The state of the HIV epidemic in the Philippines has been described as "low and slow", which is in stark contrast to many other countries in the region. A review of the conditions for HIV spread in the Philippines is necessary.We evaluated the current epidemiology, trends in behaviour and public health response in the Philippines to identify factors that could account for the current HIV epidemic, as well as to review conditions that may be of concern for facilitating an emerging epidemic.The past control of HIV in the Philippines cannot be attributed to any single factor, nor is it necessarily a result of the actions of the Filipino government or other stakeholders. Likely reasons for the epidemic's slow development include: the country's geography is complicated; injecting drug use is relatively uncommon; a culture of sexual conservatism exists; sex workers tend to have few clients; anal sex is relatively uncommon; and circumcision rates are relatively high.In contrast, there are numerous factors suggesting that HIV is increasing and ready to emerge at high rates, including: the lowest documented rates of condom use in Asia; increasing casual sexual activity; returning overseas Filipino workers from high-prevalence settings; widespread misconceptions about HIV/AIDS; and high needle-sharing rates among injecting drug users.There was a three-fold increase in the rate of HIV diagnoses in the Philippines between 2003 and 2008, and this has continued over the past year. HIV diagnoses rates have noticeably increased among men, particularly among bisexual and homosexual men (114% and 214% respective increases over 2003-2008). The average age of diagnosis has also significantly decreased, from approximately 36 to 29 years.Young adults, men who have sex with men, commercial sex workers, injecting drug users, overseas Filipino workers, and the sexual partners of people in these groups are particularly vulnerable to HIV infection. There is no guarantee that a large HIV epidemic will be avoided in the near future. Indeed, an expanding HIV epidemic is likely to be only a matter of time as the components for such an epidemic are already present in the Philippines. Southeast Asia is experiencing numerous and diverse HIV epidemics that are evolving at varying rates, in different population groups, and in different geographical areas. Approximately 5 to 10 million people are living with HIV in Asia, with prevalence estimates of well over 1% among adults in numerous countries [The Philippines is one of the exceptional countries that has not faced a large HIV epidemic. It is important to understand the reasons for the disparate nature of HIV in this country in order to ascertain whether lessons can be learnt for effective control in other settings and to ensure that a large HIV epidemic does not emerge in the Philippines. The first recorded case of HIV infection in the Philippines was in 1984 -10. SincThe geography of the Philippines may be one of the first reasons for the slow spread of HIV. The Philippines is an archipelago of more than 7000 islands and islets; its complicated geography and separateness from mainland Asia could aid in shielding it from the larger regional epidemic ,9,12,13.Additionally, the initial core group of people usually affected with HIV in Asian epidemics is not present to a large extent in the Philippines. Most HIV epidemics in southeast Asian settings initially establish among injecting drug users (IDUs) . HoweverThere also exists a culture of relative sexual conservatism in the Philippines ,17. TherThe limited reporting available from behavioural surveillance conducted a number of years ago suggests that Filipinos tend to have fewer sexual partners than their counterparts in countries with higher HIV/AIDS rates . For exaHowever, fewer sexual partners is not necessarily a clear indicator of a smaller epidemic as reflected in China's expanding HIV epidemic despite reported sexual partner acquisition rates being similarly low . One couThere has also been the establishment of social hygiene clinics to allow for regular examination and sexually transmitted infection (STI) treatment for establishment-based female sex workers ,15,22. TSome countries, such as Vietnam, Indonesia and Papua New Guinea, have shown that a delayed HIV epidemic is possible ,30. WhilThe Philippines has the lowest documented rates of condom use in Asia ,32, at 2There are various factors that may contribute to low condom use in the Philippines. A common perception is that condoms are only for birth control and not for protection against HIV and other STIs . This peThe cost of condoms is also relatively high . The majThere is anecdotal evidence among numerous media sources and organizational reports that casual sexual activity, particularly among the male population aged 15-25, has been increasing. A study from over a decade ago estimated that 55% of young men have engaged in premarital sex compared with 23% of young women . While mHowever, all of this evidence is based on relatively old data. There is a great need for behavioural surveillance data to be collected and reported systematically and regularly in order to monitor risk activities, particularly around casual sex, associated with transmission.The most recent estimates of the size of the IDU population in the Philippines suggests that the number is relatively low . HoweverA 2004 report by the Philippines National AIDS Council estimated that only 48% of IDUs reported using sterile injecting equipment the last time they injected, and most IDUs reported that they regularly share injecting equipment . A 2008 There are approximately 7.5 million Filipinos working in 170 countries around the world, with more than 2000 workers departing from the country daily ,42. By pOf all the HIV/AIDS cases reported in the Philippines, OFWs account for ~30-35% of all cases (this level has remained relatively steady over the past decade) ,32. HeteEven though awareness of the disease is high , misconcWomen in the Philippines are not largely empowered to protect themselves and negotiate for safe sex due to cultural, physiological and socio-economic factors. An estimated 43% of women have admitted to being forced into sex, and 15% believed that they were obligated to have sex with their partners [Condom use is also low among the population of men who have sex with men (MSM) ,6. UnproIn this section, we present HIV/AIDS surveillance data in the Philippines and analytical findings based on monthly diagnoses reported from March 2003 to June 2008 . There iHowever, the trends in HIV notifications differ between the genders. The cumulative number of HIV notifications among females has been increasing at a steady rate (p < 0.0001), suggesting that incidence is approximately constant and at an endemic equilibrium. In contrast, the trend among males is not constant, incidence levels are substantially greater than in females, and the rate of new notifications is increasing (evidenced by the curvature away from linear). This suggests that there may be an emerging HIV epidemic among Filipino MSM.The emergence of an increasing HIV epidemic in the Philippines is evident from trends in monthly reported HIV diagnoses Figure . In mid-However, the divergence in HIV diagnosis rates between men and women could also reflect possible differences in testing rates. There are no data to suggest differences in testing rates, and the Philippine AIDS Prevention and Control Act of 1998 encourages HIV testing of all individuals at high risk of contracting HIV, with informed consent . But thiDiagnoses of HIV in the Philippines are notified according to various categories of likely route of exposure. These include: heterosexual contact; male homosexual contact; bisexual contact; blood transfusion; injecting drug use; needle prick injury; or perinatal exposure. Bisexual contact refers to men who have had sex with both men and women. It cannot be determined whether the initial actual transmission event was male-to-male sexual contact or transmission from an infected woman. It is more likely that the transmission was via male-to-male sexual contact due to biologically higher transmission rates, but the bisexual category accurately reflects a degree of uncertainty in the route of exposure.The dominant mode of HIV transmission in the Philippines is sexual (~92%). But the largest increases in the rate of new HIV notifications are due to homosexual and bisexual contact, and not heterosexual contact Figure . Over thIt should be noted that some of the rise in HIV diagnoses could be attributable to an increase in testing rates. This is evident by the decreasing proportion of all HIV cases that are detected with AIDS disease: ~33% of diagnoses in 2003 were in AIDS stage disease and this has decreased to ~24%. However, the disproportionate trend in diagnoses between genders and between different routes of exposure strongly suggests that the trends in diagnoses reflect actual trends in population incidence. But since a substantial proportion of infections is detected in late-stage disease, it is likely that the majority of all HIV cases are currently undiagnosed in the Philippines .The cumulative number of AIDS deaths is increasing approximately constantly (p < 0.0001), suggesting that AIDS death rates are relatively constant Figure . It coulAIDS is now a reversible HIV-related condition due to combination antiretroviral therapy (ART). The number of people receiving ART in the Philippines has been increasing since 2004, with a rate of approximately 10% of diagnosed cases receiving treatment in 2006, and ART coverage has now increased to approximately 30% . But thith AIDS Medium Term Plan and its country report for the period, January 2006 to December 2007, to the United Nations General Assembly Special Sessions (UNGASS) states that it will endeavour to improve access to treatment, care and support to HIV-infected persons [One of the reasons for such low rates of ART is that funding for such care and treatment of HIV-infected persons makes up a mere 1.6% of the Philippines HIV/AIDS budget . While e persons ,21. Trea persons -59.The average age at HIV diagnosis in the Philippines was ~35-36 years prior to 2005, but recently, the average age at diagnosis has been decreasing (p = 0.0067)  was created in 1992 to act as an advisory body to the President for the development of policy for the control of AIDS. The PNAC consists of members from the government, public, civil society, private sector and non-governmental organizations (NGOs), and is the central advisory, planning and policy-making body for the comprehensive and integrated HIV/AIDS prevention and control programme . But itsThe official response of the Philippines Government to the HIV threat was to enact the Philippine AIDS Prevention and Control Act of 1998 (Republic Act No. 8504) . This AcWhile the Act is a step in the right direction, it is far from effective due to a lack of monetary commitment from the government, relying heavily on NGOs for funding for HIV/AIDS education and prevention programmes, and the current government's seemingly unwilling attitude to promote wide condom use for fear of angering the Roman Catholic Church . Its staOther programmes have also been established for monitoring the spread, understanding key epidemic drivers and planning the control of HIV in the Philippines. There are currently four types of surveillance systems in place in the Philippines:1. The HIV/AIDS Registry was established in 1987 and is a passive surveillance system. It continuously records Western Blot-confirmed HIV cases reported by hospitals, laboratories, blood banks and clinics that are accredited by the Department of Health.2. The HIV Sentinel Surveillance System (HSSS) was established in 1993 with a grant from the USAgency for International Development (USAID). It monitors 10 key cities: Baguio City, Angeles City, Iloilo City, Zamboanga City, Pasay City, Quezon City, Cebu City, Cagayan de Oro City, Davao City and General Santos City. It pays particular attention to establishment-based female sex workers, freelance female sex workers, MSM and IDUs ,32.3. Behavioral Sentinel Surveillance was added at the 10 HSSS sites in 1997 and is a systematic and repeated cross-sectional survey of behaviour related to the transmission of HIV and other STIs ,62. Its 4. The Sentinel STI Etiologic Surveillance System was set up in December 2001, but made operational in 2003. It monitors STI trends that could guide programme interventions to prevent the transmission of HIV.These surveillance systems have been monitoring the progress of HIV in the Philippines and have provided valuable data to inform appropriate response measures.th AIDS Medium Term Plan for 2005 to 2010 is one of the plans that utilized data from the surveillance systems [The PNAC's 4 systems . This plThe current state of HIV in the Philippines is not attributable to any one factor. While the Philippines response is associated with effectively controlled levels of HIV, there is no guarantee that a large HIV epidemic will be avoided in the near future. Indeed, an expanding HIV epidemic is likely to be only a matter of time as the components for such an epidemic are already present in the Philippines.Mathematical modelling studies have shown that even in countries where overall HIV prevalence has remained relatively low , moderate changes in behaviour or HIV infections could initiate a large epidemic that may otherwise have taken numerous decades to develop ,64. CurrThe current behavioural, social and epidemiological conditions suggest that an HIV epidemic in the Philippines may be unavoidable in the near future. The number of diagnoses is increasing, particularly due to homosexual and bisexual contact; there are low condom-use rates; and the age at diagnosis is decreasing. The underlying cause of these symptoms needs to be addressed in order to prevent an emergent epidemic. The promotion of HIV prevention and education messages is underfunded and has been relatively ineffective. It is recommended that more investment be made into these programmes in order to maintain the "low and slow" development of HIV in the Philippines.The authors declare that they have no competing interests.ACF conducted the extensive literature search, collated available data, produced the figures and wrote the first draft of the manuscript. DPW conceived and supervised the review project and contributed to the writing of the manuscript. Both authors read and approved the final manuscript.


Evaluating complex interventions in health services faces various difficulties, such as making practice changes and costs. Ways to increase research capacity and decrease costs include making research an integral part of health services and using routine data to judge outcomes. The purpose of this article is to report the feasibility of a pilot trial relying solely on routinely collected register data and being based on ordinary health services.The example intervention was education to public health nurses (PHN) (childbirth classes) to reduce caesarean section rates via pre-delivery considerations of pregnant women. 20 maternity health centers (MHC) were paired and of each 10 pairs, one MHC was randomly allocated to an intervention group and the other to a control; 8 pairs with successful intervention were used in the analyses (1601 mothers). The women visiting to the study maternity centers were identified from the Customer Register of Helsinki City. A list of the study women was made using the mother's personal identification number, visit date, the maternity center code, birth date and gestation length. The mode of delivery and health outcomes were retrieved from the Finnish Medical Birth Register (MBR). Process data of the intervention are based on observations, written feedback and questionnaires from PHNs, and project correspondence.It took almost two years to establish how to obtain permissions and to actually obtain it for the trial. Obtaining permissions for the customer and outcome data and register linkages was unproblematic and the cluster randomization provided comparable groups. The intervention did not succeed well. Had the main aim of the trial been to cause a change in PHNs behavior, we would have very likely intensified the intervention during the trial.Our experiences encourage the use of trials that obtain their outcomes from registers. Changing the behavior of ordinary health service providers is a challenging intervention.not registered (see Results) Trials are common in evaluating simple health care interventions that have commercial interests, such as drug therapy, but not in the case of trials involving more complex interventions or technologies with no commercial benefits. Obstacles to complex trials include a difficulty to make experimental practice changes, ideological resistance to or ignorance of trials, unknown levels of generalizability, and costs. Ways to increase research capacity and decrease costs include making research an integral part of health services, rather than a separate task to be paid for by researchers, and using routine data to judge outcomes. Collecting outcome data from routine administrative registers may notably reduce costs  and alloRegisters with personal identification numbers have been widely used in non-experimental health and health service research ,3,4, andLike in other Nordic countries, national health registers using personal identification numbers and having complete coverage and good quality are numerous in Finland ; additioThe purpose of this study was to pilot the feasibility of a trial relying solely on routinely collected register data and being based on ordinary health services in the field of maternity care. The example intervention was the further training of public health nurses on prenatal childbirth education to pregnant women  to reduce caesarean section rates via pre-delivery considerations by pregnant women.The purpose of this paper is to report the experiences of doing such a health services and register based trial. Furthermore, we briefly describe the impact of the intervention on cesarean section rates.The trial context is given in the Appendix.The trial used matched-pair design. At the time of the study (2002–2003) there were seven health areas in Helsinki city, divided into 32 health stations, each including at least one maternity health centre (MHC). All 20 MHCs in four health areas (three areas did not participate due to other development projects) were paired using the delivery hospital (HUH or CH) and the way of organizing childbirth classes  as primary matching criteria. Additional matching criteria included the size of the MHC, number of women per PHN, and the proportion of pregnant women aged over 34 in 2001. The characteristics of MHCs were obtained from an e-mail survey to the nurse managers of the health stations. One of each of the 10 pairs was randomly allocated to an intervention group and the other to a control group on the throw of a dice. There were 67 PHNs in the intervention and 70 PHNs in the control MHCs.In addition to our survey to nurse mangers and the PHN survey (see below) in 2002, statistical data of the intervention and control MCHs were available from an unpublished quality measurement report of Helsinki health center in 1999. Based on these data sources, the intervention and control MCHs were similar in regard to type of personnel  and the main delivery hospital. The control MCHs were, as a mean somewhat larger, measured by the mean number of PHNs per MCH (6.1 and 8.2 in 2002) and the mean number of births per MCH (163 and 200 in 2002). However, the number of mothers per PHN was higher in the intervention PHNs (mean births 34 and 26 in 1999).The intervention was the further training of PHNs to pay more attention to the mode of delivery in childbirth classes and informational material given to the pregnant women. The intervention consisted of: a) a joint educational session (1.5–2 hours) to all PHNs in the MHC, given by an experienced midwifery teacher (KH) using instructional conversation in small groups; b) a leaflet on childbirth and preparation for it, which PHNs were asked to give to the pregnant women and to discuss its contents both during childbirth classes and other visits from week 32 onwards, c) a file of evidence-based research material on the same topics for each MHC, d) a questionnaire to PHNs on their opinions and knowledge of childbirth to be filled before the educational sessions. All these four items dealt with the benefits of vaginal delivery, the reasons for and consequences of caesarean section, and the possibilities of pregnant women to influence the mode of delivery.Description of the intervention process is based on observation notes, written feedback from PHNs, PHN questionnaires (60% response rate) and project correspondence. The difficulties encountered with organizing educational sessions to PHNs (see Results) were reflected on and the causes discussed and noted during the study. Six months after the intervention a questionnaire with semi-structured questions was given (by KH) to all PHNs in the control and intervention MHCs during their ordinary staff meetings; 54% of the intervention PHNs responded. In addition to this questionnaire, the success of the intervention was judged by observations made during the educational sessions; notes of the sessions and the feedback given were written down immediately after each session.We aimed to obtain a supportive statement from a research ethics committee acceptable to Helsinki city health services and registry owners. The difficulties encountered with ethics committees (see Results) were noted during the study.The hours taken to set up the trial and to get the data were estimated (partly from working time records), and changed into euros using each researcher's salaries multiplied by 1.3 ; institutional costs were not included. Costs not taken into account included the costs of planning the scientific content, of familiarization within the field situation, of carrying out the intervention , or the time spent by PHNs in the new childbirth classes.To identify the intervention and control mothers, visits to the study maternity centers in the intervention period from May to December 2002 and also for 6 months after that were obtained from the Helsinki City Customer Register, run by a commercial company (WM-data NOVO), and linked to the Finnish Birth Register (MBR), Figure The customer register includes the service unit name, the date, and patient's personal identification number. A list of women having visited the maternity centers during the study in gestation weeks 28–32 period was made using the mother's personal identification number, visit date, the maternity center code, birth date (MBR), and gestation length (MBR). Childbirth classes are usually given around 28–32 weeks of gestation.No sample size calculations were made because this study was a pilot testing the feasibility of the study design and the strength of the intervention. Because the intervention did not succeed well (see Results), no power calculations were made even later. The background characteristics of the mothers and outcomes in the intervention and control groups were first compared by cross-tabulation, and the statistical significance of the differences were tested by Chi-square and t-tests.The mode of delivery and other outcomes were retrieved from MBR. The odd-ratios of the delivery interventions and infant health outcomes were calculated by logistic regression, adjusting for the differing background characteristic . Our plan was to compare the groups, besides by simple logistic regression, by multilevel logistic regression to accommodate the cluster effect. However, because the intervention did not succeed (see Results), only basic outcome data were analyzed and cluster effect was not taken into account.It took almost two years from the beginning of the negotiations to establish how to get permissions for the trial and then getting them. Finland had new legislation relating to ethics committees in 1999 requiring "medical" research to be approved by a "certified" ethics committee. However, for interventions like ours it was not clear whether it was medical research as legally defined, other health research or developing health care, and what kinds of permission were required. After several discussions and meetings between the body coordinating research activities within Helsinki City health services (TUTKA), city health planners, and the people responsible for developing prenatal care in April–November 2000, we submitted our study to the Hospital District of Helsinki coordinating ethics committee in December 2000; Helsinki City no longer had an ethics committee of its own. Because the primary health care ethics committee had not been established, the coordinating committee transferred our application to the gynecology and obstetrics committee within the Helsinki University. That committee twice asked for clarifications, mainly on the education content and the people involved in the research, but did not give a decision.After eight months, TUTKA, on our plea, decided that the project (not including data collection) is development work and no ethics committee statement is required. After four months (in January 2002) permission to carry out the intervention in four out of seven health areas was given by the City Health Director.The research part of the project was handled and approved by STAKES research ethics committee . Applying for and obtaining permission for the customer and outcome data (MBR), and obtaining an ethics committee statement went without problems.The City health administration (chief nurse manager) helped to contact the nurse managers responsible for PHN work in the MHCs, and a presentation in their monthly meeting was given. The responses varied among the nurse managers to our requests to meet the PHNs, to give an educational session and to distribute the material. Even though all agreed that the development of childbirth classes is important, many complained of too many development projects and too many studies being carried out in MHCs.Two MHCs did not want to take part in the intervention, mainly due to lack of time. They and their pairs were excluded from the analyses, leaving 16 health centers (8 pairs). The responses of PHNs in the educational sessions varied. Only 40 of the 67 intervention PHNs attended the education; other PHNs had conflicting appointments or were off work; some temporary staff did not attend either. Based on observations as well as on the answers given in the PHN questionnaires, our interpretation is that most PHNs were in principle interested in childbirth classes, but the classes were not the priority among the many tasks they had been given and needing their attention. They thought that caesarean sections and other surgical deliveries were hospital obstetricians' decisions and that pregnant women were advised and consulted by delivery hospital staff.The city health services and data keepers were sympathetic to our requests to identify the study women. Carrying out the register linkages were easy in principle , but the change in the data system in the Customer Register during the study period resulted in technical complexity and extra work. We calculated that following hours were used: negotiations with the city health administration 66, application for and negotiations with the Customer Register 18, applications for and negotiations with the hospital ethics committee 27 and STAKES ethics committee 21, data extraction from the Medical Birth register 4, data linkages and quality checks 42, total 178 hours. We do not know the number of hours used to extract the data from the Customer Register, but the bill was 1862 euros,In total 1601 mothers had visited the 16 study MHCs  at 28–32 gestation weeks during the study period  than in the control maternity centers (12% of 219 women), OR 1.23 (95% CI 0.71–2.11), but the difference was not statistically significant.Pregnancy care, delivery hospital, and pregnancy length were similar in the two groups. The distribution of the delivery hospitals was the same in the two groups . The mean birth weights were very similar.Caesarean sections were somewhat more common in the intervention group, but not statistically significant, Table When only the first-time mothers were included, results similar to those of all women were obtained. The difference in caesarean section rates was not statistically significant .In this trial, the feasibility of obtaining outcome data was shown to be unproblematic and could be easily and economically obtained from existing registers. To identify the trial subjects we used a register which had not previously been used for such a purpose, and some extra work resulted from the novelty. Future trials would very likely be easier. The intervention based on health care services turned out to be weak.A strength of the study was that it evaluated the use of routine data in a real trial. Furthermore, the process data were prospectively collected as part of the study. Record linkages and other IT work were done by experienced personnel. Thus our study – even though the first of its kind in Finland using Medical Birth Register and Helsinki Customer register – gives a realistic estimate of the work load if health registers were routinely used as a data source.However, the resource estimates were somewhat arbitrary and we had no comparison, i.e. what the costs would have been if we had identified the women, approached them, and collected the outcome data either directly from them or from patient records. However, our experience from traditional trials suggests that the outcome collection costs in this study were small. We limited the estimation of the used resources narrowly, because we wanted to study whether the costs of data collection and setting up a trial could be made cheaper. These results are more generalisable than intervention costs, which are always bound to the type of intervention. But separating the "trial set up" and "intervention" costs was difficult: a mapping of the situation and negotiations could serve both elements.The number of hours used for planning data collection, and negotiating and getting permission was reasonable. How applicable are these results to other countries or other types of trials? Because the rules governing research and salaries vary, the costs may not be directly transferable to other countries. However, the magnitude, the costs being notably smaller than if data had been collected in a traditional way, e.g. from patient records, is likely to be true also in other countries having registers suitable for research. In our example, only two relatively simple registers were used. The use of more complex or just more registers would likely lead to higher costs.The possibility to use registers depends on their existence, content, and availability. In Finland, all citizens have a unique personal identification number (ID-number), there are numerous health registers, and well-developed data protection laws allow research to be made in a controlled and ethical manner . The comHowever, the kinds of outcomes which are available from the birth register are limited, and no subjective data, such as satisfaction, are collected. This limitation is likely to remain, because adding subjective information into routine registers – even though technically easy – is likely to limit register use in research, as requirements for written informed consent may become a prerequisite.In principle, registers and other routinely collected data can be used to measure outcomes both in traditional "on invitation" trials and trials based on ordinary health services. In the former, if that possibility is thought through ahead of time and informed consent requested, registers are a useful data source, providing follow-up data of all participants without recall, selection, or participation bias . HoweverTrials based on routine health services, i.e. where it is prospectively decided to provide services differently to similar patients , are much rarer than trials based on invitation and informed consent. In trials based on routine health services, outcome measurement from routinely collected data may be the best or only feasible method. If such trials become popular, as we think they should, it is likely to put further pressure on the need for good data protection laws and the quality of registers.The intervention part of our trial was, after long deliberation, defined by the research governance system to be "developing work" rather than "research"; only the data collection part was defined as research. These definitions had a crucial impact on feasibility. The current Finnish research regulation is unclear in terms of health-services-based research, complex interventions, and cluster randomization, and research ethics committees have difficulties in applying the regulation . That ouOur original idea of the intervention was stimulated with a suggestion that information to women might contribute to appropriate CS rates  as well The intervention – education of public health nurses (PHN) to empower women to avoid caesarean sections with relative indications – did not succeed very well. We noticed that the intervention was weak already during its implementation. Had the main aim of the trial been to cause a change in PHNs behavior, we would very likely have intensified the intervention, for example, by further educational sessions or discussions with PHNs and their supervising general practitioners, as well as closer collaboration with the delivery hospital personnel. Because the intervention was weak, an impact on outcomes was unlikely.Why did the intervention remain weak? One reason may be that Helsinki PHNs do not consider delivery as their area of expertise, but that of hospitals. Due to the multitask work , some PHThis may describe the likely scenario more generally: bringing systematic and selective changes in the way services are provided so as to enable reliable evaluation is the difficult part, while measuring the impact from routine data is perhaps easier. The content of and the way in which health services are provided is an amalgamation of tradition, research results, interest-group influence, politics and costs. Making changes which researchers would like to see happen requires both health professional and political support. After such support is given, a randomized introduction may not be feasible, because decision-makers are eager to have the new service provision to all units. This may be the case even when a totally new service is launched, and even more so when existing services are modified. Differing and untested technologies and services can be used as long as their use is individually decided by professionals or patients. But the systematic offering of different services to allow proper comparison is not yet customary and hindered by current practices of research and service regulation .Our experiences are encouraging for the use of trials designed to obtain their data from registers, though research ethical rules need to be clarified. If the intervention is based on changing the behavior of either the service provider or patients/people, the difficulties in implementing these changes, and then only in the intervention group, are likely to remain a challenge.Trial context and the importance of the intervention.The trial was carried out in maternity health centers (MHC) in Helsinki, Finland. These health centers provide prenatal care as part of primary health care. Services are organized by areas, but if a woman moves during pregnancy, she can visit the maternity center of her old area. Delivery care is a part of specialized obstetric hospital care. Most births occur in the two maternity hospitals . The delivery hospital is determined by the woman's place of residence, but complicated cases are referred to HUH. Women can also apply for hospitals outside Helsinki.Prenatal care is run by public health nurses (PHN), formally supervised by general practitioners. Most prenatal care providers were solely PHNs, but some had also specialized in midwifery. Both PHNs and midwives  are well educated, with 3.5–5 years of education after high school. Traditionally, preparation for birth has been an important task of PHNs. The organizational separation of delivery and prenatal care and the scant education of younger PHNs in delivery care have, however, resulted in ambiguity. In Helsinki, the volume and content of childbirth classes varies by MHCs, and an internal document by City of Helsinki Health Centre in 2001 on prenatal care called for high-standard, uniform childbirth classes. Caesarean section rates in Helsinki have been much higher than in Finland on average, with internal hospital scrutiny being focused on the matter in recent years. Thus, there was an interest within the city's health administration in the substance of our trial.The authors declare that they have no competing interests.EH designed the study and wrote the first draft. KH did the intervention and collected the qualitative data of the trial process. TS did the register linkages and analyses. PK supervised the intervention and participated in writing the qualitative part of the manuscript. All authors read, commented and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Correction to: British Journal of Cancer (2003) 88, 1025–1031. doi: 10.1038/sj.bjc.6600831The authors have recently notified us of an error in the above paper. It had come to their attention that, due to a coding error, a number of patients who received chemotherapy or radiotherapy were misclassified as having no treatment. The proportions of patients receiving any chemotherapy, radiotherapy and any active treatment were too low as reported. The median percentage and range of patients receiving different treatments within the health authorities are shown below in the revised In the revised analyses, there was still evidence of health authority level variation in treatment and survival similar to that shown in Figure 1. The associations of area and health service characteristics are shown in the revised The main conclusion of the paper that there is significant geographical variation in the treatment of lung cancer, which may be associated with differential access to oncology services, is still supported.


Effective and timely case management remains one of the fundamental pillars for control of malaria. Tanzania introduced artemisinin-combination therapy [ACT] for uncomplicated malaria; however, the policy change is challenged by limited availability of ACTs due to high cost. This study aimed to determine factors influencing prompt access to ACTs among febrile children in rural Kilosa, Tanzania.In a community-based study, 1,235 randomly selected children under five were followed up weekly for six months, in 2008. Using a structured questionnaire, children's caretakers were asked about the child's febrile history in the last seven days, and treatment actions including timing, medicines used and source of care. Caretakers' knowledge about malaria and socioeconomic and demographic data were also obtained. About half of followed-up children had at least one episode of fever. Less than half (44.8%) of febrile children were taken to government facilities. Almost one-third  of febrile children had prompt access to ACT. Care-seeking from a government facility was the overriding factor, increasing the likelihood of prompt access to an ACT 18 times . Caretakers from the better-off household (3rd–5th quintiles) were more likely to seek care from government facilities . The majority of antimalarials accessed by the poor were ineffective , however, they paid more for them (median Tsh 500) compared to the better-offs (median Tsh 0).Prompt access to ACT among febrile children was unacceptably low, due mainly to limited availability of subsidised ACT at the location where most caretakers sought care. There is urgent need to accelerate implementation of strategies that will ensure availability of ACT at an affordable price in remote rural areas, where the burden of malaria is highest. Effective malaria case management, that is, early diagnosis and prompt treatment of malaria patients, remain to be one of the fundamental pillars of malaria control measures. The current advocated global targets include achievement, by 2010, of universal coverage of all malaria patients diagnosed and treated with effective antimalarial medicines within one day of the onset of illness In Tanzania, malaria which is the leading cause of morbidity and mortality accounts for over 40% of out-patient attendances and 36% of all death in under fives . Tanzania accommodated the malaria treatment policy change for uncomplicated malaria from sulphadoxine-pyrimethamine (SP) to ACT in October 2006 . However, procurement of ACT is mainly through the support of funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria and caters for ACT provision by government and not-for-profit private health facilities, which include Faith Based Organisation [FBO] facilities. In the former, free services are provided to under-fives, whereas in the latter, a considerable fee is charged, even if the ACT is free. Furthermore, most treatment for malaria is provided outside the formal healthcare sector, usually by shopkeepers where treatment is often inappropriate A recent Malaria Indicator Surveys (MIS) conducted in Tanzania revealed that only 13% of the febrile children had prompt access to the ACT . Studies conducted prior to ACT era indicated availability of medicines, source of care, perceptions about causes and the severity of illness, the efficacy of treatment, the ability to pay, and the distance to the health facility as factors influencing timely access to malaria treatment Kilosa district is situated about 300 kilometres west of Dar es Salaam, the largest business city in Tanzania. The district has about 488,000 people, of which 79,000 are under five years . Administratively, the district has seven divisions with 161 registered villages and is divided into four geographic-climatic areas: wet-highland, dry-highland, wet-lowland and dry-lowland . The district has an under-five mortality of 166 per 1,000, and about 32% of the people live below the poverty line . The main sources of income are farming and livestock keeping. Food crops produced at subsistence level are maize (staple food), cassava, rice and sorghum. In 2007, malaria accounted for more than half [55.5%] of the total outpatient attendance, and 60% of the total deaths among under-fives admitted to the hospitals . Malaria transmission in the wet-lowland area occurs throughout the year, with the highest incidence during and soon after the rain season, March to June.Kilosa has 71 health facilities, comprised of 3 hospitals, 7 health centres and 61 dispensaries . Of these, two hospitals, one health centre and nine dispensaries belong to FBOs, and charge a fee for consultation, drugs and laboratory tests. In the public facilities, services for under-fives are offered free of charge. There were 152 drug shops in the district, most of them found in urban and semi-urban areas. At the time of the study, about 92 drug shops met the minimum criteria set by the Tanzania Food and Drug Agency (TFDA) and were upgraded to the status of ADDO, which allowed them to sell artemether-lumefantrine (ALu). ADDOs are able to purchase ALu at a subsidised price and charge a flat rate of US $0.50 for one paediatric treatment course .This is a prospective study design, in which 1,200 randomly selected children aged 3–59 months were followed up at their homes weekly for six months, in 2008. Weekly follow ups were chosen so as to maximize recall of events. The outcome measure was prompt access to ACT among children who had fever episode as reported by the caretaker. Fever was used as a proxy for malaria given the absence in rural areas of laboratory facilities for diagnosing malaria and the national treatment guidelines that advised treating childhood fevers suspected to be malaria with the recommended first-line treatment. This proved for us to be of practical use as reported by other researchers Stratified random sampling was performed by dividing rural villages into the four geographic-climatic areas, wet-highland, dry-highland, wet-lowland and dry-lowland, using a list of villages from the national census. In each area, one village was randomly selected from among villages with health facilities, and two from those without, making a total of 12 villages. Under-five children were randomly selected from village registers. Village registers are kept by the Village Executive Officer in all villages within the country. However, in many villages these registers were not up-to-date. Therefore, village registers had to be updated by the researchers with the assistance from the village health workers (VHWs) via house-to-house visits. A sample size of 1,200 was thereby apportioned to the 12 villages, according to village population size and random selection was performed using EPI-INFO, software (version 6). The sample size was derived by requiring a maximum length of 95% confidence interval +/−5% units, and assumed a proportion of 50%. Adding 10% for possible loss to follow-up, and 38% correction factor for clustering effect on village level [ICC = 0.01], the total sample size came to 583 (approximated to 600). Available data reported by patients/caretakers indicated that the 2-week period incidence of fever suspected to be due to malaria in Tanzania was 6% Two to four VHWs were recruited in each village, depending on the village size. These were centrally trained for six days on the purpose of the study, data collection procedures and ethical issues. Three research assistants dawa mseto) were obtained from caretaker's report. Children, who had not recovered at the time of the interview, completed their information on what happened after the previous encounter during the next round. Children found to have severe symptoms on the day of interview were advised to be taken immediately to the health facility.Baseline and follow-up questionnaires were developed based on previous literature In government health facilities, medical notes are written in notebooks and are kept by caretakers. These, as well as drug containers, were examined to verify the type of drug provided. Where such evidence was not available, verification was performed by displaying samples of locally available brands Data were double entered into EpiData 3.0  and analysed using STATA version 10.1 . The outcome measure was ‘prompt access to ACT’ which was defined as treatment with any type of ACT on the same or the next day of fever onset malaria ya kawaida) and knowledge about the causes of convulsion to children. The total number of people in the household and all individual symptoms except cough were found not statistically significant. The rest of the variables were introduced in a stepwise analysis multiple regression model where only the source of care and knowledge on the recommended drug for the treatment of uncomplicated malaria were retained in the final model. In determining factors influencing care-seeking from government health facilities the same variables used in the previous model were analysed. Failure to feed, cough, SES and knowledge of treatment for uncomplicated malaria and knowledge about the cause of convulsions were found to be statistically significant. These were introduced in a stepwise regression model and all variables except cough and knowledge on cause of convulsion were retained in the final model.Bivariate analysis was performed on variables likely to influence the prompt access to the ACT as well as the source of care. All variables that were found to have a statistically significant association were introduced into the multiple regression models using stepwise analysis, with a cut-off point of 0.10. All regression analysis were weighted. Post-stratification weighting was done at the strata level  after observing that the sampling proportion did not perfectly match the true distribution of the population. Odds ratios [OR] with 95% confidence intervals [CI] were used to measure association. Significance was tested at the 5% level. Variables introduced in the multiple regression model to determine an association of prompt access to the ACT were the total number of people in the household, number of under fives, the source of care, severe symptoms , separate individual symptoms, SES, knowledge on the recommended drug for the treatment of uncomplicated malaria , Tanzania. Permission to conduct the study was also obtained from the regional and district authorities. A written informed consent was obtained from each adult caretaker of the child during baseline data collection.During the six-month collection period, 35 children were added to the enrolment after children, who had either attained the age of 60 months or who were reported to have migrated during the study period, were replaced by random selection. In all, 1,235 children aged 3–59 months were enrolled. There was no difference between febrile and non-febrile children in relation to the socio-demographic characteristics of the children and their caretakers . The medOut of the 607 children with fever, 264  were taken to government health facilities for care in the course of their illness . No carerd–5th quintiles) were more likely to receive ALu  compared to the poor , .Of the 607 children, 374  received antimalarials, of which, 268  were ACT, and all were ALu. The majority of those who were taken to government health facilities were treated with ALu , while only 14.0% (48/343) of those who were taken to the other facilities received ALu. Children from the better-off household (3The average expenditure on drugs reported by caretakers was Tanzanian shillings (Tsh) 767 , and the median was Tsh 200 . The median expenditure on drugs at government health facilities was zero. Within the private sector, the median expenditure on drugs was highest among FBO facilities  followed by ADDO  and drug shops (Tsh 900). Median expenditure was least at ordinary shops (Tsh 500). Caretakers from the poor households paid more compared to the better-offs, median expenditure Tsh 500 and zero, respectively.Overall, 223 of 607  of the children who had fever received ALu promptly. Prompt access to the ACT was higher  among children taken to the government health facilities compared to those taken elsewhere , see awa mseto (Coartem®) is the recommended drug for the treatment of malaria ya kawaida [uncomplicated malaria] influenced prompt access to ACT. Together, the two factors explained for 30% of the variability. Seeking care from a government health facility and knowledge that dmalaria ya kawaida) were 8-times more likely to access the ACT promptly  compared to those who did not have the knowledge, see Further analysis by geographic-climatic strata showed a similar pattern with regard to the source of care, except in the wet-highland stratum where the association was less remarkable  . In the Dawa mseto) is the recommended drug for the treatment of uncomplicated malaria , were more likely to take their children to a government health facility compared to those who did not know . Knowledge about mosquitoes, and that high fever causes convulsion in children, increased the likelihood of taking a child to a government health facility in dry-highland areas; however, the difference was not significant .Since seeking care from a government health facility was the main factor associated with prompt access to the ACT, further analyses was done to determine factors that influence seeking care from these facilities. Children from the better-off households were twice more likely to be taken to a government health facility compared to those from poor households . Moreover, the better-offs were found to live closer to government health facilities  compared to the poor . Further analysis showed that the better-offs were 4-times more likely to have knowledge on the recommended drug for treatment of uncomplicated malaria , and that they were more likely (2.5-times) to own radios compared to the poor .This study shows that nearly two-third of the children with fever received antimalarials on the same or next day of the onset of fever, of which less than half were ALu. Furthermore, only one-third of the children had prompt access to the ACT, and that seeking care from government health facilities was the major determining factor. The study has also shown that, despite subsidy on ACT, the poor were paying more, as compared to the better-offs, for the ineffective drugs they got from non-government facilities simply because they had less access to government health facilities. Previous studies have also reported source of care as one of several factors influencing access to antimalarials Encouragingly, prompt access to the ACT was very high among children taken to government health facilities, in this study. However, the fact that less than half of these children were taken there, raises some pertinent questions as to why most caretakers did not seek care from government health facilities where the ACT was provided free of charge. This can be explained by the findings from previous studies that reported caretakers residing closer to a government health facility were more likely to seek care from these facilities The majority of caretakers who did not seek care from government health facilities were from the poor households, this confirms the ‘inverse care law’ stating that “the availability of good medical care tends to vary inversely with the need for the population served” Subsidy has made ALu quite cheaper thus affordable to many people. But despite the subsidy, prompt access to the drug was very low among children taken to FBO facilities and ADDOs. Most of the FBO facilities are situated in rural remote areas and serve poor communities. Unfortunately, they charge a considerable fee to cover operating costs Knowledge that ALu is the recommended drug for the treatment of uncomplicated malaria was associated with increased prompt access to the ACT in the wet-lowland areas, where malaria transmission is high and occurs throughout the year. This might be an indication of the successful advocacy campaign by the National Malaria Control Programme. Radio and television adverts and programmes featuring ALu as the recommended first-line drug have been aired since the inception of the new drug policy. Such messages might have been taken more seriously in areas where malaria transmission is intense. The lack of association between SES and prompt access to the ACT found in this study might be due to the overwhelming influence of the source of care which might have concealed the influence of poverty on prompt access.Diagnosis of malaria relied on caretaker's report of fever. This might result in underestimation of prompt access to the ACT since not all fevers are due to malaria. However, the fact that Kilosa is hyperendemic area increases the likelihood of most fevers to be due malaria. Underestimation of prompt access might also have resulted from including children who were suspected to have severe malaria and were correctly treated with the second line antimalarials, or from children who were found to have a negative blood slide for malaria parasites and were treated with other drugs Ascertainment of the drug given to a child can be difficult, especially if the caretaker does not know how to read and write. Therefore samples of the drug packets and records from the clinician or drug shop were used to verify the type of drug given The use of village health workers with low level of basic education might have undermined data quality. However, given the one-week training prior to data collection, the day-to-day close supervision by RAs and the weekly meetings, the problem of data quality might have been minimized. Further, the presence of village health workers might have caused a ‘Hawthorn effect’ likely to overstate the level of prompt access to the ACT.Findings from strata analysis should be interpreted with caution because the sample size for this study was calculated to power the overall analysis and not the strata specific analysis.The major drawback to promptly accessing ACTs found in this study was the limited availability of subsidized ACT in places where most caretakers took their children for care. And despite subsidy on the ACT, a majority of caretakers, especially from the poor households, continue to pay more for ineffective drugs in non-government facilities.Government health facilities proved to be the best source for accessing prompt treatment, as judged by the highest rate of prompt access to ACTs. Therefore, greater part of the global effort on malaria should focus on strengthening the public sector. However, government health facilities were accessed mostly by the relatively wealthy. Therefore, access to government health facilities need to be improved by optimizing the location of health facilities - nearer the malaria hotspots. In the non-government sector, merely subsidizing the price of ACT is insufficient. In addition to the subsidy, the quality of services must be regulated to provide the recommended treatment. Furthermore, information must be provided effectively to the poor on the best treatment and their sources. Further research should address why prompt access to ACT in ADDOs and FBOs is low despite ACT subsidy, and how FBO facilities, located mostly in remote rural areas, can be maximally utilised to reach the marginalized children.


The group randomized trial (GRT) is a common study design to assess the effect of an intervention program aimed at health promotion or disease prevention. In GRTs, groups rather than individuals are randomized into intervention or control arms. Then, responses are measured on individuals within those groups. A number of analytical problems beset GRT designs. The major problem emerges from the likely positive intraclass correlation among observations of individuals within a group. This paper provides an overview of the analytical method for GRT data and applies this method to a randomized cancer prevention trial, where multiple binary primary endpoints were obtained. We develop an index of extra variability to investigate group-specific effects on response. The purpose of the index is to understand the influence of individual groups on evaluating the intervention effect, especially, when a GRT study involves a small number of groups. The multiple endpoints from the GRT design are analyzed using a generalized linear mixed model and the stepdown Bonferroni method of Holm. This paper addresses data analysis issues related to group randomized trials (GRTs) with multiple endpoints and a small number of groups. In GRT studies, groups serve as the primary sampling unit in the selection process; groups are randomized into two or more arms, and then responses are measured on individuals within those groups. Typical examples of groups include clinics, schools, work sites, churches, or communities.GRT is becoming a standard study design to assess the effect of an intervention program for health promotion or disease prevention, especially when the intervention is delivered more efficiently to groups than directly to individuals Consider the data from a study of the cancer Screening Office System (cancer SOS) In contrast to standard randomized clinical trials in which individuals are the sampling units for randomization, GRT designs have additional analytical problems. The major problem is due to the expected positive intraclass correlation (ICC) among observations from individuals in the same group. In addition, the number of groups involved in GRT studies is generally quite small, and thus problems arise in obtaining an accurate estimate of the ICC. In spite of its difficulties, however, the GRT approach may sometimes be the only feasible approach; and if the characteristics of the GRT design are not properly accounted for in the analysis, the statistical significance of the intervention effect is typically overestimated, resulting in misleading public health information.Data analysis issues of GRTs have been intensively discussed by health science researchers Analytically, it is most straightforward for a clinical trial to have a single primary question. For some research, however, multiple primary endpoints are important and relevant scientifically, medically, or for public health purposes, as it is often difficult to fully assess the efficacy of a new intervention using a single endpoint. Moreover, these studies are often expensive in both cost and effort, so researchers would like to get answers to many questions with a given study, if feasible. For example, the cancer SOS intervention study was designed to increase the use of three major cancer screening tests. For each patient, evaluations of the intervention were made for each test. Thus, patients were measured for the three tests as co-primary endpoints to better characterize the efficacy of the intervention, leading to an outcome variable that is a vector of three responses.Multivariate analysis involving multiple responses per subject is a major research area in statistics, and several statistical computing packages  have software procedures for analyzing such data. In spite of recent progress though, multivariate analysis is still not a standard approach for analysts who do not routinely use mixed models. Although many papers have explained the theoretical basis for multivariate analysis, few practical introductions to GRTs with multiple endpoints have been written, especially in the context of public health medicine.Generalized linear mixed models (GLMMs) When a study involves multiple endpoints addressing equally important objectives of the proposed intervention, the potential for drawing false positive conclusions exists unless an appropriate adjustment for multiplicity is used to control the overall statistical error rate. Several possible approaches exist, with appropriateness depending upon the study design. In this study, the multiple endpoints will be adjusted using the stepdown Bonferroni method, which we will refer to as Holm's method Use of a small number of groups in a GRT raises additional concerns regarding the statistical analysis of the intervention effect. Also, statistical power of a GRT generally depends more on the number of groups randomized than on the average number of individuals within a group This article provides practical advice and methodology for analyzing GRTs data, especially with multiple endpoints and a small number of groups. The overarching goal of this work is to disseminate statistical knowledge for public health benefit. This paper can be viewed as a tutorial for researchers who have little theoretical background or practical experience analyzing GRTs data, especially with multiple endpoints and a small number of groups. Mathematical details are avoided unless needed to illustrate important concepts.A GRT is a randomized clinical trial to investigate an intervention. Unlike standard randomized clinical trials, however, the intervention is delivered to individuals through “groups”, which are assigned to either intervention or control arms. Responses are measured on individuals within those groups nested in the arms. Consequently, the responses for individuals within the same group are expected to be positively correlated. This correlation is called the intraclass correlation coefficient (ICC), and is denoted by Although To explain the concept of the ICC simply, suppose we conduct a nested cross-sectional GRT design. Let the two arms have the same number of groups, Note that the ICC varies depending upon the endpoint, the design, and the analyses. For example, with a nested cohort study in which the endpoints are repeatedly observed over time from the same subject, the ICC above will include the within-subject variance over time.As seen in equation (1), ICC reflects the proportion of the total variance explained by the variance of the group-by-time interaction. The variance of the group mean in a GRT is then,Due to the GRT design, the variance includes a multiplicative factor As equation (1) shows, estimation of the ICC requires estimates of the between-group variance and the group-by-time interaction variance, with the number of groups as degrees-of-freedom. Primarily for logistical reasons, GRTs commonly have few groups , resulting in a small number of degrees-of-freedom (df). This small df will be used to estimate the standard error for the intervention effect, and will yield an inflated Type I error. Further, this will reduce the statistical power of the test. Consequently, both the design stage and the analysis stage should account for the GRTs' characteristics.In this section, we briefly review the generalized linear mixed model (GLMM) to analyze GRTs. Let's assume that a vector of binary response data We analyze the cancer SOS study by testing the intervention effect for the multiple endpoints in a global fashion. Specifically, for each of the three screening tests, let In order to account for the expected ICC, group-related factors were included in the analysis as random effects: the random effect of the When a GRT involves a small number of groups, a few statistical methods are available to adjust the degrees-of-freedom in mixed models. For example, Kenward and Roger Once the model (4) is fitted, the ICC and the VIF can be estimated based on the equation (1), with the estimated variances for the within group, between groups, and a between group-by-time interaction.www.isiknowledge.com). We refer readers to Brown and Russell Several possible approaches exist to adjust for multiplicity due to multiple endpoints, and the appropriateness depends upon the study design. The adjustment approach could be very conservative  or less conservative . We prefer Holm's method While VIF provides an interpretation of the overall variance inflation due to a GRT design, it is critical to understand the influence of individual groups on evaluating the intervention effect, especially, when the number of groups is small.Let us define the change on each endpoint within a particular interval as,If we assume that the responses at two time points are independent, the nominal variance of the average change As an index of extra variability  smears, mammograms, and fecal occult blood tests (FOBT). It is generally recommended that each of these tests be performed annually for women who are age 50 or older. One hundred fifty patient's charts from the clinics were randomly selected and abstracted to obtain the demographic and clinical variables at baseline, and outcome variables at baseline, 12, and 24 months after the intervention. By chance, a few patients were selected more than once. However, as the study was not intended to follow individuals over time, this design is called a nested cross-sectional study rather than a cohort study.This section illustrates applications of GLMMs to a GRT study where the scientific question is whether or not the cancer SOS intervention convinces patients to take cancer screening tests or not. Men were excluded from the analysis in this paper, as two of the three target screening tests applied to women only. Also, the following exclusion criteria for the women were applied: personal history of breast cancer for the analysis of mammography, personal history of cervical cancer or hysterectomy for the analysis of Pap smear screening, and personal history of colon cancer, or colonoscopy of double-contrast barium enema in the previous 10 years for the analysis of FOBT.In each of eight clinics, patients' usage of the three screening tests  was assessed at three time points . The responses were binary (1 if the patient took the test and 0 otherwise). On average, 150 patients per clinic were measured at each time point, with four clinics assigned to each of two arms (intervention or control).The distribution of each cancer screening test (numbers and percentages) at each time period is summarized by arm in The results of the analysis are shown in The huge differences of VIF across screening tests are more clearly explained in GRT designs are becoming increasingly important in public health interventions, as it is often easier to randomize at the group level. Investigators are often surprised by the degree to which information is attenuated due to intraclass correlation, even though ICC levels are often quite low in practice. Thus, GRT designs are usually improved by having as many groups as are logistically possible. We have developed an index of extra variability (IEV) with a corresponding graphical presentation for understanding in greater detail how the effects from individual groups influence the overall findings. We believe that the IEV concept will assist researchers in the planning future GRT studies.The results of the cancer SOS GRT study were disappointing. Further, the primary investigator of the study, a non-statistician, was understandably confused at the discrepancy in findings based on the statistical method employed. The original analysis, a generalized estimating equations (GEE) While the GEE method allows for correlation among patients within a group, it is inappropriate for GRT study designs when the number of clinics is small, with less than 20 groups per arm, as noted by Murray et al. While analyzing the cancer SOS study, we faced a few additional analytical issues that should be discussed. As the endpoints were measured at three times, some patients were seen at multiple timepoints by chance. Among the patients surveyed at baseline, 22% were seen at year 1, and 8% were selected at all three timepoints. Ideally, the expected intra-patient correlation, which exists as a consequence of repeated measurements across time, should be adjusted for when performing statistical inference. However, in this study we did not consider this additional source of correlation. The effect of the possible correlation across time is unknown and needs further investigation. Also, each patient had three endpoints, resulting in another source of intra-patient correlation. As the univariate approach ignores the stochastic dependence among the individual endpoints, it may yield conservative results. To account for this type of intra-correlation, one may use a multivariate approach; all three endpoints per subject unit are simultaneously analyzed by adding a random effect for individuals. By accounting for the correlation among endpoints, improved power to detect the overall intervention effect is expected. In addition, this multivariate approach needs no multiplicity adjustment, since only one test is being carried out. However, it should be noted that if the endpoints describe unrelated aspects of the individual response, or if there is considerable discrepancy across endpoints, this multivariate approach is not a reasonable analytical strategy. In this case, individual tests that are suitably adjusted, as we have done here, should be used. The cancer SOS showed striking differences in VIF across the three endpoints ; thus, averaging the three endpoints provides no reasonable interpretation.What appears to have happened with the SOS GRT is that the intervention groups were either stable or had increases in the first year, while the control groups declined. However, these modest gains were short-lived, and resulted in large year 2 drops for the intervention groups. The GRT was not designed to assess this kind of change, or cope with this degree of heterogeneity, given the small number of groups. As VIF, IEV, and the graphical presentation in Our hope is that this paper will contribute to the responsible analysis of GRTs, thereby helping with the scientific accuracy of research findings. Multivariate analysis for multiple endpoints in GRTs is obviously one area that we need to continue further investigation. Further research on small group issues also is warranted at both the design and analysis stages.http://personal.health.usf.edu/jlee2/software. Note that it also includes a Newton-Raphson optimization option to deal with convergence problems, which we otherwise frequently ran into for moderately complex mixed models.The SAS code used for this article is available at the first author's web:


The clinical consequences of whiplash injuries resulting from a motor vehicle accident (MVA) are poorly understood. Thereby, there is general lack of research on the development of disability in patients with acute and chronic Whiplash Associated Disorders.The objective is to describe the design of an inception cohort study with a 1-year follow-up to determine risk factors for the development of symptoms after a low-impact motor vehicle accident, the prognosis of chronic disability, and costs. Victims of a low-impact motor vehicle accident will be eligible for participation. Participants with a Neck Disability Index (NDI) score of 7 or more will be classified as experiencing post-traumatic neck pain and will enter the experimental group. Participants without complaints (a NDI score less than 7) will enter the reference group. The cohort will be followed up by means of postal questionnaires and physical examinations at baseline, 3 months, 6 months, and 12 months. Recovery from whiplash-associated disorders will be measured in terms of perceived functional health, and employment status (return to work). Life tables will be generated to determine the 1-year prognosis of whiplash-associated disorders, and risk factors and prognostic factors will be assessed using multiple logistic regression analysis.Little is known about the development of symptoms and chronic disability after a whiplash injury. In the clinical setting, it is important to identify those people who are at risk of developing chronic symptoms.This inception prospective cohort study will provide insight in the influence of risk factors, of the development of functional health problems, and costs in people with whiplash-associated disorders. There is general lack of research on the development of disability in patients with acute and chronic WAD. The clinical consequences of whiplash injuries resulting from a motor vehicle accident (MVA) are poorly understood. Although the prognosis of these whiplash-associated disorders (WAD) is generally thought to be favourable, a systematic review by Cote et al 2001) found that prognosis may vary according to the population sampled and the compensation system of the geographical area studied found th. SeveralGiven the above, it is clear that the consequences of a disorder, such as WAD, will be different in different people, which in turn has consequences for how patients are managed. The goal of rehabilitation is to improve the health status and quality of life of patients by minimizing the intensity and duration of symptoms. The success of rehabilitation in terms of functioning and health is influenced not only by the underlying disorder or condition, but also by personal and environmental factors. A frequThe general lack of research on the development of disability in patients with acute and chronic WAD prompted us to design a study to evaluate factors that play a role in the development of disability in acute and chronic WAD. This is important because the population with chronic WAD is not homogeneous, but includes patients with varying signs, levels of pain and disability, attitudes and beliefs, and from widely divergent social and work backgrounds. Thus th1 To gain insight into the factors that determine the development of disability and chronicity after a low-impact MVA.2. To determine the natural course of WAD, with respect to prognostic subgroups.3. To evaluate direct and indirect costs related to WAD.This descriptive and prospective inception cohort study will be conducted at the Utrecht Medical Centre. The study was approved by the Ethical Review Board of the University Medical Centre Utrecht. The study consists of two parts, a descriptive study , and a prospective cohort study . The design of this study is presented in Figure Two hundred persons who are exposed to a low-impact MVA will be recruited with the assistance of local police officers, emergency departments of general hospitals, and the emergency medical services. These people will be sent a letter informing them about the study and asking them to participate. Those interested in participating will be asked to reply  within 2 weeks. If they meet the inclusion criteria, they will receive detailed information concerning the aims and procedures of the study and will be asked to give their informed consent.Participants who have provided informed consent will be sent a postal questionnaire 3 weeks after the MVA. The questionnaire will contain a picture of a blank manikin on which respondents are asked to shade the side on which they experience any pain after the MVA. Participants will also asked to state the intensity of the pain on a numerical pain rating scale (NRS) and to complete the Neck Disability Questionnaire (NDI) Dutch Language Version. On the basis of this information, participants will be divided into two groups: 1] those with pain of the head, neck and/or upper extremity/extremities and an NDI score of more than 7, who will form the experimental group (n = 100), and 2] those who are exposed to a MVA, but without pain in the neck, head, and/or arm (NDI score of 7 or less), and who have no other symptoms, will be selected to form the reference group (n = 100). To form this reference group, every third person without complaints after the MVA will be selected in sequence of time, up to a total number of 100.Inclusion criteria are involvement in a low-impact MVA (with a speed at the time of the accident less than 50 km/h) 3 weeks before inclusion, no loss of consciousness during and immediately after the accident, and no amnesia after the accident. Subjects have to be able to speak and read Dutch fluently. Subjects must have read the information letter and signed informed consent. Involvement in litigation is not an exclusion criterion but subjects' litigation status will be recorded. Subjects will be allowed to use their current medication and may change medication if necessary.Exclusion criteria are hospitalization for more than 12 hours after the MVA, fracture or dislocation of the cervical spine and thoracic spine (as determined by X-ray), neurological disorders, head trauma, and inability to read or speak Dutch fluently.A letter will be sent to each subjects' medical practitioner to inform him/her about the participation of his/her client in the study, together with the results of the screening process. The number of people invited to participate, the number of potential subjects willing to participate, and the number of eligible people will be recorded, as will the reasons for ineligibility. The researchers will have access only to the names and addresses of potential participants before recruitment.The annual incidence of whiplash injury in the Netherlands is 94–188 per 100,000 inhabitants. Based on the epidemiological data of Borghouts et al. ,9 and PiImportant determinants and variables of WAD will be evaluated, using validated instruments -16.The Bournemouth Questionnaire for Neck Pain (NBQ) will be Potential determinants of the development of acute and chronic WAD will be measured. Based on the literature, the following were chosen as being factors that may influence the development of WAD: age, level of activities, neck pain, anxiety and depression, hypochondriasis, and perceived functional health. Recovery from whiplash-associated disorders will be measured in terms of perceived functional health (cut-off point of the sum score of the NBQ: percentage change of scores ≥ 36%), and empThus at baseline the following variables will be measured:• Average pain intensity over last week on a 0–10 scale;• General symptoms• Anxiety and depression • Hypochondriasis (Whitely Index)• Perceived functional health related to neck pain (Neck Bournemouth Questionnaire)• Activity level (Neck Disability Index).The follow-up period will be 1 year, based on the data of Kasch et al. , in whicEffort will be taken to ensure that the protocol is consistently applied. Protocol manuals will be developed and staff will be trained to ensure that screening and assessment are conducted according to the protocol.If subjects are concerned about their condition during the study, the physiotherapist will screen for potentially serious pathology and, where appropriate, refer participants to a medical practitioner. Subjects will be free to seek any treatment. Subjects will be requested to formally record the type and amount of treatment they receive.Descriptive statistics will be used to describe clinical characteristics, demographic characteristics, and psychological, and clinical factors . Central estimators of all relevant variables will be calculated. Differences in variables measured at baseline and during follow-up will be analysed with a paired Wilcoxon test. Direct and indirect costs will be calculated based on the estimated number of days that patients are not able to work. The iMTA guideline of cost analysis will be used in the data analysis,25. The This article outlines the rationale and design of a prospective cohort study of risk factors and prognostic factors for WAD, assessed over 1 year. People who have sustained a whiplash injury may develop symptoms, collectively referred to as WAD. However, little is known about which people develop symptoms and become chronically disabled as a result of these disorders,28. SeveAlthough the pathophysiology of WAD remains unclear, it is important to identify risk factors for acute and chronic WAD. Despite extensive research, the prognostic factors that play a role in the development of functional health problems, i.e. disability, have not been identified. The ICF is a suitable model to investigate the natural course of WAD and potential prognostic factors. As WAD is a complex, multifaceted problem, it is important that diagnostic studies focus on all the facets that may play a role in the development of chronic WAD. We have presented the rationale and design of an inception prospective cohort study that investigates the influence of risk factors, internal factors, and external factors of the development of functional health problems, and costs in people with whiplash-associated disorders.The authors declare that they have no competing interests.All authors participated in the design of the study. MS drafted the manuscript with input from the other authors. All authors read, revised and approved the final manuscript.The pre-publication history for this paper can be accessed here: