Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10–15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools  to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care. In the process of generating a draft sequence of the human genome, it has become clear that the extent of genetic variation is much larger than previously estimated . Most SNThe total number of SNPs in the human genome is estimated to be more than 10 million  and the Single-nucleotide polymorphisms in the same chromosomal region are not inherited randomly, but as combinations of alleles, which form haplotype blocks. It appears that the genome is organised into distinct blocks of linkage disequilibrium (LD), intercepted by regions in which LD breaks down rapidly  that influence disease susceptibility and outcome, a great effort has been directed at picking SNPs for study. The promise of utilising biallelic SNPs for whole genome linkage studies, though very exciting in theory, is still some time off in the future because of issues related to the prohibitive cost and impracticality of genotyping the required thousands of SNPs, not to mention developing the databases and analytical tools needed to interpret the data . Still, DRD2 transcript, resulting in alterated expression . For complex diseases, such as most cancers, the paucity of family pedigrees has limited the success of this strategy, especially in search of moderate or low penetrance genes ; this observation suggests that additional modifying genes as well as environmental factors contribute to cancer even in the high-risk setting. In studies of subjects with a monogenic disorder , it has been possible to identify modifying variants that influence the risk for well-defined phenotypes  or xenobiotic metabolism genes . Though early in the study of SNPs and cancer, technical and bioinformatics advances make it possible to dramatically increase the number of genes applied to a study. It is important to bear in mind that SNP studies require replication prior to acceptance, and certainly before clinical implementation. Therefore, it is critical to consider the current published literature as very preliminary analysis of what will certainly be a complex process.Genetic association studies with SNPs targeting cancer can be divided into two broad categories, investigation of susceptibility and of outcomes  with bladder and colon cancer. NAT1 and NAT2 encode enzymes that are important for biotransformation of aromatic and heterocyclic amines, known carcinogens. The risk of developing urinary bladder cancer is particularly high in the slowest NAT2 acetylator phenotype, and is exacerbated by the history of smoking. On the other hand, for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype confers a higher risk  gene. The protein encoded by the TPMT gene is a catalyst for S-methylation of thiopurines, commonly used in the treatment of haematopoietic malignancies and autoimmune disorders . Thiopurine drugs are activated to thioguanine nucleotides, which are cytotoxic. Cytotoxicity can be intended , but if prolonged, life-threatening. It was discovered that several rare variants in the TPMT gene correlated with decreased activity; homozygous individuals suffered substantial haematopoietic toxicity  within one or more chromosomal region is a common form of allelic imbalance, sites of LOH can be investigated for the presence of tumour-suppressor genes. Studies in bladder, lung and prostate cancers have discovered previously unknown allelic imbalances in multiple sites using SNPs for LOH analysis  and chemoprevention. In turn, secondary prevention will address screening and public health measures designed to identify and intervene in high-risk individuals. The latter will become more complicated as we integrate information about pharmacogenomics, second malignancies and long-term complications. This is particularly complex because the consequences of one set of SNPs could have deleterious consequences for one outcome, but yet be advantageous for another.A major challenge ahead is the development of more sophisticated analytical tools for handling the expanding data. We will need to address the complex issue of gene–gene interactions, particularly if profiles of SNPs are to be used in the clinical venue. At the same time, it is imperative to develop structures to include more individuals in population-based studies, yet preserve both confidentiality and individuality. In many respects, this is the most daunting challenge, to derive the information to interpret the significance of specific SNPs and haplotypes from population-based studies, yet apply the information to the individual. It could have a significant impact on the economics of medical practice.In the end, the clinical application of what we learn from SNP studies will probably require a major shift in the paradigm of practice. Practitioners could make treatment decisions or give advice based on an assessment of risk. To begin to address the central issues of SNPs, haplotypes and cancer, detailed knowledge of the scope and pattern of genetic variation will be required, namely SNPs, haplotypes and linkage disequilibrium for genes and pathways critical to cancer in different populations.


A major obstacle facing many lower-income countries in establishing and maintaining HIV treatment programmes is the scarcity of trained health care providers. To address this shortage, the World Health Organization has recommend task shifting to HIV-infected peers.We designed a model of HIV care that utilizes HIV-infected patients, community care coordinators (CCCs), to care for their clinically stable peers with the assistance of preprogrammed personal digital assistants (PDAs). Rather than presenting for the standard of care, monthly clinic visits, in this model, patients were seen every three months in clinics and monthly by their CCCs in the community during the interim two months. This study was conducted in Kosirai Division, western Kenya, where eight of the 24 sub-locations (defined geographic areas) within the division were randomly assigned to the intervention with the remainder used as controls.Prior to entering the field, CCCs underwent intensive didactic training and mentoring related to the assessment and support of HIV patients, as well as the use of PDAs. PDAs were programmed with specific questions and to issue alerts if responses fell outside of pre-established parameters. CCCs were regularly evaluated in six performance areas. An impressionistic analysis on the transcripts from the monthly group meetings that formed the basis of the continuous feedback and quality improvement programme was used to assess this model.All eight of the assigned CCCs successfully passed their training and mentoring, entered the field and remained active for the two years of the study. On evaluation of the CCCs, 89% of their summary scores were documented as superior during Year 1 and 94% as superior during Year 2. Six themes emerged from the impressionistic analysis in Year 1: confidentiality and "community" disclosure; roles and responsibilities; logistics; clinical care partnership; antiretroviral adherence; and PDA issues. At the end of the trial, of those patients not lost to follow up, 64% (56 of 87) in the intervention and 52% (58 of 103) in the control group were willing to continue in the programme (p = 0.26).We found that an antiretroviral treatment delivery model that shifted patient monitoring and antiretroviral dispensing tasks into the community by HIV-infected patients was both acceptable and feasible.ClinicalTrials.gov ID NCT00371540 Two-thirds of the approximately 33 million HIV-infected people globally reside in the resource-constrained countries of sub-Saharan Africa, where more than 50% of the population lives in rural areas ,2. ThougThe human resources necessary for delivery of HIV care are substantial. For example, it has been estimated that in order for Moi Teaching and Referral Hospital (MTRH), the second national referral hospital in Kenya to meet the needs of all HIV-infected patients in its catchment area of 13 million people, it will need 730 physicians and/or clinical officers  trained in HIV care protocols . Given WTo address issues related to provider resources and access to HIV care in a rural setting, we designed and implemented a model of HIV care that utilizes trained HIV-infected peers  to care for clinically stable HIV patients within their communities. This paper presents data on the development, structure and acceptability of this model. Specifically, we describe the implementation of this innovative, community-based HIV-care programme, and present the data collected as part of the continuous feedback and quality improvement programme that was integrated into this model. There is an ongoing cluster-randomized controlled trial that is being used to assess patient outcomes within this new model, the results of which will be presented in a subsequent paper.This study was approved by the Indiana University School of Medicine Institutional Review Board and the Moi University Institutional Research and Ethics Committee.This study was conducted at one of the 18 primary United States Agency for International Development - Academic Model Providing Access to Healthcare (USAID-AMPATH) Partnership clinics in western Kenya , located in Kosirai Division, 30 km southwest of Eldoret Figure . MosorioKosirai Division is parcelled into nine smaller administrative areas, called locations, that in turn are divided into 24 sub-locations. The average sub-location is 4 km in diameter and thus can be crossed easily on foot (one to two hours). As part of our clinical trial, eight sub-locations were randomly assigned to the CCC intervention, and the remaining 16 were assigned to control status.At the time of this study, the majority of patients receiving cART were scheduled for monthly clinic visits, while some stable patients, demonstrating good cART adherence and living a significant distance from the Mosoriot HIV clinic, were occasionally scheduled for visits every two months. A physician attended the clinic on one day per week, reviewed difficult cases and made decisions related to opportunistic infection treatment, as well as drug substitutions for toxicity and failure that fell outside the standard AMPATH guidelines Table . The phyIn collaboration with the clinical officer in charge, the physician also provided supervision, support and continuing education to the nurses and clinical officers practicing at the Mosoriot HIV clinic. For patients receiving cART, the clinical officers monitored and supported cART adherence, assessed functional status and symptoms, managed cART side effects, and diagnosed and treated opportunistic infections. The nurses were responsible for obtaining weights, vital signs, assisting in cART adherence monitoring and support, as well as dispensing ART and drugs for the prophylaxis and treatment of opportunistic infections.Under the CCC model, patients were seen every three months in the clinic and received the standard care from nurses, clinical officers and physicians, as described. During the interim two months, CCCs visited patients in their communities in locations that were mutually agreed on by the CCCs and their clients . CCCs travelled through the community on foot or, rarely, with the use of public transport. CCCs received a salary for their activities, which was less than half that of a nurses and a third of a clinical officer's salary.During a community visit, the CCCs measured the patient's temperature, weight and oxygen saturation with portable electronic devices, and performed a structured symptom review guided by a personal digital assistant (PDA). If a specific symptom or constellation of symptoms was identified, the PDA triggered a specified alert, which provided detailed instructions, such as contacting the clinic and reviewing the case with a clinical officer to discern whether the patient might require a formal evaluation in the clinic (see PDA programme description below). CCCs also dispensed the patients' monthly supply of cART and opportunistic infection (OI) prophylaxis.The requirements for becoming a CCC included being HIV infected and within care at the Mosoriot HIV clinic, as well as being clinically stable on cART for a minimum of six months with 100% adherence to his or her regimen. In addition, the candidates had to be at least 18 years old, literate in either Kiswahili or English, fluent in Kiswahili and Kalenjin , interested in monitoring and assisting in HIV care, willing to maintain patient confidentiality, residing in or near a targeted sub-location, and willing to give consent to participate. Cumulative self-reported adherence data from clinic visits was used to determine the candidates' adherence to cART.The HIV clinic staff assessed level of interest in monitoring and assisting in HIV care, as well as willingness to maintain confidentiality, based on previous interactions with these individuals in both the community and clinic setting, as well as during interviews at the time of recruitment. The Mosoriot clinical officers and nurses selected nine patients , who met these criteria, for training as CCCs. CCCs were paid a salary consistent with that of the outreach workers employed by AMPATH.Training of CCCs was comprised of both didactic and practical components. First, the CCC attended a one-week structured didactic training that included: an overview of antiretrovirals; performing symptom reviews; assessing adherence; providing general patient support; obtaining vitals; and using the PDA and the CCC programme. This was followed by two months of practical training at the Mosoriot HIV clinic, during which CCCs initially shadowed the clinical officers and clinic nurses through each department . They subsequently performed independent assessments of stable patients and reviewed their findings with the clinical officer caring for the patient.During the first month in the field, the CCCs visited their assigned patients and evaluated them as per protocol one to two days prior to the patients' regularly scheduled HIV clinic visits. The patients were subsequently seen at their scheduled monthly clinic appointment, where the clinical officers compared the findings of the CCCs with their own. Any important differences were discussed during CCC debriefing sessions. After this initial training period, the CCCs followed the model as outlined above.PDAs were used as the platform for the electronic decision tool in this study because they are small, and thus in rural areas where technical support is unavailable, they can be easily mailed to a service provider for repair. Each CCC PDA was programmed with a series of questions directed toward the patient that included:• New cough since last visit?• Vomiting within the last 48 hours?• Diarrhea within the last 48 hours?• New headache since the last visit?• Has the patient had any of the following occur since the last visit? • Over the last week, has the patient or a family member skipped a meal because of lack of food in the house?• Has the patient reported or is there any evidence that there has been domestic violence in the household?• Does the patient  believe that she may be pregnant?• Are there more than six pills in any of the antiretroviral bottles than there should be?• Does the patient report significant difficulty with adherence?An answer of "yes" to any of first five questions triggered a sub-screen that asked additional details about the symptoms. For example, with regard to the question about vomiting, the sub-screen asked for information about hematemesis, as well as the ability to keep food, water and medications down. Fields were also present for entering current temperature, weight and oxygen saturation. As noted, pre-programmed alerts were triggered if specified parameters were met. For example, with regard to the question on vomiting Figure , if a "yDuring the mentoring period, CCCs underwent weekly performance evaluations conducted by the in-charge clinical officer, the results of which reflected both her assessment and insights gained from the clinic staff. Being in charge of the HIV clinic, the clinical officer had substantial experience in conducting performance evaluations and was trained on the CCC evaluation instrument by one of the authors (KWK). A standard evaluation form was used to assess skills in obtaining vital signs, taking histories, using the PDA, making clinical judgments, displaying humanistic qualities, and interacting with clinic staff. Each of these domains was assessed as Superior, Satisfactory, or Unsatisfactory.The evaluation summary score was obtained by averaging the domain scores and was reported as Superior, Satisfactory or Unsatisfactory. If a domain or an evaluation was identified as unsatisfactory, the in-charge clinical officer either arranged for remediation or if the issue was related to a behaviour , discussed the observed conduct and its consequences with the CCC and reinforced project expectations.After becoming independent, CCCs met with the coordinating clinical officer weekly for the first one to two months to review patient data. Subsequently, when deemed appropriate by the clinical officer, the period between feedback sessions was extended to two weeks and then to every month.Throughout the study period, the investigators met with the clinical officers and CCCs monthly to discuss barriers and enhancers to the performance of their duties. These meetings allowed CCCs to share their experiences (both successful and unsuccessful) and to aid each other in problem solving and programme development.Two data sources were used to assess the structure and function of the CCC programme: CCC evaluations; and translated transcripts from the monthly CCC meetings. The proportion of CCCs receiving satisfactory monthly mentoring evaluations and completing clinical training, field mentoring, and one to two years of practice were assessed by summarizing the CCC evaluation forms on an annual basis.All monthly CCC meetings were audio-taped and were transcribed and translated into English by a trained and experienced research assistant, who was present at all monthly CCC meetings and fluent in Kalenjin, Kiswahili and English. These meetings formed the basis of the continuous feedback and quality improvement programme that was used to assess and perfect the community care system. One of the authors (KWK) performed an impressionistic analysis on the CCC meeting transcripts at regular intervals. Issues identified by this analysis and not previously addressed were investigated as part of the improvement plan. Themes identified and addressed during the content analysis are presented in this paper.Consecutive patients reporting to clinic who lived in and around Kosirai Division were invited to participate in a cluster-randomized trial (randomization by sub-location) of the CCC intervention. Patients who enrolled in and completed the year-long follow up were asked about their willingness to re-enrol in the programme at the end of the trial. This information was used as a surrogate marker of patient acceptance of, and satisfaction with, the CCC programme.Nine CCCs were trained, eight (four men and four women) of whom were assigned to a sub-location and one as a back-up. All eight CCCs previously assigned to a sub-location successfully passed their didactic training and clinical mentoring and entered the field. All of the original CCCs remained in the field for the entire two-year duration of the study. Each CCC managed between eight and 20 patients in their assigned community.At the end of the first year, 133 formal evaluations had been completed on the eight active CCCs . The CCCs consistently received superior summary scores, with 89% of all scores being superior and the remainder being satisfactory Table . The vasDuring the first year, six themes emerged from the content analysis of the meeting transcripts: confidentiality and "community" disclosure; roles and responsibilities; logistics; clinical care partnership; ART adherence; and PDA issues. Confidentiality and "community" disclosure were key issues during the first few months after entering the field, when CCCs frequently encountered questions from patients' partners, neighbours and the general population about their activities and role in the community. This experience is exemplified in the following quote from a CCC:"Her husband followed and as we continued, her husband was waiting for us outside the neighbour's house. When I had finished serving the patient, her husband asked me what we were doing with his wife and I answered him that I was explaining to her about the group based in Mosoriot of which she is a member and I am the leader of that group."In order to avoid the AIDS label (and its stigma) and ensure patient confidentiality, the CCCs eventually chose to define themselves as health counsellors attached to a project at the rural health centre. To ensure consistent messaging, CCCs requested that clients who were unwilling to disclose their HIV status identify the CCC as a health counsellor to individuals who expressed curiosity. Early in Year 2 of this programme, CCCs recommended that community disclosure and stigma issues be dealt with by an increase in community mobilization activities, as well as by referring patients to support groups. Though stigma remained an issue within the community after 16 months, CCCs no longer reported this as a significant issue for the project.Two sub-themes emerged within the major theme of CCCs' roles and responsibilities: client expectations and clinic staff expectations. Some clients indicated to the CCCs that they felt that the CCCs should provide them with gifts, such as sugar, or assist in times of financial crisis, as highlighted by this quote by a CCC:"She [the client] told me to be taking sugar to her during every visit ... She claims that her daughters-in-law rush to her house after my departure because they think that I usually take sugar to her with my large back bag."Initially, the CCCs felt some discomfort with these requests, but over time, they were able to more clearly define their role as patient care advocates, who could refer patients to social and food services within AMPATH, but who could not provide direct assistance to families. Year 2 meeting transcripts identified no significant conflicts between clients' expectations and responsibilities of the CCCs or the clinic.th month of field work. As individuals working from their homes, the CCCs faced issues of competing agendas, and during the 10th month, it was noted that one CCC had failed to make some of his assigned home visits due to his participation in election activities. As a result, his patients were forced to visit the clinic to collect their medications. Other issues encountered during the month included failure of two of the CCCs to come to the clinic for the weekly PDA data downloads and tardiness in getting to monthly meetings. The supervising clinical officer and study staff clearly reinforced the clinical staff's expectations of the CCCs that they adhere to their patient visits, ensure that PDAs are downloaded on a routine basis, and notify the team if they are going to be late for meetings.The sub-theme of clinic staff expectations emerged during the 10During Year 2 in the field, the majority of conflicts with clinic expectations were self-corrected by the CCCs. For example, one CCC failed to acknowledge a vital sign alert at the patient's residence. However, when subsequently reviewing the visit data, the CCC identified the alert and returned to the patient's house for a recheck, which was found to be normal. It was also noted that CCCs were turning off their cellphones during work hours and so could not be reached by the clinic. Clinic expectations about availability were reinforced and this problem did not recur.With regard to logistics, the CCCs and their clients were given the opportunity to set the times and places for monthly visits. Eventually, most visits occurred at either the patients' or the CCCs' homes because early in the process, CCCs recognized that, due to numerous interruptions and confidentiality concerns, they could not conduct visits at more public venues, such as AMPATH's food distribution site in Mosoriot. As reported by one CCC:"So, the only thing I saw in the distribution site is that there are so many patients coming to the site and most of them were pleading for help. One of them came to me and asked for help, but I told her to come to the clinic. I also noted that it could be good to meet patients privately to avoid disturbances."Some patients requested evening visits. However, this was generally discouraged by both the CCCs and the study staff because of safety concerns about travelling after dark. Visit schedules were able to accommodate patients' and CCCs' needs without adding evening visits.CCCs initially encountered some issues with patients failing to be available at the times and locations scheduled for their monthly visits because of unexpected issues arising, such as funerals, and in rare instances, because the patient had moved without informing the CCC. The strategy developed between the supervising clinical officer and the CCC was to request that patients pass by the homes of their CCCs prior to leaving the area in order to reschedule or postpone appointments. In addition, the clinical officer suggested that the CCCs ask patients about their intention to move at each visit. If CCCs were still unable to contact patients after three separate tries, they were told to refer those patients to AMPATH's outreach team for follow up.The only logistical issue raised during Year 2 of field work was related to poor cellphone coverage around some of the clients' homes, an issue that could not be directly addressed by the project, but did not prevent the CCCs from performing their duties.The position of CCCs in the clinical care partnership began evolving within the first month of field work when it became clear that the CCCs were able to identify psychosocial concerns that were not being identified and discussed during clinic visits, such as alcohol abuse, food insecurity, domestic discord, and HIV disclosure issues. Such issues were not always addressed in the clinic, and a referral form was developed that allowed the CCCs to communicate these concerns to the clinical staff.The importance of the CCCs in the care partnership remained a consistent theme throughout the two years of field work. In addition to identifying psychosocial issues, CCCs provided trusted and reliable linkages between AMPATH's pharmacy, outreach and clinical teams and the patients to deal with important issues, such as adherence to medications or clinic appointments.Over the two years of field work, the theme of cART adherence repeatedly emerged during the monthly meetings. The initial adherence issue was what to do with the excess tablets identified during monthly pill counts. Because of the complexity of collecting and returning excess pills, it was decided that the CCCs should simply record the number of excess tablets and allow the clinic to reconcile the patients' medications. The CCCs felt that they were more accurate at assessing adherence than the clinic because patients could not hide their pills during home visits. Thus, as one CCC put it:"I learnt that patients never cheat when they are at their homes than when they come here at the clinic because most of them can give you the pills to count, but they sometimes leave other pills at home when coming to the clinic."In addition to monitoring adherence, CCCs were involved in adherence support, which included identifying issues that adversely impacted medication adherence , explaining changes in the number of pills that needed to be taken , and explaining changes in formulation . One example of information that the CCCs were able to glean about adherence beliefs is as follows:"... both clients had the same problems of not adhering to their drugs because of their religious faith ... The patient had relied most on church norms and wanted to leave the drugs. So, we told him that going to church was not bad and trusting in the Lord was good, but he should do both."One CCC accompanied her poorly adherent patient to the clinic in order to provide support to the clinic staff in reinforcing adherence behaviours. CCCs also played a key role in tracking patients who had been displaced during the post-election violence that occurred during January and February 2008.CCCs initially had some difficulties with using the PDAs in the field. There were problems keeping the PDAs' batteries charged, as well as issues with data entry. Paper forms were distributed to all CCCs to be used for back up when their PDAs lost charge or the CCCs had difficulties with data entry. A PDA refresher course was given four months into field work, and a tutor was assigned to the two CCCs who were having the most difficultly with data entry. PDA issues were cited much less frequently as problems during Year 2, when the most significant problems encountered were: a stolen PDA, which was subsequently recovered, but was not functional upon retrieval; and a problem with the study computer preventing the timely download of data from the PDAs for approximately a month.The only new theme that emerged during the second year of the project was the unexpectedly large number of pregnancies among stable patients being cared for by the CCCs. The CCCs felt that the majority of these pregnancies were unintended, and there was general discussion of how to better serve the reproductive health needs of their clients. However, other than general recommendations, such as referring patients to family planning services, there was no significant resolution of this issue.The CCCs described patient acceptance of their role early during their field work, as outlined in this quote:"... some of the patients are very happy to get their drugs at their homes. It is good now because during our visits, we discuss many confidential issues that we cannot reveal to anyone what we have discussed."By December 2006, CCCs reported encountering patients in the field who told them that they wanted to enrol in the CCC programme. By the end of the trial, of those not lost to programme, 64% (56 of 87) in the intervention arm and 52% (58 of 103) in the control arm were willing to continue in the programme (p = 0.26). Individuals were not asked why they chose not to re-enrol. However, study staff felt that study visit fatigue was a factor.The CCC model of task shifting, outlined in this paper, allowed us to operationalize Recommendation 20 of WHO's Task Shifting, global recommendations and guidelines, which states: "Community health workers, including people living with HIV/AIDS, can safely and effectively provide specific HIV services both in a health facility and in the community in the context of service delivery according to the task shifting approach".accompagnateurs in the Haitian model of care,Our CCC model was found to be acceptable to the clinic staff, the patients and the CCCs themselves, it was feasible, and it accomplished an approximately 50% reduction in clinic visits by the intervention group. Like the CCCs were found to enhance the care team by providing sometimes unexpected insights into patient adherence and psychosocial issues impacting care . In addiMonitoring and evaluation has been a significant concern among those advocating task shifting as a means of improving access to ART . Our conWe have learned four major lessons from this project. The first is that despite our provision of HIV treatment in the Kosirai Division since 2001, HIV disclosure remains an issue for our patients. As such, we recommend that programmes in our region that provide community-based HIV care consider how to represent and package this care in a way that avoids the AIDS label, much as the CCCs did by defining themselves as health counsellors.Second, we found that it took longer than anticipated for the CCCs to adapt to new technologies, particularly the use of PDAs. In future, we would recommend a full week being devoted to PDA didactics and structured exercises to ensure competency prior to field entry. However, our experience shows that new technologies, such as PDAs, cellphones, and electronic scales, thermometers and pulse oximeters, can overcome otherwise overwhelming logistical barriers to high-quality continuous care. The barriers include the lack of paved roads, especially during the rainy seasons, and the cost of public transportation.The third lesson is that patient referral must function bi-directionally and that mechanisms should be put in place to facilitate CCC referral to the clinic and clinic referral of follow up of particular issues to the CCCs.The fourth lesson is that such programmes are not without cost. There are the costs of training and mentoring CCCs , CCC salaries, equipment (including PDAs), PDA maintenance, and for patients in far-flung areas, the cost of transportation. However, since the goal of the CCC model is to reduce visits to the health centre, some or all of these costs should be offset by reducing health centre personnel time needed to care for CCC patients. In addition, for other programmes considering providing similar services, it is impossible to overstress the importance of identifying fully committed and engaged individuals to be CCCs.In conclusion, we found that an ART delivery model that shifted patient monitoring and ART dispensing tasks into the community by HIV-infected patients was both acceptable and feasible. Integrating this cadre to the care team enhanced the team's understanding of the psychosocial issues that impact on an individual patient's care. These findings provide advocacy, and support further exploration of the role of HIV-infected lay individuals in providing specific HIV-care services.The authors declare that they have no competing interests.KKW conceptualized and designed the study, developed the data collection instruments, performed the primary data analysis, had primary responsibility for interpretation of the data, and drafted the manuscript. JES assisted in the conceptualization and design of the study, development of the data collection instruments, interpretation of the results, and provided final approval to the manuscript. HMS assisted in data analysis, interpretation of results, and provided final approval of the manuscript. RV assisted in data collection, data analysis, interpretation of results, and contributed to the drafting of the manuscript. EKK performed data collection, interpretation of the results, and provided final approval of the manuscript. VTJ performed data collection, interpretation of the results, and provided final approval of the manuscript. LJB performed data collection, interpretation of the results, and provided final approval of the manuscript. AEC designed the PDA programme and provided final approval of the manuscript. WMT assisted in conceptualization and design of the study, interpretation of the results, and contributed to the drafting of the manuscript. SK assisted in conceptualization and design of the study, interpretation of the results, and approved the final manuscript. All authors have read and approved the final manuscript.


Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). Data Monitoring Committees (DMCs) often undertake such analyses, but their widening role may lead to extended use of interim analysis or recommendations that could potentially bias trial results.Annals of Internal Medicine, BMJ, Circulation, CID, JAMA, JCO, Lancet and NEJM, including all randomised controlled trials (RCTs) between June 2000 and May 2005 to identify RCTs that reported use of interim analysis, with or without DMC involvement. Recommendations made by the DMC or based on interim analysis were identified and potential sources of bias assessed. Independent double data extraction was performed on all included trials.Systematic search of eight major publications: We identified 1772 RCTs, of which 470  reported the use of a DMC and a further 116  trials reported some form of interim analysis without explicit mention of a DMC. There were 28 trials , randomizing a total of 79396 participants, identified as recommending changes to the trial that may have lead to biased results. In most of these, some form of sample size re-estimation was recommended with four trials also reporting changes to trial endpoints. The review relied on information reported in the primary publications and methods papers relating to the trials, higher rates of use may have occurred but not been reported.The reported use of interim analysis and DMCs in clinical trials has been increasing in recent years. It is reassuring that in most cases recommendations were made in the interest of participant safety. However, in practice, recommendations that may lead to potentially biased trial results are being made. Randomized controlled trials (RCTs) provide essential evidence on the efficacy and safety of medical interventions. Monitoring of accruing trial data is important to ensure participant safety ,2. The IWhen formalized, this role is commonly performed by a multi-disciplinary group of specialist, often referred to as a Data Monitoring Committee (DMC), which makes recommendations to those in charge of the overall management of the trial, often referred to as the Trial Steering Committee (TSC). Also, interim analyses should preferably be pre-specified in the trial protocol to minimize bias from unplanned analyses . DMC recWhilst it is widely accepted that the primary role of the DMC is to protect participant safety, several other roles of the DMC have been suggested, including recommending protocol amendments based on interim analysis . Such am"Many kinds of trial modifications  could, if made with knowledge of trial results, have significant effects on type I error and interpretation of final results. If it is perceived that emerging results could have influenced these types of interim protocol changes, the credibility of the trial may be severely damaged. In general, to minimize the potential for bias, the trial leadership, which is insulated from knowledge of the interim data, rather than the DMC, should be responsible for proposing potential changes other than those driven by safety considerations." [ations." It is unclear to what extent protocol modifications have been made in trials based on interim analyses, and more specifically as a result of recommendations by DMCs. Therefore, we systematically reviewed the reported use of interim analyses and DMCs to identify trials in which interim data have been used for reasons other than to make one of the recommendation described above, referring to these occurrences as "extended use of interim analysis" or "extended recommendations by DMCs" for the purposes of discussion here. Patterns of interim analysis use, roles assumed by the DMCs, and potential bias-related and ethical issues arising from such actions are discussed.Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases (CID), JAMA, the Journal of Clinical Oncology (JCO), Lancet and the New England Journal of Medicine (NEJM), to identify RCTs reporting the use of interim analysis with or without specification of a DMC, between June 2000 and June 2005. These journals were selected to include major generalist and specialist medical journals.A search strategy that allowed for the identification of relevant case studies with extended recommendations based on interim analysis or by DMC was used. We conducted a systematic search of eight journals, interim, monitor, early, stop, terminate, survival, death and mortality.The title and abstract of every citation in the full-text journal content databases published within the time period searched was checked to identify whether it was indeed a main results paper of a RCT. Subsequently, the full-text of all RCT articles in the Portable Document Format (PDF) was scanned using a set of keywords. These keywords were found to be most likely to appear in relevant sections of the articles during a piloting exercise. This included Identified RCTs were classified according to therapeutic area and assessed (by P.T.) to determine: whether mortality was listed as an endpoint , whether interim analysis was reported, and whether a DMC was reported. Various names referring to DMCs were considered.All trials reporting interim analysis were categorized, based on trial progress or outcome and therefore classified as either 'Continued to or Extended beyond planned conclusion', 'Early stop for benefit', 'Early stop for harm', 'Stopped for futility' or 'Early stop for other reasons'. Next, using information in the results and where available design articles or trial protocols, trials were assessed to determine whether other actions of the DMC or release of interim data could have led to "extended recommendations" and whether these had the potential to introduce bias or complicate the interpretation of the results.Independent double data extraction  was performed on all trials considered to have "extended" use of interim data or DMC recommendations. A non-linear model accounting for journal was used to estimate whether the rate of DMC use increased by year.Lancet published most trials , with JCO reporting the most mortality trials .In total, 1772 trials were identified, of which 470  reported the use of interim analysis and specified use of a DMC . A further 116 trials reported some form of interim analysis without explicit mention of a DMC, giving a total of 586  trials that reported the use of interim analysis. There was a higher rate of reported use in trials that included mortality as an endpoint . The BMJ to 58% (160/274) in the NEJM. The reported use in mortality trials also varied with the JCO reporting interim analysis in 35% (81/233) of such trials compared to over 70% in JAMA (44/69),NEJM (112/149) and the Lancet (94/130).The proportion of trial reports describing the use of interim analysis, with or without specification of a DMC, ranged from 10% (21/209) in the The reported use within specific therapeutic areas ranged from 30% 22/71) in Pediatrics to 47% (20/43) in Obstetrics and Gynecology (Table  in PediaThere was a significant (P < .001) rise in the number of trials reporting use of interim analysis over the period reviewed, with 86 trials reporting use between June 2000 to May 2001, and 151 trials for June 2004 to May 2005.Of the 586 trials that reported use of interim analysis, with or without specification of a DMC, 444 trials  continued as planned, 75 trials  stopped early because of benefit or harm to study participants, 26  stopped early for other reasons and 28  were stopped for futility  had "extended" use or recommendations and were further examined Figure . Of thesThere were 28 trials , randomizing 79396 participants, identified as having extended recommendations based on interim analysis with the potential to introduce bias to trial results, or to lead to problems with interpretation. Most were either cardiovascular or oncology trials and the extended use or recommendations noted in these trials are detailed in Additional file Among these, 24 trials  reported use of DMCs while there was reported use of interim analysis without specific mention of DMCs in the remaining four studies. Nine of these 28 trials were regulatory trials Figure .In 27 of the 28 trials that were judged to be open to bias, some form of SSR was recommended subsequent to the review of interim data. The recommendation for SSR was implemented as a protocol amendment in 26 of these  investigated the effects of carvedilol, a beta-blocker, in patients with left ventricular dysfunction following myocardial infarction . The oriIn a trial in chronic lymphatic leukemia that compared fludarabine with chlorambucil, the initial sample size was based on a comparison of the rates of complete remission . HoweverThe use of interim analysis and DMCs in clinical trials reported in major journals has increased in recent years. A possible explanation for the variation in the rate of reported use of interim analysis or DMCs among the journals searched Table  is the nAlso of note is the large proportion of trials that included mortality as an endpoint in the JCO but comparatively low rate of interim analysis and DMC use among the trials published in that journal, possibly indicating a need for increased uptake or improved reporting in the oncology sector.The majority of recommendations based on interim analysis or by DMCs were either to continue the trial as planned or to terminate early. This is reassuring as DMCs can be seen to be fulfilling their primary role of protecting participant safety. Our review also shows that, in practice, extended use of interim analysis or extended DMC recommendations are being made, some of which could potentially introduce bias and produce disputable results.A limitation of our review is that we relied on information reported in the primary publications and methods papers relating to the trials, therefore trial publications that did not acknowledge the use of interim analysis or DMC and related protocol amendments might not have been identified. Furthermore, many trials that are terminated early or amended during the course of the trial may never be published.The amendments identified were mostly sample size re-estimations due to insufficient accrual of participants or events. Power calculations are made based on assumptions that may not be reflected in the actual experience of a trial . SSR is A SSR made by the TSC based on overall event rates, without knowledge of the rates of events in specific groups, is not contentious and may be considered good practice. However, a recommendation for SSR made with knowledge of interim data introduces bias to the trial. For example, if SSR is undertaken based on a comparison of event rates observed during an interim analysis or if an SSR is conducted because of a lower than expected event rate in the control group. The latter introduces bias because rates in one group are integral to the result of the difference between the groups; this is a special case of regression to the mean .In PAD , the CPRIn the trials where SSR was performed subsequent to interim analysis based on overall rates or the review of masked data, it would seem that the investigators were on the whole attempting to be explicit that the SSR recommendation was made without introducing bias. However, whether in all these cases the DMC were truly blind to treatment allocation is debatable since in the former, DMCs often also have access to treatment arm-specific rates and in the latter, differences in adverse events or trends in data may have inadvertently led to unmasking.A trial examining whether low-dose dopamine attenuates renal injury as compared to placebo, where masking was implemented during the interim analysis , provideshould be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial [The primary endpoint he trial . ChanginIn the cases where changes were made to the primary endpoint ,15, it aIn the leukemia trial , multiplOur review of published trials indicates that the reporting of DMCs and interim analyses use in major journals has increased in recent years. Many trials, including those with mortality as an endpoint, did not appear to have any formal interim analysis, which is inadequate if we are to protect participant safety. In the majority of cases, recommendations were made based on interim analysis in the interest of participant safety and it is reassuring that there was only a small proportion of trials where extended use of interim analysis or recommendations made by the DMC had the potential to introduce bias.However, these trials involved nearly eighty thousand participants and most had formal DMCs. Many trials that stop early may never be published or are published in relatively obscure journals . Thus, tEmpirical evidence has shown that trialists can attempt to achieve a positive trial using multiple strategies and this is a very real concern . This rePT and MC have received research funding and consultancy fees from the pharmaceutical and medical device industry. JH and NF have received funding from a range of sources including the pharmaceutical industry, research charities and governmental bodies to undertake a number of roles in the design, conduct and interpretation of randomized trials.PT conducted the systematic literature review, selection and categorization of cases, data extraction, data analysis, writing of the manuscript, and is guarantor. MC conducted data extraction, data analysis, and writing of the manuscript. NF contributed to the data extraction, data analysis and writing of the manuscript. JH contributed to the development of the manuscript.The pre-publication history for this paper can be accessed here:NEURO-Neurology. Information in brackets:. * R denotes a regulatory trial or that the intervention was investigational when the trial was completed and DMC denotes specification of a DMC in the trial publication. DMC specified in 24/28 cases, R trials: 9/28 cases. ** TTE denotes time to event. *** Information in brackets: TA denotes that treatment arm specific rate were analyzed during interim analysis, OA denotes that overall rates were analyzed during interim analysis, Masked denotes that masking of data was maintained during interim analysis .RCTs identified as having extended use of interim analysis or extended recommendations made by DMCs, with potential to introduce bias. A list of trials identified as having reported extended use of interim analysis or recommendations by DMCs with the potential to introduce bias. Trials are sorted based on the interim trends observed or reason for interim analysis related recommendation. ^ CVD-Cardiovascular Disease, INF-Infection, OBGYN-Obstetrics and Gynecology, ONC-Oncology, Click here for file


While there is considerable research on medical workforce supply trends, there is little research examining the determinants of labour supply decisions for the medical workforce. The "Medicine in Australia: Balancing Employment and Life (MABEL)" study investigates workforce participation patterns and their determinants using a longitudinal survey of Australian doctors. It aims to generate evidence to support developing effective policy responses to workforce issues such as shortages and maldistribution. This paper describes the study protocol and baseline cohort, including an analysis of response rates and response bias.MABEL is a prospective cohort study. All Australian doctors undertaking clinical work in 2008  were invited to participate, and annual waves of data collections will be undertaken until at least 2011. Data are collected by paper or optional online version of a questionnaire, with content tailored to four sub-groups of clinicians: general practitioners, specialists, specialists in training, and hospital non-specialists. In the baseline wave, data were collected on: job satisfaction, attitudes to work and intentions to quit or change hours worked; a discrete choice experiment examining preferences and trade-offs for different types of jobs; work setting; workload; finances; geographic location; demographics; and family circumstances.The baseline cohort includes 10,498 Australian doctors, representing an overall response rate of 19.36%. This includes 3,906 general practitioners, 4,596 specialists, 1,072 specialists in training, and 924 hospital non-specialists. Respondents were more likely to be younger, female, and to come from non-metropolitan areas, the latter partly reflecting the effect of a financial incentive on response for doctors in remote and rural areas. Specialists and specialists in training were more likely to respond, whilst hospital non-specialists were less likely to respond. The distribution of hours worked was similar between respondents and data from national medical labour force statistics. The MABEL survey provides a large, representative cohort of Australian doctors. It enables investigation of the determinants of doctors' decisions about how much, where and in what circumstances they practice, and of changes in these over time. MABEL is intended to provide an important resource for policy makers and other stakeholders in the Australian medical workforce. Many countries are experiencing health workforce shortages ,2. MedicResearch has a key role to play in the development of effective policy responses to challenges such as these. There is increasing recognition of the need for and value of close connections between health services research and health policy, through making policy more evidence-based, and making research more policy-relevant,9. This Decisions made by doctors about where, when, and how much to work have profound effects on health systems, including equity, capacity, and quality of care. Doctors' labour supply decisions are influenced by a complex mix of factors, including their own preferences about work, leisure, family and lifestyle; economic and non-economic incentives embedded in health system financing and organisation; the culture of medical practice; and longer term trends in demand for health care, demographic change and the composition of the medical workforce.Existing research has described some of the key trends in Australian medical labour supply, many of which are similar to those in other developed countries. There are notable changes in the gender composition of the workforce, with 34% of Australian doctors in 2006 being female, compared to 18% in 1981,11. FemaThere are a number of important changes associated with these trends, such as decreases in average working hours and differences between cohorts in preferences about workforce participation. Average working hours for female doctors have decreased by 4.6 hours per week 11%) since 1994, while those for male doctors have decreased 9.3 hours per week (17%),11. This% since 1While there is a considerable body of research and data describing trends in Australian medical labour supply, there is little research, nationally or internationally, examining the determinants of labour supply decisions for the medical workforce. Although many of these trends are influenced by differences in the preferences of younger cohorts of doctors, they are also influenced by the institutional structures of the health care system, and can therefore potentially be influenced by government policies. This is especially the case for workforce participation, hours worked, workforce distribution, and specialty choice. Although global health workforce shortages suggest that more doctors need to be trained, this is expensive and has very long time lags. There are many other potential policy responses that could increase the productivity of the existing workforce, change the distribution of doctors, or shift tasks to other health workers. Longitudinal data and appropriate statistical analysis are essential for exploring the links between labour supply and its determinants, and large longitudinal data sets covering the entire medical workforce (not just recent graduates) that can be used for this purpose are scarce. The dynamic nature of medical labour markets  makes the use of longitudinal data especially important.We have commenced a longitudinal survey of medical labour market dynamics in Australia, focusing on several key outcome measures including the number of hours doctors work, and decisions to change job, move location, enter a particular medical specialty, or leave the medical workforce. The Medicine in Australia: Balancing Employment and Life (MABEL) study is designed to describe and understand key determinants of these outcomes, including working conditions, job satisfaction, family circumstances, and incentives.As noted before, the MABEL study was designed to provide research evidence of direct relevance to identified policy issues. The study is advised by a national Policy Reference Group which is a key mechanism to support research-policy linkage. This group comprises representatives from Commonwealth and State government health departments other key organisations such as Rural Workforce Agencies and the Australian Institute of Health and Welfare. The Group helps to ensure that the study is informed by current policy issues and priorities, and to assist in the translation of findings into the policy context.Implementing a national longitudinal medical workforce study such as MABEL is not without significant challenges. The aim of this paper is to describe the methods and the baseline cohort of the MABEL study. We provide a detailed examination of representativeness, through analysis of response rate and response bias.http://mabel.org.au. The first wave of data collection, establishing the baseline cohort for the study, was undertaken in 2008, and annual waves of data collection are planned until at least 2011. For the second and subsequent waves, the initial group of responding doctors will be surveyed in addition to a 'top-up' sample that will include all new doctors in the sample frame since the first wave. This will help replace any attrition and maintain the cross-sectional representativeness of each wave.MABEL is a prospective cohort study of workforce participation and its determinants among Australian doctors. Further information, including copies of the survey instruments, is available on the study's website, Our population of interest is doctors providing clinical medical services in Australia. The most recent estimate of the total medical workforce in Australia (for 2006) was 62,425 doctors, with 58,167 (93%) of these working as clinicians. Within MABEL's sampling frame was the Australasian Medical Publishing Company's (AMPCo) Medical Directory. This national database is used extensively for mailing purposes . The Directory is updated regularly using a number of sources. AMPCo receives 58,000 updates to doctors' details per year, through biannual telephone surveys and checks medical registration board lists, Australian Medical Association membership lists and Medical Journal of Australia subscription lists to maintain accuracy. The directory contains a number of key characteristics that can be used for checking the representativeness of the sample and to adjust for any response bias in sample weighting. These characteristics include age, gender, location, and job description (used to group doctors into the four types).At the time of the study's first wave in June 2008 the AMPCo database recorded 58,620 doctors practising in Australia, excluding those known to be not working due to retirement, maternity leave, overseas location or other reasons. Of the 58,620 doctors, 1,552 (2.6%) could not be assigned to one of the four doctor types, either because they did not supply this information to AMPCo  or because they were not undertaking clinical practice (291). 1,263 doctors (2.2%) did not allow their contact details to be released and 1,059 (1.8%) were non-contactable because they were in the process of having their contact details verified. This left 54,746 doctors in the sampling frame.Based on results from our piloting, we decided to invite the entire population of doctors rather than select a random sample from the AMPCo list as our sampling frame for MABEL. Our third pilot survey , indicated that the census approach was the most cost-effective method to produce a large and representative cohort .Response rate calculations were based on the combined totals from respondents in the third pilot study (February 2008) and those in the main wave (May 2008), as the survey content was very similar. The numerator included respondents to the third pilot and main wave. The denominator included 54,746 from the main wave sample frame from AMPCo in May 2008; plus 35 doctors who were in the sample frame for the third pilot in February 2008 but not in the main wave sample frame in May 2008 (i.e. they were no longer listed in the AMPCo database); less 31 doctors who responded to the first two pilots in October and November 2007. We felt it was not appropriate to send these respondents an invitation to participate in the main wave, due to the short time interval since they completed the pilot study. Thus, the final denominator for the baseline cohort used to calculate the response rate was 54,750.Study questionnaires went through four stages of piloting. First, the content and face validity of the questionnaire was examined through face-to-face interviews with two to three doctors for each of the four doctor types. Three pilot surveys were administered to random samples of doctors from the AMPCo list , helping to ensure that the final versions were as relevant, concise, and clear as possible. The Policy Reference Group provided input to ensure relevance to current policy issues.The baseline Wave 1 questionnaire included eight sections: job satisfaction, attitudes to work and intentions to quit or change hours worked; a discrete choice experiment (DCE) examining preferences and trade-offs for different types of jobs; characteristics of work setting ; workload ; geographic location; demographics ; and family circumstances (partner and children).Job satisfaction was measured using a widely used measure, the ten item version of the Warr-Cook-Wall Job Content Questionnaire -20. The Different versions of the survey questionnaire were created to tailor the content to the four groups of doctors. A different DCE was administered to each type of doctor. For general practitioners (GPs), the focus was on working in a non-metropolitan area. For non-specialist hospital doctors (the majority of whom are junior doctors in their early postgraduate years), the focus was on speciality choice. For doctors enrolled in a specialty training program and for specialists, the focus was on the balance between public and private sector work. The longest version of the questionnaire  contained 87 questions in a 13-page booklet. There is strong evidence that shorter questionnaires yield higher response rates, but in our case it was important to be able to adequately test hypotheses about the potentially wide range of factors that influence labour supply decisions, thus reducing confounding.Invitations to participate in MABEL were distributed by mail through AMPCo, in early June 2008. The invitation package included:• A cover letter on university letterhead using personalised participant information and coloured ink• A copy of the survey questionnaire, printed in colour• An explanatory statement providing information about the study, in colour• A reply-paid envelope,26.• A form to request another version of the survey, for example where the doctor was no longer in a specialist training program but was now a specialist.Doctors were given the choice of completing a paper copy of the questionnaire or an online version through the secure study website, and were provided with login details in the invitation letter. The content of the online version was identical to the paper version. Participants were able to move forward and backward through the online survey sections and to complete the survey in multiple sessions. Participants completing the online version are presented with a consent form on the log on page for the survey. By logging on, the participant consents to taking part. Participants completing the paper version provide consent by the return of their questionnaire by mail.In order to be able to draw meaningful inferences about recruitment and retention in rural and remote areas, we needed to ensure a high response rate in these regions, where absolute numbers of doctors are small. Pre-paid monetary incentives, not conditional on response, have been shown to double response rates. Cost coIn the eight months prior to the mail out, the study was widely publicised through direct contact with over 100 medical organisations and medical training colleges and providers. Articles were included in the newsletters and on the websites of many of these organisations. Prior to mail out, MABEL was formally endorsed by over 31 major medical professional organisations such as royal colleges, rural medical groups and medical educational agencies, and this information was included on the cover page of the questionnaire and the study website.Approximately 4-6 weeks after the initial mailout, a reminder letter was posted to those yet to respond. A copy of the questionnaire was not included with the reminder. The reminder letter was personalised and included an invitation to request another copy of the survey questionnaire, or to log on to the website to complete the survey.The study was approved by the University of Melbourne Faculty of Economics and Commerce Human Ethics Advisory Group (Ref. 0709559) and the Monash University Standing Committee on Ethics in Research Involving Humans (Ref. CF07/1102 - 2007000291).Data collected through paper questionnaires were entered into an electronic database by a commercial data entry company using double-entry for all variables. A subsequent check of a random sample of 5% of the items entered from the paper questionnaires  found 99.72% accuracy. Additional analysis and cleaning took place to further improve the accuracy of data entry.Data collected using the online versions of the questionnaires automatically generated a record in an electronic database. These data were downloaded, and data from paper and electronic versions were merged. Standard data checks and cleaning procedures (e.g. range and consistency checks) were used to minimise errors and missing values and to maximise data quality. As noted earlier, all respondents from the third pilot were included in Wave 1.Data from subsequent waves of the survey will enable more sophisticated analyses which exploit the longitudinal nature of the data on each individual to arrive at more precise and unbiased estimates. Microsimulation models will simulate the effect of changes in determinants such as earnings, taxes, subsidies, job satisfaction, and modifiable job characteristics on key measures of labour supply for the whole population of doctors, providing a valuable resource for national and state workforce planning.The overall response rate was 19.36% . For the 566 doctors practising in small remote and rural communities who received a cheque with their invite letter, the response rate was 58.44%.A key issue in survey research is whether respondents differ from non-respondents in some way that is likely to impact systematically on the estimated outcome values. Variables which are of particular relevance to our key outcome variables include age, gender, doctor type, geographic location and hours worked.Age is a key factor that captures a number of issues including: life-cycle labour supply decisions, such as the decision to raise a family; the propensity of different age cohorts to fill out questionnaires; the 'middle' age ranges being more likely to respond due to lower satisfaction with work and with life in general; and doctors closer to retirement perhaps being less likely to complete the questionnaire because they may regard the survey as less relevant to their situation , especiaCompared to the total AMPCo population, MABEL has slight over-representation of doctors in all age groups up until age 60 Figure . RespondTable The locality and postcode of doctors' locations of practice were matched to the Australian Standard Geographic Classification Remoteness Areas to compare geographic distribution. Over-reFemales were over-represented within all doctor types. Over-representation of rural and remote doctors is most marked for GPs but is also apparent to varying degrees for other doctor types. Under-representation of doctors aged 60 and over mainly affects GPs and specialists. Many of the differences in response rates with respect to age, gender, doctor type and location are statistically significant, partly reflecting the large cohort size. The final dataset includes a detailed set of response weights based on a logistic regression model estimated for each doctor type.It seems likely that doctors who work longer hours would be less inclined to complete a survey than those who are less pressed for time. In general, the opportunity costs to respondents of filling out the survey are related to the time taken to complete the survey,31. To eWe have recruited a very large cohort of 10,498 Australian doctors who will be followed prospectively to explore trends in workforce participation and their determinants. This is the largest cohort of Australian doctors in any single research project - cross-sectional or longitudinal. Its size allows us to undertake multivariate statistical analyses, and over time we will draw additional statistical power from the longitudinal aspect of the data.This study adds to the methodological literature regarding adoption of new technologies in survey research, combining traditional and new methods for contacting potential participants and collecting data. We used posted letters for initial contact, and provided a paper copy of the questionnaire together with the option to use a secure, user-friendly, and flexible online version of the questionnaire.The study's adoption of explicit mechanisms to connect with the policy context is another notable methodological feature. The Policy Reference Group is a key aspect of this, assisting in translation of findings into the policy context, and ensuring that each wave of the survey is informed by an understanding of current policy issues. Another aspect is the release of de-identified MABEL data for use by other organisations. Release of baseline data is anticipated to occur in early 2010, with annual releases thereafter for subsequent waves. While this is relatively unusual in medical cohort research, it is common for large-scale longitudinal social research studies to make data available to other researchers  survey). We believe this will maximise the use of MABEL data and its utility to stakeholders and decision-makers.Our response rate of 19.4% is at the lower end of the scale for survey research. Published reviews of response rates for medical practitioners in large studies  have reported averages of 52%, with a range from 11% to 90%. There iOur analyses demonstrate no serious response bias in MABEL with respect to age, gender, geographic location and hours worked. Population data on hours worked are from two years before MABEL. If hours worked were decreasing over that time, then the observed differences may understate the true difference between MABEL respondents and the population. The evidence provides some confidence that we have successfully captured a reasonably representative cohort of doctors across the spectrum of hours worked, including those working long hours.Our findings accord with literature indicating that response bias is lower in surveys of specific populations, such as medical practitioners, compared to general populations,31,32,36Although many governments and organisations survey doctors, these are usually for census purposes to identify how many doctors there are, where they are practising, and hours of work. Most surveys are not linked over time at the individual level and cannot be used to understand the determinants of labour supply because of their limited range of information. MABEL is a unique longitudinal survey of Australian doctors, focusing on the determinants of labour supply decisions. MABEL will explore workforce dynamics over time, and identify influences on doctors' workforce participation patterns to inform policies for workforce support and management.The authors declare that they have no competing interests.AS, CJ, JH and GK conceived of the study. All authors participated in designing and developing the study instruments and procedures. SHJ performed the data analyses. AS, CJ, and SHJ interpreted the data. CJ and AS drafted the manuscript. All authors read the draft and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/50/prepub


We describe fundamental weaknesses in U.S. chemicals policy, present principles of chemicals policy reform, and articulate interdisciplinary research questions that should be addressed. With global chemical production projected to double over the next 24 years, federal policies that shape the priorities of the U.S. chemical enterprise will be a cornerstone of sustainability. To date, these policies have largely failed to adequately protect public health or the environment or motivate investment in or scientific exploration of cleaner chemical technologies, known collectively as green chemistry. On this trajectory, the United States will face growing health, environmental, and economic problems related to chemical exposures and pollution.Existing policies have produced a U.S. chemicals market in which the safety of chemicals for human health and the environment is undervalued relative to chemical function, price, and performance. This market barrier to green chemistry is primarily a consequence of weaknesses in the Toxic Substances Control Act. These weaknesses have produced a chemical data gap, because producers are not required to investigate and disclose sufficient information on chemicals’ hazard traits to government, businesses that use chemicals, or the public; a safety gap, because government lacks the legal tools it needs to efficiently identify, prioritize, and take action to mitigate the potential health and environmental effects of hazardous chemicals; and a technology gap, because industry and government have invested only marginally in green chemistry research, development, and education. Policy reforms that close the three gaps—creating transparency and accountability in the market—are crucial for improving public and environmental health and reducing the barriers to green chemistry. The European Union’s REACH  regulation has opened an opportunity for the United States to take this step; doing so will present the nation with new research questions in science, policy, law, and technology. Chemicals and products are bought and sold primarily on the basis of how much work they perform per unit cost, with very little attention given in the market to their potential impacts on human health and ecosystems throughout the chemical lifecycle. Hazardous chemicals have thus remained competitive, and broad industrial investment in green chemistry has lagged, despite efforts of some leading companies. Reflecting these market conditions, the nation’s research and education agendas have neither prioritized green chemistry development nor adequately prepared the next generation of scientists to lead the chemical enterprise toward sustainability. Collectively, the three gaps—and the market conditions they have engendered—present a formidable barrier to the scientific, technical, and commercial success of green chemistry in the United States.Facing a similar set of chemical management problems—and their consequences for human health and the environment—the European Union in 2006 enacted a sweeping new chemicals regulation known as the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) . REACH rBecause REACH applies equally in most aspects to manufacturers in the European Union and foreign importers, it is forcing change among chemical and product manufacturers far beyond Europe’s borders . ManufacAs U.S. producers prepare hazard and exposure information for the European Union Chemicals Agency (ECHA), the United States has a unique opportunity both to make use of the data and to revisit its own chemicals policy. In doing so, the United States should consider a portfolio of measures that simultaneously close the data, safety, and technology gaps. This approach will most effectively—and with minimal delay—instill within the chemicals market a more appropriate set of incentives and disincentives that are a precondition to motivating broad investment in green chemistry.As with REACH in the European Union, a new chemicals policy in the United States has the potential to fuel global demand for safer substances and processes, increasing the incentive for research and development in green chemistry while improving human and environmental health. It also could move the United States into a position of greater collaboration in international sustainability efforts and position the country as a global leader in green chemistry innovation. Environmental health scientists have an essential role in identifying and addressing the research questions that will arise with the development of a new U.S. chemicals policy.Over the last 150 years, the U.S. chemical industry has contributed significantly to both the national and global economy . The indThe scale of chemical production is correspondingly enormous: Data from the TSCA Inventory Update Rule (IUR) show that the United States produced or imported about 15 trillion pounds of chemical substances during the 2002 reporting cycle, or about 42 billion pounds per day . For theGlobal chemical production is projected to continue growing—about 3% per year, with a doubling rate of 24 years, rapidly outpacing the rate of global population growth  America. This grBecause of their wide distribution throughout the economy and environment, many industrial chemicals come in contact with people: in the workplace, in homes, through the use of products, and via air, water, food, and waste streams. Ultimately, at some point in their life cycle, all industrial chemicals will enter the earth’s ecosystems. Biomonitoring studies are demonstrating widespread human exposure to certain industrial chemicals and pollutants. In 2001–2002, the U.S. Centers for Disease Control and Prevention (CDC) looked for, and found, 148 synthetic chemicals and pollutants in the blood and urine of a representative sample of the U.S. civilian population . The 200Evidence that many xenobiotic chemicals pass through the placenta, entering and, in some cases, accumulating in the fetus, suggests they could pose significant risks to human development . Rising Workers are at particular risk from chemical exposures because, depending on their occupation, they can be more highly exposed to hazardous substances than the general public . AlthougOccupational health data are more readily available in Europe. During the development of REACH, European Union research on potential occupational health benefits afforded by the regulation projected that the improved safety of workplace chemicals could prevent up to 40,000 cases of asthma annually , an equal number of dermatitis cases, and 10,000 cases of COPD each year . The EurThe management and cleanup of hazardous waste is another externalized cost largely attributable to existing chemical technology choices. Each year, the United States spends more than $1 billion managing Superfund sites, and future costs are estimated at $250 billion . On the The cases noted above illustrate the expanding health and environmental problems attributable to an antiquated U.S. chemicals policy that has failed to keep pace with developments in either green chemistry or the environmental health sciences. Given the size of the chemical enterprise, the extent to which it is woven into the fabric of society, and the backlog of unexamined chemicals, a new approach is needed that does not rely on resource-intensive, chemical-by-chemical risk assessments in which government, at great public expense, bears the burden of proof. An integrated chemicals policy is needed that enables identification and prioritization of chemicals of concern and employs market and regulatory tools sufficient to motivate investment by industry in the design and production of safer chemicals and materials, based on the principles of green chemistry. Making this transition will require a chemicals policy that departs markedly from the federal policies of the last 30 years, of which TSCA is emblematic.The principles of green chemistry offer an upstream solution to many of the health, environmental, and economic problems related to industrial chemicals . ImplemeTo date, producers have not invested in green chemistry at a level commensurate with the scale and pace of chemical production . This isThe laws governing the chemical enterprise help define the incentives and disincentives that guide economic behavior in the market . We use Of the federal environmental statutes, TSCA is the only U.S. law intended to enable regulation of industrial chemicals both before and after they enter commerce. Other federal laws that pertain to chemicals are essentially “end-of-pipe” statutes that aim to control chemical emissions and exposures but do not permit premarket review of chemicals. Whereas TSCA potentially applies to some 83,000 chemical compounds, five other major U.S. statutes combined currently apply to only 1,134 chemicals and pollutants  Table 1Table 1.TSCA was the U.S. response to conditions in which, before 1976, tens of thousands of chemicals entered markets without any form of accountability or oversight . CongresChemical producers should develop adequate data on the health and environmental effects of chemical substances and mixtures.Government should have adequate authority to regulate chemical substances that present an unreasonable risk to health or the environment, and to take action on imminent hazards.The government’s authority over chemical substances should not create unnecessary economic barriers to technological innovation.Based on these goals, TSCA promised to be an important step forward in the regulation of industrial chemicals. In practice, however, its legal and procedural requirements have largely thwarted these objectives.a) that a substance may present an unreasonable risk to human health or the environment, or b) that there is either significant human exposure potential or substantial quantities of the chemical are produced, imported, and released into the environment  chemicals—those produced or imported at more than one million pounds per year—made up > 99% by volume of the 15 trillion pounds of chemicals in commerce. Although these HPV chemicals constitute only one-third of existing chemicals by count, their high volume raises concern about the lack of basic hazard information on existing chemicals. Although the U.S. EPA’s New Chemical Program requires some minimal data on chemicals introduced since 1976, these chemicals make up < 1% of the production volume of the substances under the jurisdiction of TSCA .In tacit acknowledgement of its constraints, the EPA has turned to voluntary initiatives to close the data gap on existing chemicals. The HPV Challenge  is one sGiven that the U.S. EPA bears the burden of proof, the agency is further constrained by the level of evidence required to take regulatory action. To regulate a chemical, TSCA §6 requires the U.S. EPA to provide substantial evidence of all of the following conditions: The chemical presents or will present an unreasonable risk to health and the environment; the benefits of regulation outweigh both the costs to industry of the regulation and the lost economic and social value of the product; the U.S. EPA has chosen the least burdensome means of addressing the source of unreasonable risk; and that no other statute could adequately address the risk .Under this evidentiary burden, the U.S. EPA has been able, since 1976, to use its formal rule-making authority to partially regulate five existing chemicals : polychlorinated biphenyls (PCBs), chlorofluoro carbons, dioxins, asbestos, and hexavalent chromium . Of thesTSCA does grant the U.S. EPA relatively more authority to regulate new chemicals introduced since 1976, as well as new uses of existing chemicals. Producers must submit premanufacturing notices (PMNs) before marketing a new chemical. However, there is no required minimum data set beyond information already in the possession of the producer at the time they file the PMN. This has created a disincentive for manufacturers to investigate their products’ potential hazards because, although known hazards must be reported, ignorance of hazard is not penalized. Not surprisingly, an EPA evaluation found that 85% of PMNs lacked data on chemicals’ health effects, and 67% lacked health or environmental data of any kind . HindereExtensive trade secret claims permitted under TSCA have exacerbated both the data and safety gaps. Although some protection of proprietary information is necessary, in practice the statute’s allowances for confidential business information (CBI) claims have severely limited access to basic information on chemical identity and use. In 2005, the U.S. EPA reported that 95% of PMNs submitted by producers contained some information claimed as confidential . One assVision 2020 report, the Web sites of the 50 largest U.S. chemical companies all state their commitment to reaching sustainability goals, but their spending on research and development has remained level or declined since about 2000  and by stymieing effective regulation of well-known hazards (safety gap), TSCA has produced a chemicals market that favors existing chemicals over newer and potentially less toxic substances. As a result, the statute provides little motivation for industry investment in green chemistry research and development. The vast majority of chemical products manufactured in the United States rely on technologies developed 40–50 years ago, a fact that led the Council for Chemical Research to call for new technologies that incorporate economical and environmentally safer processes, use less energy, and produce fewer harmful byproducts . Twelve out 2000 . A Natioout 2000 .Public investment is also critical to the development of green chemistry. The U.S. experience in other sectors illustrates that investment by government, federal laboratories, and research universities helps spur innovation of new technologies .It is a reflection of the priorities of the U.S. chemicals market that, with rare exception, students can earn an undergraduate or graduate degree in chemistry at universities throughout the United States without demonstrating an understanding of the principles of toxicology, ecotoxicology, or green chemistry . EducatiThe most striking implication of the data gap is that the U.S. EPA lacks the information it needs to identify potential threats to public health and the environment. Perhaps equally significantly, the data-poor market makes safer alternatives difficult to distinguish from hazardous chemicals, distorting market signals . FurtherThe safety gap compounds these problems by allowing the commercial circulation of hazardous substances. The high level of evidence TSCA requires of the U.S. EPA makes it difficult for the agency to act on information it does have and impose restrictions on chemical use. With the burden of proof on government, lack of information increases the likelihood that hazardous chemicals will not be regulated. Some have argued that what begins as a regulatory disincentive for producers to generate or disclose hazard information has become an incentive to create misleading information that casts doubt on scientific evidence . Given tFinally, as a result of the incentives created by TSCA, chemical producers are rationally motivated to defend existing chemicals . Those iAlthough large “sunk” investments in existing chemicals and processes could make it difficult to transform the industrial system to one based on the principles of green chemistry, industry will have to make this transition if the United States is to meet the challenge of economic and environmental sustainability.The transition to a sustainable chemical enterprise in the United States will require a fundamental reform of TSCA that meets three overarching objectives:Close the data gap: Provide for the effective operation of the chemicals market by requiring that chemical producers generate, disclose, distribute, and effectively communicate sufficient information to stakeholders on the hazard properties of chemicals.Close the safety gap: Provide government with the legal tools necessary to identify, prioritize, and take action to reduce chemical hazards and exposures.Close the technology gap: Build capacity in cleaner chemicals and processes by incorporating scientific, technical, legal, and policy-related elements of green chemistry into the nation’s education and research infrastructure.Accomplishing these objectives will require both supply-side and demand-side strategies . Supply-The two approaches operate in tandem: Demand-side strategies provide the requisite drive for supply-side solutions by generating the market need for new science and technology. That is, demand stimulates the private and public investments necessary to advance green chemistry innovation. The importance of market demand as a driver for industrial innovation is well established in the environmental sector. A survey of the executives of 90 leading companies operating in 13 European Union countries identified public policy and market demand as the two most important factors necessary for motivating environmental innovation in their companies . Recent Undertaking meaningful chemicals policy reform in the United States will engender new research questions that must be informed by the environmental health sciences. Through the lens of the three policy gaps, these questions include the following:What is the most useful and attainable body of standardized hazard and exposure information that should be generated for chemicals, and how should a chemical’s sales volume and inherent hazard traits drive the scope of data requirements?What is the proper role of producers in generating these data, and how can the credibility, standardization, and quality of these data be assured?In what ways can emerging predictive toxicity testing and exposure methods be applied to meet these data needs?What information on chemical hazards, exposures, and uses if made publicly available would most effectively protect public and environmental health and motivate the development of safer alternatives?What are the most effective means of communicating chemical hazard and exposure information to stakeholders, including product formulators, downstream businesses, communities, workers, consumers, and government agencies?On what measures of hazard and exposure  should chemicals be prioritized and safer alternatives defined?To what extent (and in what ways) should producers carry the burden of proof of chemical safety?What level of evidence of potential harm to health or the environment is sufficient to trigger government action?What portfolio of actions should government employ to efficiently address identified hazards?What are the appropriate bounds of producer responsibility over the life cycle of chemicals and products, and what policies can best ensure producer responsibility within these bounds?How can developments in the environmental health sciences  best be communicated to the chemical enterprise so as to drive continuous improvement in chemical design?What are the high-priority chemicals and processes that warrant publicly funded research into green chemistry alternatives?What are the scientific, technical, and practical barriers to implementing these alternatives, and how are these barriers best addressed?How should green chemistry inform the development of next-generation environmental technologies, such as alternative energy and building materials, to reduce their health and environmental impacts and improve their overall sustainability?How should green chemistry education be designed to better prepare scientists, engineers, and decision makers to respond to the challenges of sustainability?Although some leading businesses have adopted green chemistry methods, the vast potential of green chemistry remains untapped. This primarily reflects the priorities of the U.S. chemicals market, in which chemical safety is undervalued relative to function, price, and performance. Hazardous chemicals have thus remained competitive, despite the many costs society bears as a result of their production, use, and eventual disposal. These market conditions are a consequence of the chemical data gap, safety gap, and technology gap that have grown out of weaknesses in the language and implementation of TSCA. A new U.S. chemicals policy has the potential to address the societal costs—human, environmental, and economic—that have accompanied advancements in the chemical enterprise.New chemical and product laws in the European Union have opened an opportunity for chemicals policy reform in the United States. A fundamental restructuring of TSCA will need to simultaneously correct the data, safety, and technology gaps using strategies that improve both the demand for and supply of green chemistry technologies. The attendant research questions demand engagement from the environmental health sciences, and their solutions offer the possibility of improving human health and environmental protection while moving the United States to a position of global leadership in green chemistry innovation.