frequency. Finally, disease phenotypes that experienced balancing selection (e.g. sickle cell disease, where disease is balanced by resistance to malaria in carriers) or that may even have been evolutionarily advantageous (as has been proposed for obesity under the thrifty gene hypothesis) should be due to variants that are even more common than those found throughout the genome as a whole. Given the speculative nature of such evolutionary hypotheses, as well as the experience from rare monogenic disorders, there has been great attention to the importance of studying rare genetic variants for a role in common disease (see, for example, Ref. 6). However, studying rare variants introduces important methodological challenges. First, investigators must discover the variants in each of their populations, often by directly resequencing affected individuals. Moreover, because they are rare, much larger samples must be examined before an accurate estimate of frequency can be obtained for the comparison of cases and controls. In making such comparisons, it is critical that controls be scrutinized for variation in the exact same manner as cases, because resequencing only of cases leads to a significant problem called ascertainment bias. In brief, sequencing a large group of individuals will nearly always identify a particular collection of vanishingly rare variants (including missense variants) that will be absent from any second collection of individuals that is tested. Thus, finding a few rare, apparently deleterious mutations in affected individuals does not signify a role in disease, unless controls have been examined with the same intensity as have cases, and the preferential presence of variants in affected individuals is strong and statistically convincing. In fact, the statistical analysis of rare variation almost always requires that collections of different rare variants be considered as a group, because no individual variant is sufficiently common to permit an accurate assessment of its frequency in realistically sized disease or control populations. It is important that the grouping of rare variants not be done post hoc in a subjective (and, therefore, potentially biased) manner. Rather, the grouping must be on the basis of obvious sequence characteristics (e.g. all missense variants, all nonsense and frameshift mutations, etc.), or on the basis of a valid functional assay. To avoid a biased assignment of functional importance to variants identified in affected individuals, such a functional assay should be developed and validated independently of the results of association analysis. Despite these additional challenges, association testing of rare and common variants is fundamentally similar. Once a relevant common variant âor group of rare variantsâis identified, the frequency of variants must be rigorously compared in affected individuals and in controls. The choice of a threshold for declaring a significant association has been a matter of some debate. The P value for differences in frequencies between affected individuals and controls reflects the likelihood of observing an association by chance if the true frequency were the same in both groups. This obviously is not equivalent, however, to the likelihood that the experimenterâs hypothesis of association is in error, because this latter calculation requires knowledge of the a priori probability that the variant in question was associated with disease. In most such studies, this prior probability is extremely lowâthere are hundreds of candidate genes, each of which contains a hundred or more commonly varying sites; moreover, many causal genes will not be obvious candidates, and the entire genome contains 10 million common variants and many more rare variants. In this Bayesian framework, the P values for most association studies are not low enough to meet a conservative threshold for declaring significance that minimizes type 1 errors (false positive studies). Thus, a single report of association is almost always inadequate to prove causation. Rather, replication, preferably in multiple independent studies, is required. However, consistent replication of associations has been difficult to achieve. Indeed, a review of associations between common variants and disease found that the vast majority of such associations have not been consistently reproduced (2). The possible reasons for the inconsistency include false positives due to type 1 error, false positives due to population stratification, false negatives due to lack of power in potential replication studies, and true differences between study populations (e.g. different phenotypes, or different environmental or genetic modifiers). These explanations probably all contribute to the lack of reproducibility and are relevant to both studies of individual common variants and of grouped rare variants. However, to interpret an association that has not been consistently replicated, it is important to try to distinguish which of these explanations is truly relevant to that particular association. Lack of power for true associations with modest effects can clearly contribute to inconsistent replication. For example, several studies failed to detect an association of the Pro12Ala variant with type 2 diabetes and concluded that no such role was likely to exist. In fact, this PPARG variant has a much lower relative risk (1.25-fold) than was initially estimated, and consequently many studies were underpowered to detect the true effect of the allele on diabetes risk (7). To assess power, then, the range of genetic effects that are consistent with the negative data should be compared with the genetic effect estimated by considering all of the previous studies together. In this context, Jacobson et al. (3) report in this journal their failure to replicate the previously described association of rare functional variants in the MC4R gene with morbid human obesity. MC4R was originally implicated in obesity by mouse studies (see, for example, Ref. 8); two groups then independently identified severely obese individuals (one in each study) with a frameshift mutation in the MC4R gene (9, 10). Several additional studies subsequently found at least 34 additional missense or frameshift mutations in MC4R in obese individuals, but no functional missense variants were identified in control individuals who were resequenced (see Refs. 18â24 in Ref. 3). It is worth noting that there are three somewhat common missense variants that are present at approximately equal frequencies in obese and nonobese individuals (Val103Ile, Thr112Met, and Ile251Leu). These variants have been distinguished from the putative functional variants because they do not affect MC4R function in in vitro tests (11, 12). If these common variants were included in statistical analysis, they would swamp out any signal due to the rarer, apparently functional mutations. Thus, the statistical arguments in favor of association rely critically on the relevance of the in vitro assay used to assess protein function. In total, at least 34 putative functional MC4R mutations have been identified in 1187 obese individuals (2.9% frequency) as compared with zero in 827 controls. Nearly all of the obese individuals who were found to carry mutations are either severely morbidly obese [body mass index (BMI),50] or had onset of obesity in childhood or early adolescence. However, some carriers and relatives were identified who also carry MC4R mutations but have less severe phenotypes (12). These findings led to the hypothesis that mutations in MC4R might be a common cause of morbid obesity (12). It was the intent of Jacobson et al. (3) to test this hypothesis. To study the role of MC4R mutations in obesity, they resequenced the MC4R gene in over 200 obese white subjects and 47 obese black subjects, plus a similar number of controls. None of the previously described putative functional variants were identified. Three new missense variants were identified, each in one black control (Ile102Thr, Phe202Leu, and Asn240Ser). Unfortunately, no functional evaluation of these variants was performed. In addition, one frameshift mutation leading to a predicted premature termination codon was discovered in an obese white female. The authors interpret these data as failing to replicate the previous findings of a high rate of MC4R mutations in obese individuals. To evaluate whether the authors have failed to replicate the previous finding, or have simply asked a different question, we consider below each of the main possible explanations for the failure to replicate: false negative study (inadequate power), a falsely positive original report, and true differences between study populations. Jacobson et al. (3) state that they can strongly reject the hypothesis that mutations in MC4R account for 4% of cases of obesity, with 80â85% power in blacks and greater than 99.9% power in whites. These arguments are based on not having observed any of the previously reported functional variants. However, the spectrum of variants that can affect MC4R function is apparently quite diverse (few or none of the functional variants have been identified independently in separate studies), so the expectation should be that most functional variants in MC4R would be novel. Indeed, Jacobson et al. (3) did discover one such variant (the frameshift mutation, although they did not test it for function in vitro). Thus, a more appropriate interpretation of their data is that they identified one apparently functional mutation in approximately 200 unrelated obese white individuals and 47 obese black individuals. Furthermore, 4% is the highest estimate of MC4R mutations in the literature (12). A more appropriate figure to test would be 2.9% (the estimate from all available data), and even this value may be too high because some of the rare missense changes identified in obese individuals do not impair function in vitro (see Ref. 12) and, thus, may not represent functional MC4R mutations. What range of frequencies of MC4R mutations could be consistent with the data in Jacobson et al. (3)? Given the observation of one mutation in 200 individuals, the 95% confidence interval for the frequency of MC4R mutations is quite wide; values from 0.12â2.75% are all consistent with the data. Even if the data from blacks and whites are pooled, the 95% confidence interval extends from 0.1â2.2%; the data from blacks alone are actually consistent with mutation frequencies as high as 7% in this population. If power is set at a more conservative 80%, the data can reject frequencies of mutations greater than 1.5% in whites, 3.3% in blacks, and 1.2% in the pooled sample. Although the confidence intervals are wide, the data are apparently inconsistent with the 2.9% frequency of mutations found in previous studies. Thus, additional explanations are required other than inadequate power of the current study. The second possibility is that the previous studies were false positives: all of the functional variants were found in the obese individuals by chance or due to a biased selection of which variants were considered functional. However, this explanation also seems unlikely. The P value for finding 34 functional variants in 1187 obese individuals but no functional variants in 827 controls is under 10â6. In addition, many of the variants are obviously deleterious, and there is no reason to suspect that the functional assay is biased. Thus, one must consider the possibility that the authors of the present study may have asked a different question than that posed before, specifically that the populations used in previous studies and the populations used in Jacobson et al. (3) are in some way fundamentally different from each other. The possibility of differences in populations seems quite plausible if one compares the characteristics of the populations used in previous studies with those of the obese individuals in this most recent study. In previous studies, almost all MC4R carriers were found among severely obese individuals (BMI, >50) and/or individuals with early-onset obesity (usually in childhood). By contrast, only 42% of the white individuals in the study by Jacobson et al. (3) had early-onset obesity (childhood or adolescence), and less than 10% had a BMI greater than 50. If one only considers these approximately 100 subjects in the study, there is no longer 80% power to reject a mutation frequency of 2.9%, although the estimate of the frequency (now 1% rather than 0.5%) is still much lower than the 2.9% estimated by previous studies. However, a potentially more important conclusion is suggested from these data: Jacobson et al. (3) observe no MC4R mutations in 100 individuals with a BMI under 50 and onset of obesity in adulthood. Indeed, the only other studies to examine populations not selected or enriched for severe or early-onset obesity also failed to find mutations in MC4R despite screening 90 individuals (13, 14). This suggests that although MC4R mutation might be a rare (2â3%) but significant cause of early-onset or severe obesity, it is likely to be a less common cause of obesity in the general population. This could be explained (post hoc) by invoking the possible selective disadvantage of relatively penetrant alleles that cause severe, early-onset obesity (where rare MC4R mutations are observed) compared with the less easily predicted evolutionary history of the more common form of the disease. How can one reconcile this apparent absence of MC4R mutations in cases of less severe obesity with the fact that some relatives of severely affected probands carry MC4R mutations but have milder obesity (12)? Shouldnât some of these relatives have turned up in the studies of âtypicalâ obesity? The answer probably lies in the fact that there are many, many more people with typical obesity than there are relatives of MC4R carriers. This theory predicts that if one studied people with mild obesity who had a relative with severe or early-onset obesity, it would be possible to enrich for carriers of MC4R mutations. This dichotomy is reminiscent of the situation for BRCA1 and breast cancer, where mutations are found at appreciable frequencies in highly familial cases, early-onset cases, or women with multiple cancers. Where family members of such women are tested, carriers with later onset breast cancer (or no cancer at all) are found at appreciable when more typical cases of breast cancer are BRCA1 mutations are found at much lower the current study many of the important in association studies of genetic variants and disease. is because prior of true association are low and, thus, all genetic associations a high of failure to replicate can be due to many possible explanations false positive studies and type 1 Lack of power to modest effects and different phenotypes of patients in different collections can both contribute to apparent among studies. Moreover, genetic variants both rare and common are to a role in most diseases, but their relative in any given are to Given the of resequencing and the of grouping rare variants and an of the hypothesis is even for candidate rare variants such as are found in MC4R will no a great about and the in which human can be by severe genetic rare variants also out to much of the population burden of disease is an important question that will for some to mass
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Genetic Associations and Epidemiology
Genetic Mapping and Diversity in Plants and Animals
Social assistance as the technique providing means-tested income guaranteed financed by general taxation in Spain is composed by different benefits. There is not a only one policy, but different measures oriented to different groups of population and organised by different public administrations. During the last two decades, the different levels of public administration have implemented a set of benefits, which observed together can considered as the Spanish âsafety netâ. The main lines of this development has been: a) fragmented in different protection systems (unemployment, pensions, social services), b) subsidiary of the development of these systems and c) decentralized in different levels of public administration (mainly in regional level, i.e. Autonomous Communities).
This paper studies optimal earnings taxation in a three period life cycle model where the taxes raised to finance an exogenous amount of public expenditure are allowed to be differentiated across ages. Agents choose their level of education when young and their age of retirement when old. We first look at the problem of optimal taxation when the young can borrow and then turn to the case where young face borrowing constraints. It is shown that, without borrowing constraints, a first best optimum can be decentralized by setting a zero tax rate in the third period and a first period tax lower than the second one.\nWith the borrowing constraint, the government may not be able restore intertemporal efficiency in which case a zero tax rate when old may not be optimal.
An optimal linear world income tax that maximizes a border-neutral social welfare function provides a drastic reduction in world consumption inequality, dropping the Gini coefficient from 0.69 to 0.25. In contrast, an optimal decentralized (i.e., within countries) redistribution has a miniscule effect on world income inequality. Thus, the traditional public finance concern about the excess burden of redistribution cannot explain why there is so little world redistribution.
Bob Searle, Jun Ma, Stefano Piperno, Ehtisham Ahmad
Intergovernmental equalization grants have been described as âthe glue that holds a nation together.â Getting the grants system right is critical to countries as they decentralize. This paper illustrates general principles with an example based on Indonesia in 2000. A general grant should be used to supplement own revenues and to finance local service provision where there are no central mandates. The special needs of backward regions would be better provided for by specific grants. Specific grants need to be taken into account in the general grants scheme.
The voting plays important roles in a democratic country. Due to the problems of the existed voting m ethod, the new voting methods, electronic voting system, have been developing using the computer net work and cryptographic techniques. Many electronic voting schemes have been introduced for secure electronic voting systems. In this paper, we propose the secure electronic voting for absentee e-voting system. The absentee voting plays the important percentage in the existing voting system. But, the abs entee vote can not look forward to the security because of transmit by mail. The absentee does not kno w whether oneâs voting is exactly counted or not. In this paper, we propose the absentee e-voting syste m based on security, completeness and verifiability. We use r-th residue cryptography for homomorphi c encryption, ZKIP (Zero-Knowledge interactive proofs), RSA algorithm. Also, we propose the ne w method of tallying for multi-candidate. The goals of out voting system are the absentee vot ing based on privacy, universal verifiability, reuseability and multi-candidate.
In this paper, we propose the absentee e-voting system based on security, completeness and verifiability. We use r-th residue cryptography for homomorphic encryption, ZKIP (Zero-Knowledge interactive proofs), RSA algorithm for the secure absentee e-voting.
Carlos Centeno, S. Hernansanz, Luis Alberto Flores, Ălvaro Sanz Rubiales ¡ 5 authors
Abstract This chapter offers an in-depth look at health politics and the tax-financed, universal health system in Spain. It traces the development of the Spanish healthcare system, focusing in particular on its double transition in the 1980s and 1990s from a centralized social insurance system, mostly funded through workersâ and employersâ contributions, to a decentralized universal model financed by general taxation. The new national health system aimed at covering all residents and transferred healthcare competences to the regions, i.e. the seventeen Autonomous Communities, a process completed in 2001. Key issues include rationalization, harmonization, and territorial equity-building of the decentralized healthcare system; efficiency improvement through the introduction of private management elements; and cost containment to bolster the systemâs financial sustainability in the context of growing demand and scarce resources. As the chapter argues, these challenges along with the remarkable changes in the political party system have increased the political salience of healthcare in public debate in the 2010s, but the prospects for developing consensual healthcare policies have worsened, such that structural problems are likely to persist.