Several reviews of published cluster randomised trials have reported that about half did not take clustering into account in the analysis, which was thus incorrect and potentially misleading. In this paper I ask whether cluster randomised trials are increasing in both number and quality of reporting.British Medical Journal over 20 years.Computer search for papers on cluster randomised trials since 1980, hand search of trial reports published in selected volumes of the British Medical Journal contained more such reports than any other journal. In this journal there was a corresponding increase over time in the number of trials where subjects were randomised in clusters. In 2003 all reports showed awareness of the need to allow for clustering in the analysis. In 1993 and before clustering was ignored in most such trials.There has been a large increase in the numbers of methodological papers and of trial reports using the term 'cluster random' in recent years, with about equal numbers of each type of paper. The Cluster trials are becoming more frequent and reporting is of higher quality. Perhaps statistician pressure works. Cluster randomised trials are those where research subjects are not allocated to treatments independently, but as a group. For example, in a study of counselling patients on physical activity in general practice, practices were allocated to counselling or control and patients aged 40–79 years who attended during a five day period and who did not take regular exercise were invited to take part. Patients in the same practice received the same treatment, counselling or usual care, depending on how the practice was allocated.  The grouMembers of a cluster will be more like one another than they are like members of other clusters and we need to take this into account in the analysis, and preferably the design, of the study. Methods which ignore clustering may mislead, because they assume that all subjects provide independent observations. Applying simple statistical methods to such data, without taking the clustering into account, can lead to confidence intervals which are too narrow and P values which are too small.British Medical Journal Statistics Notes on this topic [There has been an increasing interest in cluster randomised trials over the past 20 years. For example, by the end of 2003 the is topic  had beenet al. [et al. [British Medical Journal website found that only 3 out of 36 ignored clustering. The review of the American Journal of Public Health and Preventive Medicine in 1998 – 2002 [There have been several reviews of published cluster randomised trials -13  that once we have carried out a study, the sample size calculations are not particularly informative. Analysis which ignores the clustering, however, can be highly misleading, finding significant differences where there are none. We may have incorrect conclusions in the literature, which are then uncritically repeated and become false knowledge.We should not be surprised that clustering is ignored. In the past, few textbooks have cautioned against this and the assumption of independence of observations is seldom stressed. Many statisticians will admit to having incorrectly ignored clustering in the analysis of clustered designs, including myself when I was younger and more ignorant than today. However, it can be very important.In this paper I attempt to chart the changes in both the number of cluster randomised trials reported and the proportion of these reports where clustering has been taken into account in the analysis.I first carried out a search on the ISI Web of Science, looking for papers on cluster randomisation and reports of trials. I classified these by type , year of publication, and journal.British Medical Journal. I identified and scanned all papers reporting trials for the years 1983, 1988, 1993, 1998, and 2003, recording any where subjects were allocated in clusters. I excluded any studies where subjects were not allocated to groups by the investigator, for example several comparisons of fund-holding and non-fund-holding general practices.To identify cluster randomised trials we have to read the papers. We cannot tell whether a trial is cluster randomised from title, keywords, or abstract. Many authors are not aware of the importance of clustering and do not mention it. In this paper I report the results of a hand search of the For each trial identified, I noted whether clustering had been taken into account in the analysis. There are several approaches which can be used to allow for clustering. The easiest is to calculate a summary statistic for each cluster.  This is I also noted whether ignoring the possible effects of clustering might have an important effect on the conclusions. Clustering may result in P values and confidence intervals which are sufficiently biased to have a major effect if any of the following are true: the cluster size is large, the number of clusters is small, or the intra-cluster correlation coefficient is large. Whether any of these applies in a trial which ignores clustering is a matter of judgement.Figure There are many potential biases. In the first part of the period, the Web of Science database did not include abstracts, so there was less opportunity to pick up the search terms. More recently, several journals began to include a description of the trial design in the title of the paper, for example 'Effect on hip fractures of increased use of hip protectors in nursing homes: cluster randomised controlled trial'.  This wilStatistics in Medicine and Statistical Methods in Medical Research on cluster randomisation, so there were a larger number of methodological papers than might be expected in those years. The numbers of papers found in the two categories were similar in each year before 2001: as many papers were about how to do such trials as were reports of actual trials. It is hard to believe that there are so few such trials being reported and it is likely that many have been reported without any acknowledgement of the importance of clustering.I divided the papers into those which were methodological, either educating researchers into the appropriate design and analysis of cluster randomised trials or developing new methods of analysing such trials, and those reporting actual trials. The data for 2000 and 2001 includes special issues of The Design and Analysis of Group-Randomized Trials.All the papers up to 1990 are due to Donner and his colleagues. ,15,16 HoBritish Medical Journal was the journal most frequently represented in the survey, no fewer than 43 of the 332 publications found, 13%, appearing there. The next was Statistics in Medicine with 39 publications (12%), all methodological, then the British Journal of General Practice with 17 (5%), Controlled Clinical Trials with 16 (5%), and Family Practice with 10 (3%). Figure British Medical Journal reflect the literature as a whole. The first paper in the BMJ was a report of a trial, [The a trial,  which waBritish Medical Journal had most reports and had been published for many years, this was the obvious journal with which to begin.When I first did the search reported in Figure BMJ papers in Figure BMJ Statistics Notes on clustering. [The results of the search are shown in Table stering. -72 analysis. The role of potential covariates was explored using linear regression specified as a two level model  using the software package MLn'. [2 tests. This was a trial of community based management in failure to thrive by babies. Thirty eight primary care teams were randomly allocated to intervention or control and all children identified in the practice were offered the same intervention, so clearly clustering should be taken into account.The noted query relates to a paper in which the authors stated that 'Univariate comparisons were calculated by t test and χge MLn'.  I could et al. [The trials which I regarded as failing to take the clustering into account were as follows. Russell et al.  investiget al. [Rink et al.  investiget al. [In a trial of clinical guidelines to improve general-practice management and referral of infertile couples, Emslie et al.  randomisThe trial where I judged ignoring clustering to be unimportant had many very small clusters. Wetsteyn and Degeus  comparedOnly five of the 18 trials had been found in the Web of Science search, showing that that was indeed an underestimate. However, the growth in numbers of trials is indicated by both electronic and hand searches.British Medical Journal. A hand search of the British Medical Journal has confirmed this increase, at least in this journal. Although the effects of clustering have often been ignored in trials, producing potentially misleading conclusions, the situation has certainly improved in the British Medical Journal. This has followed many articles on the topic in the Journal. Perhaps statistician pressure works.A bibliometric survey has suggested a rapid increase in the number of cluster randomised trials, many of which appeared in the et al. [et al. [British Medical Journal, is valid. Whether we would find a similar improvement in other journals is less certain. It is likely that reporting of cluster randomised trials in the British Medical Journal is especially good, as the journal reports many such trials, has carried many articles on their correct analysis and reporting, has a fairly rigorous statistical refereeing system, [BMJ's current statistical checklist [Identification of cluster allocation is subjective. I included one year, 1998, also searched by Puffer et al.  and iden [et al.  identifi system, -27 and ihecklist  does notThere are still many other aspects of trial reporting where improvement is possible ,12 but tCluster trials have become much more frequent since the mid 1990s. Reporting of these trials has improved and in the journal which publishes more than any other the quality had improved greatly. This improvement has followed a large number of articles advocating methods of analysis which take clustering into account, Perhaps statistician pressure works.British Medical Journal, including articles written for payment.The author has been published frequently in the J. M. Bland is the sole contributor.The pre-publication history for this paper can be accessed here:Papers in the survey List of papers in the survey of the BMJ, Word file.Click here for file


Several family structure-related factors, such as birth order, family size, parental age, and age differences to siblings, have been suggested as risk factors for schizophrenia. We examined how family-structure-related variables modified the risk of schizophrenia in Finnish families with at least one child with schizophrenia born from 1950 to 1976.We used case-sibling design, a variant of the matched case-control design in the analysis. Patients hospitalized for schizophrenia between 1969 and 1996 were identified from the Finnish Hospital Discharge Register, and their families from the Population Register Center. Only families with at least two children  were included in the analysis. Conditional logistic regression with sex, birth cohort, maternal schizophrenia status, and several family-related variables as explanatory variables was used in the case-sibling design. The effect of variables with the same value in each sibship was analyzed using ordinary logistic regression.Having a sibling who was less than five years older , or being the firstborn  predicted an elevated risk, but having siblings who were more than ten years older predicted a lower risk .Several family-structure-related variables were identified as risk factors for schizophrenia. The underlying causative mechanisms are likely to be variable. Several factors relating to family structure have been suggested as risk factors for schizophrenia. They include sibship size, number of older siblings, birth order in the sibship, age difference to older siblings, and age-at-onset, and sex of the affected siblings. These family-related risk factors may provide useful hints about the nature of environmental and genetic risk factors for schizophrenia .In several studies, siblings of female probands have had a higher risk of developing schizophrenia than siblings of male probands in several studies, with the number of cases varying from 123 to 500 . The effThere are mixed results about the effect of birth order on risk. Two studies reported lowest risk for the firstborns ,10, and The number and age of older siblings at the time of birth is hypothesized to be connected to the risk of schizophrenia through infection pressure. In a Swedish register-based study (270 cases), having siblings who were 3–4 years older was associated with increased risk (relative was 2.02) . The DanAll risk factors concerning birth order, family size, number of older or younger siblings, and paternal and maternal age are correlated. For example, the number of older siblings is dependent on both the individual's birth order and family size, which are connected to maternal age. If all these correlated variables are not in the model simultaneously, spurious associations may be found. Therefore, a large, population-based data set that contains a sufficient number of sibships with variable structures is needed to analyze family-related variables. Our aim was to investigate which of these variables were risk factors for schizophrenia in Finland among those who were born between 1950 and 1976.Using the Finnish Hospital Discharge Register of Finland, we obtained information on all hospitalizations with a diagnosis of schizophrenia . The information was sought for all Finns born between 1950 and 1976 for the period between 1969 and 1996. Sibship was defined as a group of individuals having the same mother. Since many of the variables we examined are related to maternal characteristics, we considered it essential that each sibship has the same mother. It should be noticed that generally the mother has a stronger influence on the child than the father especially in early childhood: e.g. mother's womb provides the fetal environment, and after birth the mother has more of a close physical relationship to the child through breast feeding. Siblings and parents of the probands were identified using the data from the Population Register Centre, and their information was then linked back to the Hospital Discharge Register to obtain data on relatives' hospitalizations. Only those who were born between 1950 and 1976 were qualified as probands, but their younger siblings were included in analyses as family members.We assumed our ascertainment was complete, because the two registers used, the Population Register and the Finnish Hospital Discharge Register, are nationwide and accurate . The relAltogether, we identified 17549 sibships with 35481 siblings, of whom 31004 were born between 1950 and 1976. There were 12 siblings in the largest family, and the highest number of cases in one family was six  women. In the 1966 and 1986 Northern Finland birth cohorts, primiparity was a risk factor for having a low birth weight infant and for perinatal mortality . In an eOur results concerning the effect of paternal and maternal age are not comparable to previous studies -18, becaConsistently with a recent meta-analysis , the risOur results showed that the higher was the age-at-onset of the first proband in the family, the lower was the siblings' risk Tables  and 2, wA case-sibling design has some limitations. It can only provide approximate estimates of relative risk. In our analyses only families with two or more siblings were informative, and therefore our results are not applicable to one child families. However, whether matching was taken into account or not did not largely affect the results.Our study was based on a nationwide, representative sample of patients with schizophrenia and their siblings, and our sample size was considerably larger than in any of the previous studies. Register-based information is not as accurate as information based on face-to-face interview, but Finnish registers are quite reliable. The two registers we used, the National Population Register and the National Hospital Discharge Register, are nationwide. The National Hospital Discharge Register covers all public and private hospitals in Finland, and the National Population Register registers all Finnish citizens. However, as information on parents enabling the identification of sibships first appeared in the Population Register only in 1974, sibship data may be more accurate in the younger cohorts. Information in both registers is accurate. Some proportion of siblings of the study population are really half-siblings, but even in this case, the case-sibling design is applicable, because it does not assume that familial aggregation is due to a genetic mechanism. When entries in the National Hospital Discharge Register were compared with data on hospital case notes, the primary diagnosis in the register and hospital case notes was identical in 99 percent of cases for schizophrenia and in 98 percent of cases for all mental disorders -22,37.We investigated concurrently several family-related factors which independently have been suggested to be risk factors for schizophrenia. We were able to verify some of the previous associations, while others were refuted. The risk factors we identified probably have different underlying causative mechanisms. For example, the risk associated with being the firstborn might be explained by increased risk to obstetric complications, while the combination of decreased risk among females but increased risk among siblings of female probands might be explained by genetic factors. The risk factors we identified should be studied further in samples that include more detailed information on possible causative factors, such as infections and obstetric complications.The author(s) declare that they have no competing interests.JH participated in the design of the study, performed the data-analysis and drafted the manuscript. JS participated in the design of the study, and the drafting of the manuscript. JL participated in the design of the study and its coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Unlike salmonellosis with well-known routes of transmission, the epidemiology of campylobacteriosis is still largely unclear. Known risk factors such as ingestion of contaminated food and water, direct contact with infected animals and outdoor swimming could at most only explain half the recorded cases.Campylobacter; 2) the ability of flies to function as mechanical vectors; 3) a ubiquitous presence of the bacteria in the environment; 4) a seasonality of the disease with summer peaks in temperate regions and a more evenly distribution over the year in the tropics; 5) an age pattern for campylobacteriosis in western travellers to the tropics suggesting other routes of transmission than food or water; and finally 6) very few family clusters.We put forward the hypothesis that flies play a more important role in the transmission of the bacteria, than has previously been recognized. Factors supporting this hypothesis are: 1) the low infective dose of Campylobacter infection, we believe it would be unwise to rule out flies as important mechanical vectors also of this disease.All the evidence in favour of the fly hypothesis is circumstantial and there may be alternative explanations to each of the findings supporting the hypothesis. However, in the absence of alternative explanations that could give better clues to the evasive epidemiology of  Campylobacter infection is a zoonotic disease, observed in most parts of the world. The disease is caused by Campylobacter jejuni, or less commonly Campylobacter coli. It is estimated to cause 5–14% of diarrhoea, worldwide [Campylobacter infection has emerged to be the most important bacterial cause of gastrointestinal infection. Animals  are the major reservoir for the bacteria. Campylobacter does not easily grow in food, but the critical infective dose is low [Campylobacter infections, that may coincide with the summer peaks in the temperate regions include direct animal contact, eating barbecued meals, swimming in lakes, and drinking untreated water from streams and other natural sources [e is low . Unlike e is low . Known re is low ,4-6. Dire is low ,5,7,8. I sources . However sources . InsteadMusca domestica) and other muscid flies thrive in excreta and other filth. They could act as mechanical vectors, by carrying bacteria on the hairs and surface of their bodies or on the glandular hairs on their feet, but they could also act as biological vectors by passage through the alimentary tract, where pathogens have opportunity to multiply [E. coli infection [Campylobacter from animals to human food [Campylobacter infection has been largely neglected [The common houseflies , and non typhoidal Salmonella species (105-1010 bacteria). Although less tolerant to desiccation than some other food-borne pathogens [Campylobacter can survive on dry surfaces for at least seven days [The infective dose of bacteria , which iby flies ,12,15, aathogens , Campyloven days , thus enCampylobacter could easily be transmitted from the environment to flies [Campylobacter could also be transmitted from flies to chickens [Campylobacter could be isolated from 4 of 49 (8%) of flies caught outside a broiler house in Denmark. Furthermore, Wright showed that Campylobacter could be isolated from five of 210 (2.4%) living flies, isolated from three different locations [Campylobacter from animals to human food is small. On the contrary, giving the numerous contacts between flies and human food, we find it highly likely that if one out of every 40 flies carries Campylobacter the health hazard would be significant.Studies have shown that to flies ,24, and chickens . In a reocations . From thShigella is a strict human pathogen, while the major source of Campylobacter is the faeces of both humans and animals such as chickens, cattle and pigs, which are often kept in close proximity of humans. Stanley and Jones have previously shown the importance of cattle and sheep farms as reservoirs of Campylobacter [Campylobacter is also common in the droppings from wild birds [Campylobacter spp have been isolated from sewage contaminated water [Campylobacter than Shigella in the close vicinity of humans. Since flies have been shown to be an important mechanical vector of shigellosis, it would be surprising if they could not also be so for campylobacteriosis. Direct transmission from the soil could probably account for some of the cases in children, but less likely for adult cases.lobacter . Campylold birds ,28, and ed water , contamied water  and aquaed water , and in ed water . There aCampylobacter. Some of the recorded association between barbeque and campylobacteriosis could very well be due to contamination of the food by flies, rather than undercooked meat or cross-contaminations, as has previously been postulated. A recent study from the UK has shown a close temporal association between the incidence of campylobacteriosis and fly density [The distinct seasonality in the temperate regions ,5,7,8,33 density . Althoug density ,14. Ther density . Lack ofCampylobacter infection is largely confined to children below the age of two years, and the decreasing incidence thereafter has been attributed to a lasting immunity [Campylobacter was ingestion of contaminated food, one would expect the infection to be relatively evenly distributed among the largely non-immune westerners coming to high prevalence countries. Again we turned to the risk estimates for campylobacteriosis in returning Swedish travellers. While, the incidence pattern in travellers returning from temperate countries closely mimicked the age pattern of indigenous Swedish cases, we noted that among travellers returning from tropical areas of Africa and Asia, the youngest children had twice as high risk as young adults, and more than four times the risk compared to older children [Small children are less able to protect themselves from flies than older children and adults, and are more likely to have their hands on fly-soiled surfaces. In the tropics, the immunity . On the immunity ,36. Thenchildren . This agIf intake of chicken and undercooked meat (or cross-contamination from these food items) was a major route of transmission, clusters of cases within the same family should be common. Instead a striking feature of indigenous campylobacteriosis in Sweden is that the cases (except for in a few larger outbreaks) are solitary. A survey of notification data in one Swedish county over several years showed that it was exceptionally rare that cases shared the same address . InformaCampylobacter infection by fly control, as has previously been done for shigellosis and diarrhoea [Campylobacter sources, e.g. cattle farms, sewage treatment or fowls, should be included in forthcoming case-control studies on campylobacteriosis. This has been a neglected line of questioning so far. More data on the carriage of Campylobacter by flies in different settings where people could be exposed are also needed. An alternative, and more innovative, approach would be to combine information on the likely place/s of infection with data on environmental sources, in analytic studies using geographical information systems (GIS) tools.The fly hypothesis needs to be backed by further experimental and epidemiological studies. The best evidence would be if controlled intervention studies could show an effect on the incidence of iarrhoea -15. SuchCampylobacter infection, we believe it would be unwise to rule out flies as important mechanical vectors also of this disease.All the evidence in favour of the fly hypothesis is circumstantial and there may be alternative explanations to each of the findings supporting the hypothesis. However, in the absence of alternative explanations that could give better clues to the evasive epidemiology of Campylobacter; 2) the ability of flies to function as vectors; 3) a ubiquitous presence of the bacteria in the environment; 4) a seasonality of the disease with summer peaks in temperate regions and a more evenly distribution over the year in the tropics; 5) an age pattern for campylobacteriosis in western travellers to the tropics suggesting other routes of transmission than food or water; and finally 6) very few family clusters. The hypothesis should be further tested with experimental and epidemiological studiesWe put forward the hypothesis that flies play a more important role in the transmission of the bacteria, than has previously been recognized. Factors supporting this hypothesis are: 1) the low infective dose of The author(s) declare that they have no competing interests.Bengt Normann raised the original idea and has studied the (lack of) family clustering. Yvonne Andersson contributed with in depth knowledge of campylobacteriosis. Karl Ekdahl did the literature search, looked into the seasonality and age distribution of the disease in domestic cases and returning travellers, and prepared the first draft of the manuscript. All authors have participated in revising the draft manuscript.The pre-publication history for this paper can be accessed here:


Public satisfaction with policy process influences the legitimacy and acceptance of policies, and conditions the future political process, especially when contending ethical value judgments are involved. On the other hand, public involvement is required if effective policy is to be developed and accepted.Using the data from a large-scale national opinion survey, this study evaluates public appraisal of past government efforts to legalize organ transplant from brain-dead bodies in Japan, and examines the public's intent to participate in future policy.A relatively large percentage of people became aware of the issue when government actions were initiated, and many increasingly formed their own opinions on the policy in question. However, a significant number (43.3%) remained unaware of any legislative efforts, and only 26.3% of those who were aware provided positive appraisals of the policymaking process. Furthermore, a majority of respondents (61.8%) indicated unwillingness to participate in future policy discussions of bioethical issues. Multivariate analysis revealed the following factors are associated with positive appraisals of policy development: greater age; earlier opinion formation; and familiarity with donor cards. Factors associated with likelihood of future participation in policy discussion include younger age, earlier attention to the issue, and knowledge of past government efforts. Those unwilling to participate cited as their reasons that experts are more knowledgeable and that the issues are too complex.Results of an opinion survey in Japan were presented, and a set of factors statistically associated with them were discussed. Further efforts to improve policy making process on bioethical issues are desirable. In Japan, it was not until 1997 that a law was finally enacted to legalize organ transplant from a brain-dead body. Since 1968, when the first heart transplantation from a person declared brain dead was performed, there have been long-standing struggles in Japan for and against this procedure. In addition to many non-governmental institutions and individuals, the Japanese government – both the legislature and administrative bodies – engaged in a variety of efforts for this enactment. A number of factors have been suggested for the prolonged lack of policy in this area: deep public mistrust of the medical profession caused by the 1968 heart transplant; the Japanese culture which still holds traditional Japanese view of death and the body; and the lack of the broad public consensus required as a precondition for a policy . In 1986, the Japan Medical Association formed the Bioethics Discussion Group, a study group of interdisciplinary nature, and in 1988 issued its Final Report, which encouraged brain death legislation to facilitate organ transplantation. With the goal of shaping public opinion, the Japan Organ Transplantation Society sponsored a series of open symposia in 1989. [Period 2]. A group of politicians from the major party started investigating the current situation in other countries, considering possible legislation. Activities of patients' groups reportedly helped shift public attention away from the brain-dead potential donor to the seriously ill person who needs a transplant ,11. At tFinally, in early 1990, more than 30 years after the first transplant, the office of the Prime Minister established a special commission, Provisional Commission for the Study of Brain Death and Organ Transplantation. To encourage public involvement, the Commission held a series of public hearings and town meetings, and issued newsletters. Its 1991 interim and 1992 final reports presented both a majority view and a minority view. The former stated that a social consensus on brain death had already been achieved, and the latter argued that such a consensus had not yet been achieved. Both groups approved organ transplant when the consent of the donor was definitely obtained. A number of scholars argued that it should be a personal decision whether or not one's death is to be determined by brain death criteria, making individual consent the basis of both brain death and organ donation . . In 1999, two years after the law was passed, the first heart transplantation was successfully conducted, at Osaka University Hospital . That saAs was indicated in Figure Our results also indicate that as the number of people approving organ transplants from brain-dead bodies increased, the number of opponents increased in parallel, although in smaller numbers. This increase in political awareness or in political knowledge, as suggested elsewhere , led to As in other countries, the public debates on brain death and organ transplant, both in the private sphere and in the public sphere, were new attempts at governance of socio-technical innovation in the field of biomedicine. If social mobilization is fueled by the inability of the institutional system to respond adequately to public concerns, the issue status in Japan in the 1980s, when many individuals and institutions started to pay attention and get involved in the debate, might indicate insufficient mediation of the actors for conflict resolution (by the government) before and during that period. Generally in post-war Japan, a relatively small number of political and administrative elites have left the handling of many social conflicts to the workings of traditional social relations . SimilarIn the early 1990s when the Ad-hoc Council was set up, the Japanese government introduced a variety of measures to resolve social disputes by inviting the public into policy discussions. Our finding that many people recognized the issue and formed their opinions at times other than this period, however, suggests that these tactics were not very effective in terms of raising public awareness. In European countries, it was reported, public involvement measures served well as focusing devices, which helped attract attention and facilitate discussion among the various public . The difIt is remarkable that more than 40% of respondents were unaware of any past government policy, despite longstanding struggles around the issue and much media coverage. Of those who were aware, about half of them had favorable opinions of government efforts, while a slightly larger percentage had negative views. The fact that only 30% of respondents reported satisfaction indicates that there is much room to improve public awareness, acceptance, and appraisal in the policy process on bioethical issues.Multiple regression analysis disclosed that age, period of opinion formation, and knowledge of donor cards are independent factors affecting public appraisal of past governmental efforts. Individuals tended to give higher appraisal points when they were older. Indeed, age seems to be a major factor in opinion formation on several policy issues . PerhapsA national effort to incorporate ethical considerations into policy rests on an academic reservoir of technical experts, legal scholars and humanists, and on the public understanding of science and its social implications, as well . The proAccording to Taylor and Fiske , people In relation to this point, it should be noted that some changes in the policymaking process were regarded as important. A majority of respondents suggested that better information disclosure and more respect for both patients' and experts' opinions are desirable in the policy process. It follows that more effective involvement of the public, especially those stakeholders, in policymaking is warranted. Although an empirical assessment is not available, some procedures used in France and Germany might merit attention in modeling future policymaking for other countries. The National Consultative Bioethics Committee of France holds an annual public conference where, in addition to an activity report from the Committee, many ethical topics are discussed, with the participation of both experts and laypeople . The GerIn many countries, participation has gained momentum in a variety of policy domains . In healIn our study, a majority of people (61.8%) responded that they would not participate in future policy discussions, while the rest (38.2%) responded that they would. The absence of association between government appraisal and participation intent indicates that the latter is determined by factors other than the former. Multivariate analysis showed that younger age, earlier period of first attention, earlier period of opinion formation, and more knowledge of past governmental efforts are positively associated with the intent to participate in future policy discussions. This indicates that the more attentive members of the public, namely those long-term observers with their own opinions and knowledge of current policy, have more interest and consequently a greater intention to participate in policy discussions. This finding is consistent with past studies indicating that participation is facilitated by policy knowledge and/or political sophistication . PositivReasons cited for being unwilling to participate in the process indicate that many feel unqualified or unknowledgeable but not necessarily too busy or uninterested. Further analysis revealed that older people are more likely to cite "Experts better" and "Ineffective", and are less likely to choose "Busy"; that females are more likely to cite "Difficult", and that people tend to cite "Ineffective" when they are more knowledgeable about past government efforts, while choose "Busy" or "Uninterested" when they are less knowledgeable. These findings suggest that despite their latent interest in the issue, people are unwilling to commit themselves to policy discussions because of their perception of inadequacy stemming both from their lack of knowledge and sense of inefficacy, as judged from past experiences. The absence of an association between appraisal and participation suggests that people might be uncertain about their own competence and efficacy in policymaking. It can be inferred that people hope for a means of understanding the issue, so as to formulate their opinions for themselves.Political participation is facilitated by having a personal stake and perceived self-efficacy in policymaking. Conversely, it could be hampered by both indifference to the issue and a sense of powerlessness . More spIn the context of Japan, it is important to remember that public involvement measures thus far used were not very effective in raising public awareness and that people consider some changes desirable in the policymaking process. It is possible that more people could be inspired to participate by changing the design of public involvement measures, from a consultation type of involvement to a partnership model . EffortsMore innovative methods of public participation show promise and deserve consideration in improving policy process on medico-ethical issues and increasing public satisfaction with policy and politics. These include consensus conferences, citizens' juries, scenario workshops, deliberative opinion polls, among others . DistincAs is always the case with mass opinion surveys, this study cannot escape the possible bias introduced by the low response rates of polls . A samplAmong many topics to be considered for future research is the function of (mass) media vis-à-vis public opinion formation. The media should be examined critically as they influence both experts, policymakers, and the public. Mass media have a dual function in these processes: as a conduit of debates and negotiations as well as a source of influence . Also onGovernment decisions and their outcomes, namely the enactment and subsequent implementation of organ transplants, attracted public attention and helped formulate public opinion on the issue, more than did the processes leading to enactment. In the case of the concept of brain death and the legalization of organ transplant in Japan, many people still were unaware of past government efforts in policymaking, including the measures used for public involvement, despite past longstanding social debates. Only a small percentage of the public indicated satisfaction with the process. However, those who were attentive to the issue, knowledgeable of the past policy process as well as of the current policy, tended to rate the policy process more positively. Although people do not always manifest their intent to participate in future policy discussions, they might maintain sufficient interest in biomedical issues and have a latent wish to get involved in the policy process.The author(s) declare that they have no competing interests.All the authors  fully participated in the planning, designing, and carrying out of the surveys for this study. HS performed the statistical analysis and drafted the article. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Genetic control of drug metabolism was well established by the 1960s, and pharmakokinetic-based individualized therapy was in use by 1973.Adjusting drug therapy to the individual, a common approach in clinical practice, has evolved from 1) dose adjustments based on clinical effects to 2) dose adjustments made in response to drug levels and, more recently, to 3) dose adjustments based on deoxyribonucleic acid (DNA) sequencing of drug-metabolizing enzyme genes, suggesting a slow drug metabolism phenotype. This development dates back to the middle of the 20 Despite tremendous advances in the science and technology of drug development, as well the emergence of guidance and consensus building among scientists, many clinicians, pharmacists, and consumers remain uninformed regarding the scientific basis of establishing bioequivalence, the generic-drug approval process, and the issues related to individualizing therapy in general ,8. The crelative risk reduction [RRR]) of therapy and thereby decrease the treatment's net benefit. Not prescribing an agent will effectively nullify the potential benefit to individuals, and when repeated frequently enough, failure to prescribe the agent will significantly decrease the benefit to the population as a whole. At other times, doctors tend to prescribe a drug more generally than clinical trials dictate. The treatment of a population with lower outcome prevalence (OP) decreases net benefit and may lead to harm. Overdosing may increase treatment-related harm, and underdosing may erode efficacy; both will result in diminished treatment benefits. Finally, noncompliance on the part of the patient may lead to a decrease in efficacy and a requisite decrease in net treatment benefit. If a patient reduces the dose without totally eliminating the drug, the risk of non-dose-related side effects of treatment may remain.Recent information  indicateThe relationship between the terms mentioned above, which govern treatment success, can be expressed mathematically as follows -12:Net Benefit = RRR * OP - HarmThe graphical representation in Figure equivalence/similarity, pharmaceutical equivalence/therapeutic equivalence, and bioequivalence/bioavailability. Problems are further compounded by the increasing use of generic drugs and the interpretation of such terms as prescribability and switchability.The difficulties in drug prescription that are mentioned above are not related to the physicians' training or experience but result instead from difficulties in relying with confidence on label claims of efficacy, safety, and interchangeable use of new drugs "within class." The common denominator among these problems seems to be an insufficiently well crystallized knowledge base regarding the proper use and interpretation of general terms such as Bioavailability (BA) indicates a measurement of the rate and amount of therapeutically active drug that reaches the general circulation and its presumed site of action [f action .Bioequivalence is the absence of a significant difference in the rate at which, and the extent to which, the active ingredients in pharmaceutical equivalents become available at the site of drug action in the body when administered under similar experimental conditions in an appropriately designed study. A product may also be considered bioequivalent to an innovator product if (a) the difference in rate of drug absorption between the two products is intentional and (b) no significant difference is found in the extent of absorption of the two products when they are evaluated under similar experimental conditions -17.Bioequivalence requirement refers to a requirement, imposed by the Food and Drug Administration (FDA), of in vitro and/or in vivo testing of specified drug products that must be satisfied as a condition of marketing [arketing .Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standards of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates [on rates .To be considered pharmaceutically equivalent, two drug products must (a) contain identical amounts of the same active ingredients in the same dosage form, (b) be formulated to meet the same compendial or other applicable standards of quality and purity, and (c) generally be labeled for the same indications. However, pharmaceutical equivalents may differ in the excipients  that they contain, as well as in their shape, scoring, packaging, and in certain circumstances, their labeling .Average bioequivalence involves assessment of pharmacokinetic parameters such as area under the curve (AUC) and peak concentration (Cmax), as well as calculation of a 90% confidence interval for the ratio of the averages of these parameters for the two products that are compared, usually a test product (T) against a reference product (R). The calculated confidence interval should fall within a conventionally established BE limit of 80% to 125% for the ratio of the product averages [averages . The cliSince the implementation of the FDA Bioavailability and Bioequivalence Requirements in 1977, the assessment of bioequivalence has been a subject of continuous debate ,20-22. Tpopulation and individual approaches reflect differences in the objectives of BE testing at various stages of drug development. These differences are embodied in the concepts of prescribability and switchability (interchangeability) [The average BE reflects comparison of population averages and therefore fails to assess the subject-by-formulation interaction variance . In contrast, the newer ability) -22.These concepts underscore the difference between the population and individual bioequivalence approaches. Population bioequivalence assesses total variability of the measure in the population, and it becomes important when physicians are initially prescribing a medication and they need to rely on the average performance of the drug product . In contPrescribability refers to the clinical setting in which a practitioner prescribes a drug product to a patient for the first time. In this setting, the prescriber relies on the understanding that the average performance of the drug product has been well characterized and relates in some definable way to the safety and efficacy information from clinical trials. Switchability refers to the setting in which a practitioner transfers a patient from one drug product to another. This situation arises with generic substitution, as well as with postapproval changes by an innovator or a generic firm in the formulation and/or manufacture of a drug product. Under these circumstances, both the prescriber of the drug and the patient should be assured that the newly administered drug product will yield safety and efficacy comparable to that of the product for which it is being substituted. However, such a switch may, in fact, occur without the patient's or clinician's knowledge, and this concern is addressed in equivalence studies designed to minimize the risk to the patient in both situations.Although average bioequivalence is the recommended parameter for most bioequivalence studies, the current FDA guide titled Statistical Approaches to Establishing Bioequivalence  recommenThe outcomes , can be measured as clinical or surrogate endpoints or as biomarkers. The relationship between exposure and outcomes, expressed as dose- or concentration-response curves that have efficacy and toxicity levels at their extremes, define the optimal dose and the therapeutic window . TheoretThe approach described above is a simplified framework of successive steps to be taken in phases I and II of the development of any drug, with the aim of generating data for drug labeling . The dose regimen of such a new agent, explored and established through phases I and II, is to be demonstrated in phase III as "safe and effective" for the claimed indication. Proper study design and research methodology, as well as appropriate statistical analysis, should be applied to ensure that the drug's effectiveness can be substantiated. Further, the outcome derived from two such randomized clinical trials should document that the estimate of the true treatment effect favors the new drug over the reference drug and that the toxicity of the new agent does not exceed acceptable limits. In other words, a first risk/benefit assessment would favor the new drug.external validity, meaning the extent to which the conclusions of a study would hold true for other persons, in other places and at other times. Examples from most therapeutic areas indicate that approved drugs may not work as expected when applied in broad community populations, in real-world settings, and among diverse practitioners operating under real-world constraints [Having come that far, a question justifiably arises: what logic leads to the conclusion that the new drug is likely to be effective in future patients? That is, are the treatment benefits generalizable to an actual clinical population? The question is extended to straints . In suchempiric confirmation at a conventional α level). However, despite all their methodological rigorousness, these trials may not entirely eliminate factors that influence bioavailability in earlier development stages and internal validity in later-phase studies .Conventionally, the dose-response trials mentioned above, exploring the behavior of biomarkers both cross-sectionally between individuals treated with different doses of an agent, and longitudinally within individuals as doses (or concentrations) change with time, supply the necessary information on the drug's pharmacologic action  -32.• Product-related factors, such as: physical and chemical properties of the drug , as well as variables related to manufacturing, formulation, or both  -33.To control for as many variables as possible, most bioequivalence trials are conducted with healthy volunteers as subjects, ,34,35 ancausal confirmation is much more complex than the empiric confirmation, even if the drug's previously established pharmacologic action is believed to ensure that the drug has the same intrinsic property that alters the clinical outcome – in the RCT patients – in a similar way and to a similar extent as in the previous patients.The A number of other causes, however, may interfere in the conduct phase of an RCT. These causes include• Confounding – a distortion of an association between an exposure and disease brought about by extraneous factors.• Interaction – the interdependent operation of two or more factors that produce an unanticipated effect.• Transience – an idiosyncratic property of a drug that displays its expected pharmacologic property when tested in one batch, but not in others.Many of the specific design and analysis features applied to RCTs  are meant to ensure that the possibility of confounding is minimized or eliminated. The same does not apply in the case of transience or interaction, for which independent evidence is needed to eliminate those possibilities.Drugs that tend to exhibit high degrees of variability in their pharmacokinetic profiles are known to complicate the assessment of bioequivalence ,36,37. TSmall changes in systemic concentration of such drugs can lead to marked changes in pharmacodynamic responses -22. A brA typical drug in this category is warfarin, which is widely used for its anticoagulant properties. For the most part, metabolism of S-warfarin occurs by means of the gene CYP2C9 . InhibitFactors that increase PT ratio or international normalized ratio (INR) response include:Endogenous factors: 11Exogenous factors: 117 specific drugs and 49 different classes of drugsFactors that decrease PT ratio or INR response include:Endogenous factors: 5Exogenous factors: 42 specific drugs and 24 different classes of drugsPhysician surveys have indicated that most clinicians favor more rigid bioequivalence guidelines for these types of drugs . Others Drug products suspected of having bioequivalence problems are listed in the Orange Book  . Such drIn light of serious concerns about risks incurred from using medical products, a variety of public and private agencies involved in health care are dedicating more attention to examining the current system of managing these risks. The main goal is to focus on the costs and value of better data concerning the incidence and causes of injuries from medical products and the roles of all stakeholders in risk management.The FDA has issued a concept paper  presenti• Important risk assessment concepts.• Generation and acquisition of safety data during product development.• Analysis and presentation of safety data in an application for approval.Risk assessment, defined as the process of identifying, estimating, and evaluating the nature and severity of risks associated with a product, should be continuous throughout the life cycle of any product, whereas the process of risk management intervention is intended to enhance the safe use of a product by reducing risk.systemic risk confrontation, the FDA, Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation and Research (CBER) appear ready to develop and finalize, by fall 2004, guidance documents regarding risk assessment, clinical pharmacovigilance, and risk management. Table With regard to the current trend toward Determining the optimal initial dosage regimen (prescribability) and maintaining safety and efficacy outcomes when the regimen is changed in some way (switchability) demand careful decision making in the application of equivalence approaches. These approaches must be applied differently during the three phases of the drug development process, and the knowledge-base that is derived from this process must be transferred to and utilized by physicians and pharmacists to assist them in prescribing and dispensing medicines to patients. Consistent and appropriate management of equivalence approaches supports good assessment, management, and communication about risks associated with a therapeutic product, as expressed in product labeling, as well as in specifications and standards that control the quality of a therapeutic product in the marketplace.


Malnutrition in children can be a consequence of unfavourable socioeconomic conditions. However, some families maintain adequate nutritional status in their children despite living in poverty. The aim of this study was to ascertain whether family-related factors are determinants of stunting in young Mexican children living in extreme poverty, and whether these factors differ between rural or urban contexts.A case-control study was conducted in one rural and one urban extreme poverty level areas in Mexico. Cases comprised stunted children aged between 6 and 23 months. Controls were well-nourished children. Independent variables were defined in five dimensions: family characteristics; family income; household allocation of resources and family organisation; social networks; and child health care. Information was collected from 108 cases and 139 controls in the rural area and from 198 cases and 211 controls in the urban area. Statistical analysis was carried out separately for each area; unconditional multiple logistic regression analyses were performed to obtain the best explanatory model for stunting.In the rural area, a greater risk of stunting was associated with father's occupation as farmer and the presence of family networks for child care. The greatest protective effect was found in children cared for exclusively by their mothers. In the urban area, risk factors for stunting were father with unstable job, presence of small social networks, low rate of attendance to the Well Child Program activities, breast-feeding longer than six months, and two variables within the family characteristics dimension .This study suggests the influence of the family on the nutritional status of children under two years of age living in extreme poverty areas. Factors associated with stunting were different in rural and urban communities.Therefore, developing and implementing health programs to tackle malnutrition should take into account such differences that are consequence of the social, economic, and cultural contexts in which the family lives. Despite improvements in the health of children under five years of age, malnutrition remains as an important public health problem in Mexico  and in oPrevious reports have stated that malnutrition occurs mainly in rural areas and worsens under conditions of extreme poverty ,14,15. IPoverty is not confined to rural areas, nor is malnutrition; they are also present in urban environments . UncontrMalnutrition is an outcome of various factors resulting from unfavourable socioeconomic circumstances such as difficulties in obtaining food, unemployment -which determines an irregular income for the family's breadwinner-, limited access to education and health services, or illness caused by unsanitary conditions ,14,20-24A case-control study was conducted from August through December 1998. Two extreme poverty level areas  were selected. Each area was analysed separately.The study took place in the south-western State of Guerrero, one of the poorest in Mexico, with a population of nearly three million.The rural area, named Alto Balsas, is located next to the Balsas River; the urban area, named El Sinai, is a poor neighbourhood on the outskirts of the port of Acapulco, which has half a million inhabitants. For the rural area, four villages with a combined population of 4,638 were included in the study. The closest city is approximately 45 miles away. The principal language spoken in these villages is Náhuatl, and agriculture is the main economic activity. Because of seasonal conditions there is a high rate of cyclic migration each year. This migration occurs during harvest season, where farmers migrate from the State of Guerrero to another states. There is one medical doctor and one primary care centre per approximately 2300 people.El Sinai is located in the outskirts of Acapulco and has 6,860 inhabitants, most people speak Spanish and they work in the local industry as unskilled manual workers. In this area, there is one medical doctor and one clinic per 3400 people. In both study areas, sanitation and public services are deficient. Table The units of study were children between 6 and 23 months of age. Children older than 6 months were included on the assumption that this is the minimum amount of time the child is exposed to family-related factors; also, this is the average age in which children are weaning (this is defined as the time when mothers begin to introduce food other than milk into the child's diet). Thus infants become more exposed to environmental causes of under-nutrition. The family was defined as next of kin, or persons sharing the same household and food expenses . Only onCases were stunted children. This was ascertained by using the height-for-age indicator . The criControls were children without stunting: equal to or above -2.00 SDs below the median in families that had no stunted children.The sample size was calculated by using the case-control study formula in accordance with the following assumptions  a number of conceptually grounded dimensions that could be associated with stunting.As mentioned earlier, rural and urban environments are different. Regarding the results of the rural area, within the family income dimension, the variable father's occupation (farming) was found to be a risk factor for child's stunting. In this area, availability of food depends upon local production, which in turn is related to father's occupation. Maize is the staple, and there is lack of food variability or inability to produce sufficient food for the family's nutritional requirements .per capita family income, which was statistically significant in the bivariate analysis, did not show significance in the multivariate analysis. This finding could be interpreted as the ability of the family to cope with a difficult environment. Analysis of microeconomic variables shows the need of further studies to confirm plausibility of our findings and its association with malnutrition.In the urban area the instability of the father's employment (working in the same place for less than 2 years) was found to be a risk factor. Lack of stable employment is a common problem among unskilled workers; their income is low and irregular, thus affecting their capacity to purchase goods and food, which in turn affects child nutrition . NeverthThe dimension of family structure, which included socio-demographic characteristics of the parents, migration, and literacy attainment, has been repeatedly associated with the nutritional status of children. ,23,34,35An interesting finding in this study was the relationship between social networks and children's nutritional status. It is often assumed that extended families have extensive social networks, and that this can be advantageous for the care of young children. However, we found quite the opposite in the rural area: the presence of family networks was associated with stunting, while exclusive provision of child-care by the mother showed a protective effect. These findings stress the role of the mother as primary caregiver, at least for young children; such findings also suggest that when a mother is present to care for the child, some of the effects of living in a poor community can be ameliorated.In the urban area, conditions seem to be different, and the sizes of social networks influenced the nutritional status of the children positively. Urban families living in a more aggressive environment might be more likely to obtain health benefits if they have greater family or social support.Use of health services, based on preventive measures from the Well Child Program, was also analyzed. Few visits to the Well Child Program activities were associated with stunting in the urban area. Restricted access to health care services in deprived areas is an important shortcoming with regard to monitoring child's growth and health . Based oMigration was also explored. In the final explanatory model addressing the urban area, parents' migration from rural to urban area was found to be a risk factor for stunting. Migration from rural to urban settings is frequent among young people looking for improving their living conditions. However, families' adaptation to the new situation is a long process, given that such families live in a hostile environment and they have limited access to information regarding how to care for the child. In contrast, migration of one member of the family from one urban setting to another did not show a relationship with nutritional status of children. Adult male family members, mainly the heads of household, migrate to other states in Mexico or to the U.S. in search of better income. Perhaps the influence of this variable could be identified by a qualitative approach. Therefore, further research on this aspect is necessary.The study has some limitations. Firstly, the study groups were of unequal size; this is a consequence of including all children aged from 6 to 23 months of age identified by the census. Additionally, since children of the control group were significantly younger than cases, some of them could have become stunted by the time they were of comparable age to the cases. To solve this limitation, the covariate age was adjusted in the multivariate analysis. However, it is possible that an age-matched cases-control design would have been preferable.Secondly, the fact that almost 25% of eligible children in the rural area were not included due to migration of their families could have led to selection bias.Another limitation is the lack of precise information regarding food practices among participating families. The interview allowed identifying general aspects such as duration of breast-feeding and age of weaning. Breast-feeding beyond 6 months of age entailed a risk of stunting, but only in the urban area. This issue has been controversial; some authors suggest that the relationship between prolonged breast-feeding and malnutrition may indicate a maternal decision to continue breast-feeding to a nutritionally disadvantaged child -39, rathThis study suggests the influence of the family on the nutritional status of children under two years of age living in extreme poverty areas. Factors associated with stunting were different in rural and urban communities.Therefore, developing and implementing health programs to tackle malnutrition should take into account such differences that are consequence of the social, economic, and cultural contexts in which the family lives.The author(s) declare that they have no competing interests.HR and AS conceived, designed and co-ordinated the study. RPC participated in the design of the study, statistical analysis and interpretation of data, and drafted the manuscript. RC co-ordinated the acquisition of data and participated in the statistical analysis. SD collaborated in the data analysis and drafted the manuscript. JIS and GG participated in the conception and design of the study, interpretation of data and critical revision for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


To examine the prevalence of major chronic diseases and their risk factors in different socioeconomic groups in the Australian population, in order to highlight the need for public policy initiatives to reduce socioeconomic inequalities in health.Data were provided by the Australian Bureau of Statistics (ABS) from the 2001 National Health Survey (NHS) for selected chronic diseases and associated risk factors. Conditions selected were those, which form the National Health Priority Area (NHPA) conditions ; plus other 'serious' chronic conditions, in line with the classification developed by Mathers; and for which sufficient cases were available for analysis by socioeconomic status. Indirectly age-standardised prevalence rates were calculated by broad age group for Australia and for five groups of socioeconomic status; rate ratios were calculated to show variations in prevalence between these groups.Significant socioeconomic inequalities were evident for many of the major chronic diseases; the largest was for diabetes mellitus (at ages 25 to 64 years); and for many diseases, there was also a strong, continuous socioeconomic gradient in the rates.Circulatory system diseases  and digestive system diseases also exhibited a strong differential in the 25 to 64 year age group.In the 65 years and over age group, the strongest inequalities were evident for mental and behavioural problems, diabetes (with a continuous socioeconomic gradient in rates) and respiratory system diseases.A number of risk factors for chronic diseases, namely self-reported smoking, alcohol misuse, physical inactivity and excess weight showed a striking association with socioeconomic status, in particular for people who were smokers and those who did not exercise.This analysis shows that the prevalence of chronic disease varies across the socioeconomic gradient for a number of specific diseases, as well as for important disease risk factors. Therefore, any policy interventions to address the impact of chronic disease, at a population level, need to take into account these socioeconomic inequalities. As in other developed countries, chronic diseases in Australia are major contributors to the extent of illness, disability and premature mortality in the population. They are estimated to make up the greatest proportion of the burden of disease, mental problems and injury for the population as a whole (about 80%), and for particular sub-population groups .Chronic diseases are exemplified by having multifactorial aetiologies, including common disease risk factors and determinants; significant latency periods and protracted clinical courses; and are seldom cured completely ,3. CausaThe inequalities in health observed across populations are many – some of them are inevitable and others, unnecessary and unfair. Those inequalities that are potentially avoidable are deemed 'inequitable' . DespiteThere have been a number of studies published in Australia on socioeconomic inequalities in mortality from various chronic diseases and conditions. The earlier ones were analysed using information on occupation recorded on the death certificate -10. An aHowever, to date, there have been fewer studies that have examined socioeconomic inequalities in chronic disease prevalence in those still living  . One of The work of Mathers is significant for its systematic documentation of health inequalities among working aged Australians (25 to 64 years) in the late 1980s. He examined mortality, disability, disease groups, specific diseases, self-perceived health, risk factors, health service use and use of preventive screening services, using data from the 1989–90 National Health Survey (NHS) . MathersCurrent information on inequalities in health other than mortality is limited in Australia because of a dearth of suitable data collections. However, the release of data from the 2001 NHS provides an opportunity to examine the prevalence of self-reported chronic disease in Australia and the way in which this impacts on different socioeconomic groupings within the population.Information for a selection of chronic diseases is shown in Table The main findings are:The largest differential between those in the most well off and those in the most disadvantaged areas was for diabetes mellitus at ages 25 to 64 years, with the prevalence in the most disadvantaged areas being just over two and a quarter times (a rate ratio of 2.28) the prevalence for the least disadvantaged; there is also a strong, continuous gradient in the rates, with the rate ratios in each of the third to fifth quintiles statistically significant.There was a statistically significant differential of 67% at ages 25 to 64 years, with a strong, continuous gradient, in the prevalence of self-reported mental and behavioural problems across the socioeconomic gradient; differentials  in the 0 to 14 year and 65 years and over age groups were 52% and 56%, respectively.Circulatory system diseases  and digestive system diseases also exhibit a strong differential in the 25 to 64 year age group .In the 65 years and over age group, the strongest differentials were evident for mental and behavioural problems , diabetes  and respiratory system disease .Asthma accounted for almost two thirds of the rate of reporting of respiratory system disease in the 0 to 14 year age group, almost half in the 15 to 24 year age group, and for about a third of the rate in the 25 to 64 year age group.The NHS also included data on a number of risk factors for chronic diseases, namely self-reported smoking, alcohol misuse, physical inactivity and excess weight. A number of these risk factors show a striking association with socioeconomic status, in particular for people who are smokers and those who did not exercise, with continuous gradients and highly elevated rates of statistical significance Table . The difIt is important to note that the inequalities reported above relate to the health of those people living in a geographic area and to the overall level of socioeconomic disadvantage of that area. Most areas will contain varying levels of individual socioeconomic disadvantage and, to the extent that the poorer health is associated with individual economic circumstances and living conditions rather than communal environment, the inequalities will understate the true differences in health status according to socioeconomic disadvantage .Furthermore, there are limitations to the use of area-based measures of SES. Due to misclassification error , estimates of difference across the quintiles will be smaller than if data on individual-level measures of SES were used . Thus, cOur analysis indicates that socioeconomic inequalities in the prevalence of chronic diseases and their concomitant risk factors are evident across the Australian population. However, the diseases with substantial disparities across the socioeconomic quintiles are different, for different stages in the life course. Although these results cannot be directly compared with those of previous studies, because of definitional and methodological differences, the recurring finding of inequalities for chronic disease morbidity and risk factor prevalence across the socioeconomic gradient remains a significant concern.The burden in the Australian population attributable to socioeconomic inequality is large, and has far-reaching implications in terms of unnecessary disability and suffering, the loss of potentially economically productive members of society, and increased costs for the health and social care systems . DespiteWhat should we be doing differently? There is a growing body of knowledge that will help to provide direction for developing policies to reduce inequities across the population. The socioeconomic environment is a powerful and potentially modifiable factor, and public policy is a key instrument to improve this environment, particularly in areas such as housing, taxation and social security, work environments, urban design, pollution control, educational achievement, and early childhood development .However, attention must be paid to the nature of any action that is taken, to ensure that social and economic inequalities are not increased. Some programs, by their very success, can increase inequality by widening the gap between groups in the population; for example, such programs may be more attractive to those who are already healthier, or not as effective for certain groups with poorer health, less education or more stressful lives. In one smoking cessation initiative, it was found that the prevalence of smoking decreased predominately in those adults with higher education, thus increasing the existing difference with those who were more disadvantaged . While sIt is also evident that the ways in which systems such as education and health are delivered and structured can increase existing inequality. For example, schooling can be a way of addressing inequality and also a way of reproducing it. It has been suggested that there are two goals for a social justice program in education: to work to eliminate the contribution that the education system makes to the production over time of social inequality in general; and to maximise the positive contributions that the education system makes to reducing social inequality . TherefoPolicy-makers who wish to address socioeconomic inequalities in health may favour one of the following approaches. Some view the impact of socioeconomic disadvantage on those groups with the poorest health in the population, such as Aboriginal people and Torres Strait Islanders, as the priority policy goal. Others identify the gap between the health of those groups at the outer ends of the socioeconomic hierarchy , and see the narrowing of the gap as the goal. Others prefer to focus on the socioeconomic gradient in health that runs across the whole population .Graham has identified that the last approach widens the policy debate in three ways . FirstlyShe also observes that, "improving the health of poor groups and improving their position relative to other groups are necessary elements in a strategy to reduce the socioeconomic gradient. However, neither is sufficient on its own. To reduce the socioeconomic gradient, health in other socioeconomic groups also needs to improve at a faster rate than in the highest socioeconomic group. Thus, policies to ameliorate health disadvantage, to close health gaps and to reduce health gradients need to be pursued together, and not at the expense of each other" .There is also an urgent need to make health inequalities a research priority for each stage of the life course – not just to monitor the size and extent of the disparities but also to undertake research that will find preventive approaches and further policy interventions that will be effective in reducing them, and that are likely to be implemented by governments and communities.Clearly, any moves to address the impact of chronic disease at a population level must take into account socioeconomic inequalities in prevalence. More research is needed to determine which approaches are effective and why others have failed to have the desired impact, particularly for those who are from socioeconomically disadvantaged areas. Finally, although rates are generally highest at the oldest ages, the development of risk factors for many chronic diseases occurs early in life, and thus, it is essential those health inequities are addressed right across the life course.The ABS conducts the National Health Survey (NHS) on a regular basis, most recently in 2001 . The NHSThe survey includes self-reported details of health conditions (both acute and long term) and major risk factors, as well as demographic and socioeconomic information about the survey respondent. Respondents were asked if they had been told by a doctor or nurse that they had asthma, cancer, heart and circulatory conditions, and/or diabetes. These conditions, together with injuries and mental health, form the NHPAs . HoweverThe particular conditions for which data were requested from the ABS for this analysis were:the NHPA conditions ; plus other 'serious' chronic conditions, in line with the classification developed by Mathers ; and forThe risk factors used by the ABS were those identified for the NHPA conditions .The ABS has coded conditions reported by respondents to output disease categories based on ICD-10. Conditions described as 'chronic' in this article include those long-term conditions reported in the NHS, which are commonly recognised by health practitioners as chronic diseases . The risGiven the policy importance of the NHPAs, the 2001 NHS questionnaire underwent significant revisions to more precisely capture information on several of the NHPAs. Consequently, while the quality of the information on NHPAs has been improved from the 1995 NHS, the degree of comparability with previous surveys has been somewhat compromised for many of the major health conditions. Some specific conditions  appear to be comparable between the 1989–90 and 2001 surveys, however, for most groups of conditions based on ICD chapter headings  the ABS advise that the combined effect of major conceptual changes as well as major classification changes between the 1989–90 and 2001 surveys would make direct comparisons very difficult. This analysis is therefore restricted to the 2001 data.The socioeconomic status (SES) of the address of residence of each survey respondent is available at the Census Collection District (CD) level and was added to the NHS file, as was the quintile of socioeconomic disadvantage of area into which that CD fell at the Census. The measure used to allocate CDs to quintiles was the 1996 Census Index of Relative Socio-Economic Disadvantage (IRSD). The IRSD is one of five Socio-Economic Indexes for Areas produced by the ABS using Principal Components Analysis. It summarises information available from variables collected in the 1996 Population Census including those related to education, occupation, and income. The variables are expressed as percentages of the relevant population.The NHS records were aggregated to the quintiles derived from the Census data, where Quintile 1 comprises the CDs with the highest IRSD scores  and Quintile 5 comprises the CDs with the lowest IRSD scores . Each quintile comprises approximately 20% of CDs.The ABS produced the estimates of the number of people with chronic diseases and risk factors by quintile. The method used resulted in the production of quintiles of varying sizes, ranging from 17.4% of the population in Quintile 5 (most disadvantaged areas) to 22.8% in Quintile 2 and 21.1% in Quintile 1 (most advantaged areas). This is a differential of over five percentage points between Quintile 5 and Quintile 2, or 1,027,030 fewer people in the most disadvantaged areas when compared with Quintile 2 . The effect of this lack of precision on the results by quintile is not known. Although, in part, the difference arises as a result of the method used , it may also reflect different response rates to the survey from different socioeconomic groups.The NHS includes other measures that could potentially be used to measure socioeconomic status. For example, income reporting in ABS surveys is known to be incomplete, in particular for low income groups and, in the 2001 NHS, income was only collected for the respondent and their spouse. Information on education is also available, but a single measure has yet to be agreed. Problems in using education include that it is typically completed early in adulthood; it captures neither differential on-the-job training and other career investments made by individuals with similar levels of formal schooling, nor the volatility in economic status during adulthood that has been shown to have adverse implications for health . The ageChronic disease and risk factor rates are expressed as rates per 100,000 population, indirectly age-standardised. The rates were also calculated by age although, given the small sample size of the NHS, only broad age groups  were available. The standard population and quintile populations are the weighted 2001 survey populations from the NHS. The extent of any differential between the quintiles is shown by the rate ratio, which expresses the ratio of the rate in each quintile to the rate in Quintile 1 .The author(s) declare that they have no competing interests.JG conceived the study, and was responsible for its design and coordination. ST participated in the design of the study and performed the statistical analysis. DH participated in the drafting of the manuscript. All authors read and approved the final manuscript.