AbstractDevelopments in soil ecotoxicology started with observations on pesticide effects on soil invertebrates in the 1960s. To support the risk assessment of chemicals, in the 1980s and 1990s development of toxicity tests was the main issue, including single species tests and also more realistic test systems like model ecosystems and field tests focusing on structural and functional endpoints. In the mean time, awareness grew about issues like bioavailability and routes of exposure, while biochemical endpoints (biomarkers) were proposed as sensitive and potential early-warning tools. In recent years, interactions between different chemicals (mixture toxicity) and between chemical and other stressors attracted scientific interest. With the development of molecular biology, omics tools are gaining increasing interest, while the ecological relevance of exposure and effects is translating into concepts like  stress ecology, ecological vulnerability and trait-based approaches. This contribution addresses historical developments and focuses on current issues in soil ecotoxicology. It is concluded that soil ecotoxicological risk assessment would benefit from extending the available battery of toxicity tests by including e.g. isopods, by paying more attention to exposure, bioavailability and toxicokinetics, and by developing more insight into the ecology of soil organisms to support better understanding of exposure and long-term consequences of chemical exposure at the individual, population and community level. Ecotoxicogenomics tools may also be helpful in this, but will require considerable further research before they can be applied in the practice of soil ecotoxicological risk assessment. Ecotoxicology studies the effects of chemicals on organisms in the environment, with the final aim to protect the structure and functioning of ecosystems. This aim generally is achieved by assessing effects on single species of selected test organisms and trying to extrapolate the obtained (no) effect concentrations to safe levels for populations and communities. In the ecotoxicological risk assessment of chemicals, such safe levels are then compared with predicted or measured exposure levels to assess the possible risk for exposed ecosystems.This paper will give an overview of developments in soil ecotoxicology, focusing on soil invertebrates, starting with a historical overview. Based on that, the state-of-the-art of current soil ecotoxicology will be depicted. This is done by first describing the way soil ecotoxicological data are used in the risk assessment of new and existing chemicals or the assessment of the risks of soil contamination. Next, the development of soil toxicity tests is outlined, followed by considerations on the inclusion of bioavailability, and the use of multiple species, model ecosystem and field tests. Then tools of assessing the possible risk of contaminated soils are described. Finally, some thoughts are given on the future of soil ecotoxicology. As this paper was written on the basis of a presentation at an isopod meeting, special attention will be given to the use of isopods in soil ecotoxicological testing.When thinking of ecotoxicological effects, it is often referred to Rachel Carson, publishing her book ‘Silent Spring’ in 1962. This book was among the first describing the negative side-effects of the increasing use of synthetic pesticides that started from the second World war onwards. The book mainly focused on pesticide effects on birds, especially singing birds that apparently became silent due to the effects of chlorinated pesticides accumulating in the food chain. This book however, was not unique in ringing the alarm bell, although other bells did not sound that loud.PageBreaksurvival  uses laboratory toxicity tests to obtain toxicity data that are used to derive safe levels of chemicals in the environment. The second approach is assessing the actual ecological risk or damage in case of pollution. This diagnostic approach (diagnosis) enables setting priorities for remediation and risk reduction, and may provide triggers for the management of contaminated land.In ecotoxicological risk assessment, two approaches can be distinguished. One approach aims at predicting possible effects of (new) chemicals in order to regulate their use or prevent their introduction onto the market. This predictive approach , EC10 and EC50 , and NOEC and LOEC . Since there is no ‘most sensitive species’ a battery of toxicity tests is needed to obtain proper insight into the potential hazard of a chemical for the ecosystem. In prognosis, the outcome of toxicity tests is used to establish thresholds or safe levels of chemicals in soil, which can be compared with measured or predicted exposure data (soil concentrations) to assess the  risk.PageBreakA critical part of this procedure is the derivation of safe levels of chemicals on the basis of available toxicity data. When only short-term (acute) toxicity data are available  or data for a limited number of species, somewhat arbitrary application factors are applied to derive safe levels that should protect ecosystems. For example, when only one or two LC50 values are available, a factor of 1000 is applied to the lowest LC50 value; this factor should be sufficient to extrapolate from acute to chronic effects (factor of 10), from one or few species to many species (factor of 10), and from laboratory to field (factor of 10). When sublethal toxicity data  are available for 3 or more species, application of a factor of 10 to the lowest value is considered sufficiently protective. When many toxicity data are available (preferably ≥ 8) for species representative of different taxonomic groups (see below), a statistical method may be applied. Such a statistical method is used to construct a species-sensitivity distribution (SSD), which assumes a log-normal or log-logistic distribution of the sensitivities of species in an ecosystem. From such an SSD the 95% lower limit is selected as the safe level. At this level, at least 95% of the species in the ecosystem are supposed to be safe . But also Environment Canada, the United States Environmental Protection Agency (EPA) and ASTM International  have described similar methods. Recently, for the same organisms, avoidance behaviour tests have been described, while for earthworms and enchytraeids a bioaccumulation test is available. PageBreakuseful exposure method for the rapid screening of chemicals, assessing the uptake and/or biotransformation of chemicals or other types of mechanistic research.The oldest standardized toxicity test guideline with soil invertebrates, OECD 207 , describEisenia fetida or Eisenia andrei and the enchytraeid test with Enchytraeus albidus, this means exposing adult worms for 28 and 21 days, respectively, after which they are collected from the soil; the cocoons are incubated for another 28 or 21 days, respectively to enable determining the number of juveniles produced. Nowadays, Enchytraeus crypticus seems to be more commonly used for toxicity testing than Enchytraeus albidus. Since that species is smaller, adults are not removed from the soil and reproduction is determined after 28 days of exposure. Considering the shorter life cycle of Enchytraeus crypticus and its high reproductive output, limiting test duration to 21 days has recently been advocated  after 28 days exposure.A standardized test with snails has been developed by Folsomia candida (Folsomia fimetaria (Hypoaspis (Geolaelaps) aculeifer , endpoints  and test durations  depending on the aims of the study  reproduction also has been proposed as a test endpoint , and by Porcellio scaber of some chemicals with suspected endocrine-disrupting effects. Other isopod species, like Porcellionides pruinosis, are more easily cultured in the laboratory, and therefore may be more suitable for performing reproduction toxicity tests  and different endpoints. see e.g. . Anothersee e.g. . Neverthendpoint . Successts e.g., .Recently, avoidance response was introduced as an easy, fast and sensitive endpoint. For some chemicals avoidance response may be as sensitive as reproduction, while for others it is at least as sensitive as survival. Great advantage of avoidance tests is that they are fast, with test durations of no more than 2 days. Standard test guidelines for avoidance tests have been developed for earthworms  and CollIn addition to these tests with soil invertebrates, ISO and OECD have also developed a number of toxicity tests with plants, which are important in soil ecosystems as primary producers. Also, several tests are available focusing on the effects of microbial communities or processes performed by microorganisms, like nitrification.PageBreakConsidering the fact that for a proper risk assessment a battery of tests is desirable, it is important to consider the currently available test methods. The current set of available tests  field soils. Also with the aim to increase realism, the SECOFASE project started using the natural LUFA 2.2 soil  of lead (Pb). While in some soils all worms died, in other soils no mortality was seen and in the remainder of the soils only part of the earthworms died. This finding could be explained from the differences in soil properties, especially pH, clay and organic matter content that affected the availability of lead for the earthworms. The pore-water hypothesis or equilibrium partitioning theory was developed to enable linking toxicity of organic chemicals to the concentration available in the pore water  from a metal-contaminated and a non-polluted site to zinc via the food. Both groups showed the same EC50 expressed on the basis of zinc concentrations in the diet, but contrary to the expectation effects could not be explained from zinc concentrations in the animals. So, it seems that flux of zinc through the animals rather than total zinc concentration was determining their sensitivity.The notion that soil type was important when determining the toxicity of chemicals went along with the increasing insight into the concept of bioavailability: only a fraction of the total amount of chemical in the soil is available for uptake by organisms and therefore of relevance for risk assessment. This was, for instance, demonstrated by re water , 1990. F complex  and many complex . It nowa complex . This waThese findings also suggest that when considering bioavailability, not only chemical partitioning of chemicals in the exposure medium  and pore-water concentrations have to be considered. The biology of bioavailability also needs attention. One aspect of this is the way organisms deal with chemicals. For metals, internal compartmentalization has been shown to be an important aspect , as it dFolsomia candida , which are excreted by these organisms with half lives of approximately 1 day . Earthwo candida . As veryLumbricus terrestris, which come to the soil surface to forage and mate at night, may experience a very high exposure shortly after pesticide spraying  being key items  ecotoxicology is the understanding of the long-term effects of chemicals on ecosystems. As such, focus on long-term sub-lethal effects is essential, but it also requires detailed understanding of the processes of exposure, uptake, internal processing  and intoxication in individual organisms as well as the translation of effects to higher levels of biological organization. From the overview presented in this paper, it may have become clear that soil ecotoxicology has shown a tremendous development in the past 40 years. From the initial realization that chemicals may affect soil organisms, through the development of standardized toxicity tests and the use of soil chemistry to develop the concept of bioavailability, soil ecotoxicology has grown to a mature field of science. The incorporation of biochemical and omics tools on one hand and the link with ecology on the other hand, does guarantee that soil ecotoxicology remains an important player in the field of stress ecology. In spite of the promising developments outlined above, the following aspects need further attention in the near future:Although several toxicity tests are available for soil organisms , it is oFor better enabling extrapolation from laboratory tests to the field and among soil types, it is essential to get better understanding of the routes of uptake of chemicals in organisms. This not only requires attention for the chemical aspects, but also needs a greater emphasis of the ‘biological’ aspects of bioavailability. This may also require paying closer attention to the way organisms are exposed in the field, and attention for the dynamics of exposure and bioavailability.For a better understanding of bioavailability but also of the toxicity of single chemicals and mixtures, it is essential to increase our understanding of toxicokinetics and toxicodynamics. Such understanding will also enhance the possibilities to extrapolate effects in time and to higher levels of biological organization, like the population level. Kinetics also is of great importance when considering the toxicity of new chemicals, like nanoparticles, that may show changing properties with time as a consequence of aggregation, agglomeration and dissolution processes. Finally, kinetics should not only address whole organisms but should also include the way organisms deal with chemicals internally .PageBreakand functional endpoints and for the application of trait-based approaches to understand and predict effects of chemicals on soil invertebrate communities and ecosystem services provided by these communities.For better understanding exposure in the field and predicting ecosystem effects, our knowledge on the ecology of soil invertebrates needs much better development. Such knowledge also is crucial for the description of the normal operating range of structural For the application of genomics tools in the diagnosis of soil pollution it is essential to better understand the link between gene expression level responses and ecologically relevant endpoints. A better understanding of gene expression responses may also help unraveling the mechanisms of action of chemicals, single and in mixtures, and as such be helpful in predicting toxicity. In the long run, a better understanding of responses at the genomics level may even provide tools for cross-species extrapolation and the development of completely new models for mixture toxicity, especially when combined with toxicokinetics and toxicodynamics data. Genomics tools may also help unraveling the causes of long-term effects of chemicals, e.g. multi-generation effects as a consequence of accumulation of damage in earlier generations. But all these applications will require an enormous amount of information on the meaning of gene expression profiles in relation to background conditions, in relation to chemical exposure both outside and inside the body and related to ecologically relevant endpoints like growth and reproduction.


He is describing the photograph by Gertrude Kasebier in 1908, which inspired his print Mary's Turn. "…it was the drama of the purposeful woman and the pensive man which established the direction Mary's Turn was to take" (Born to an affluent Pennsylvania family, Cassatt enjoyed a privileged childhood and cultural opportunities at home and abroad. Independent and strong willed, she prevailed upon her reluctant parents to let her enroll, at age 16, in the Pennsylvania Academy of Fine Arts in Philadelphia. Against convention, she soon resolved to pursue an artistic career and set off to Paris to study the Old Masters. When the Franco-Prussian War broke out in 1870, she returned briefly to the United States but left again to travel in Italy, Spain, and Belgium and to finally settle in Paris, where she lived the rest of her life.In the late 1800s, Paris was the center of the art world. Its architecture and transportation system set the standards for 20th-century urban living. Émile Zola described the travails of common people, Claude Debussy found new musical expressions, and French politics was undergoing a democratic revolution. Cassatt set up her studio and studied with academic painter Jean-Léon Gérôme. Her early work was influenced by the realism of Gustave Courbet and Eduard Manet (The rigid rules of the Salon and passion for creative freedom drove artists to independent exhibits. "I only began to live," Cassatt asserted, "…at the moment Degas persuaded me to… exhibit with his friends in the group of Impressionists. I accepted with joy….I hated conventional art" ("It's true. There is someone who feels as I do," Degas once exclaimed in front of one of Cassatt's paintings ("It is essential to do the same subject over and over again, ten times, a hundred times," advised Degas ("You who want to make color prints wouldn't dream of anything more beautiful….You must see the Japanese," wrote Cassatt to fellow impressionist Berthe Morisot, after visiting an exhibition at the École des Beaux-Arts ("I suppose it is…Palmer's French blood which gives her organizing powers and determination that women should be someone and not something," reflected Cassatt about the exceptional qualities of Bertha Honoré Palmer, business woman and philanthropist (Americans were the first patrons of the impressionists, amassing substantial private and museum collections. Cassatt was a frequent advisor to collectors of both Old Masters and the avant-garde. When Louisine Havemeyer sought advice about a New York exhibition in 1915 showing paintings by Cassatt and Degas, as well as by Holbein, Rembrandt, and Vermeer, she advised, "…put a Vermeer of Delft near the Degas and let the public look first at the one and then at the other. It may give them something to think about" ("I doubt if you know the effort it is to paint! The concentration it requires, to compose your picture, the difficulty of posing the models, of choosing the color scheme, of expressing the sentiment and telling your story" (The Child's Bath, on this month's cover, is characteristic of Cassatt's mature work and elaborates on her preferred theme: women caring for children. Preference for the theme reflects her own affection for children and knowledge of 19th-century child-rearing practices. Several cholera epidemics in the mid-1880s prompted official promotion of regular bathing as prevention against disease. And after 1870, French mothers were encouraged to take care of their own children, instead of employing caretakers, and to use modern hygiene practices (Cassatt captures a private moment between a woman and a child. The two are absorbed in a domestic ritual, looking down, heads touching, arms interlocked. Aligned along strong diagonals, chubby legs boldly cross ample striped dress, in sharp contrast with circular shapes: heads, washbasin, pitcher. She gently rubs the small foot with one hand, the other holding the child securely in her lap. Lips are parted imperceptibly. Perhaps she is explaining the reflections inside the washbasin. The tender moment, is punctuated by the surroundings: a painted chest-of-drawers, placing the activity on the floor, from the child's perspective, while we have the oblique view from the top. Flowered wallpaper and portions of decorative carpet define the cropped edges of the composition."Even more important than the discovery of Columbus which we are gathered here to celebrate," said Bertha Honoré Palmer in her speech on the opening day of the World's Columbian Exposition in 1893, "is the fact that the general government has just discovered women." Though times have changed, Mrs. Palmer's words still ring true in much of the world. Caregiving and safeguard of the physical and emotional health of children go beyond the hygienic benefits of the bath and are tightly connected with the physical and emotional health of the caregiver. To remedy long neglect of the caregiver and protect against emerging health threats, it is time, as Cassatt put it, for women to pluck the fruits of knowledge and science.


The increasing global prevalence of suicide has made it a major public health concern. Research designed to retrospectively study suicide cases is now being conducted in populations around the world. This field of research is especially crucial in Aboriginal populations, as they often have higher suicide rates than the rest of the country.Qaujivallianiq Inuusirijauvalauqtunik (Learning from lives that have been lived) is a large case-control study, including all 120 cases of suicide by Inuit that occurred in Nunavut between 1 January 2003 and 31 December 2006. The article describes the research design, ethical considerations and strategies used to adapt the psychological autopsy method to Nunavut Inuit. Specifically, we present local social and cultural issues; data collection procedures; and the acceptability, reliability and validity of the method.This article presents the methodological aspects of the first psychological autopsy study on suicide among Inuit in Nunavut. A retrospective case-control study using the psychological autopsy approach was carried out in 22 communities in Nunavut. A total of 498 individuals were directly interviewed, and medical and correctional charts were also reviewed.The psychological autopsy method was well received by participants as they appreciated the opportunity to discuss the loss of a family member or friend by suicide. During interviews, informants readily identified symptoms of psychiatric disorders, although culture-specific rather than clinical explanations were sometimes provided. Results suggest that the psychological autopsy method can be effectively used in Inuit populations. Suicide, especially among youth, is one of the most important causes of death worldwide . Due to Qaujivallianiq Inuusirijauvalauqtunik (“Learning from lives that have been lived”) which included all 120 cases of suicide by Inuit that occurred in Nunavut between 1 January 2003 and 31 December 2006. This article describes the strategies used to adapt the psychological autopsy method to the investigation of suicide among Inuit living in Nunavut and presents the research methodology in detail. Findings from the study will be reported in subsequent publications.From 2005 to 2010, our group conducted large case-control study on suicide among Nunavut Inuit called Suicide is a multidimensional and complex phenomenon resulting from the interaction of many factors . In the The current international literature is marked by a mismatch between the enormous impact of suicide on Inuit communities and the paucity of scientific investigations in this field , 20. TheThis gap in the literature may be due, in part, to the methodological challenges involved in conducting studies on death by suicide compared to suicide attempts. In most populations, death by suicide is a rare event, and it is therefore not feasible to conduct prospective studies. Retrospective case-control designs using the psychological autopsy method to compare individuals who died by suicide with matched controls are practical alternatives to prospective studies.The psychological autopsy method was originally developed by Shneidman  as a tooInformation is usually obtained from multiple sources, including those closest to the deceased , 26. ForThe interviews used in psychological autopsies are semi-structured. They combine open-ended questions with standardised instruments. Open-ended questions are suitable to collect information about the trajectory of life events, childhood development and parent–child relationships. Standardised instruments can gather information about psychiatric disorders, impulsiveness, aggression, childhood abuse and personality traits. The selection of instruments for psychological autopsy interviews is dependent on the objectives of each study . TypicalPsychopathology alone does not account for suicide. For example, while major depression is the most prevalent diagnosis among those who die by suicide, the vast majority of people with major depression do not make suicide attempts , 42, 43.kappa coefficients above 0.65 for inter-rater and test-retest reliability and above 0.79 for most Axis I disorders , this methodology has been applied more recently to non-Western populations. Zhang et al. , 34 demoPsychological autopsy studies raise specific ethical issues. Particular care is required when approaching bereaved relatives and friends of those who died by suicide. In the case of Inuit communities, suicide directly affects both the immediate family and friends of the deceased and the entire community . Thus, cFor this project, we formed a network of collaborators who were familiar with Inuit and other Aboriginal communities and who were well versed in the ethical issues of the study before beginning their fieldwork. In keeping with the principles of participatory research  and the In order to minimise emotional distress and avoid the initial period of bereavement, we decided to approach families and friends of the deceased no earlier than 1 year after the death. In addition, the project was explained in great detail to each participant before the interview, and a consent form was provided in both English and Inuktitut. Informants were asked the language in which they would prefer to be interviewed. The choice was often English, especially among younger informants. When an informant requested that the interview take place in Inuktitut, they were invited to select an interpreter  with whom they were comfortable speaking openly. Participants were free to stop the interview at any point, as well as to interrupt and resume later on. The interviewers reassessed the participant's will to continue several times during the interview .Finally, separate consent forms were collected to review the medical charts of the individuals who died by suicide and the controls. For the former, consent was obtained from the closest first-degree relative . The controls provided consent for the review of their own medical records and indicated which informants the researchers should approach. Participants were financially compensated for their contribution (100 Canadian dollars) and could opt to receive the payment or to donate the compensation to an organisation of their choice.Individuals’ privacy and confidentiality were respected at all times. All names and personal details were omitted in research protocols and reports. As well, the interviews were always conducted in places where the informants’ privacy was assured. Given the high density of inhabitants per household in Nunavut, this was made possible by the personnel from health centres and local community administration.Before approaching each community, the research coordinator contacted the nurse in charge of the community health centre to inform them of our project and to collect any relevant information on the current status of the community . Upon arriving in the community, we met with the senior administrative officer and/or the mayor, the nurse in charge, and the RCMP to report our presence in the community and gather additional information. We discussed the families of the cases and controls  with the nurse in charge  in order to prepare for issues that could be raised during interviews. For example, it was crucial to ensure that no other deaths (by suicide or otherwise) had occurred in the family after 2006. In addition, it was important that the local professionals and community members be aware of the study in case informants needed assistance of any kind.Qaujivallianiq Inuusirijauvalauqtunik (Learning from lives that have been lived) project included all 120 cases of suicide by Inuit that occurred in Nunavut between 1 January 2003 and 31 December 2006, and 120 controls matched on age, gender and community of origin (Our f origin . The corThe mean age of the cases was 23.4 years (SD 9.13). Since the interviews took place after the completion of the suicide , the controls were older than the deceased at the time of the suicide. We analysed the difference between the dates of birth for each pair of case and control. To do so, we transformed the raw differences in days into absolute values, since controls could be selected even if they were born earlier than the case. As a result, the estimation of the raw differences yielded both positive and negative values that, if not transformed, might produce artificially minimal means and standard deviations. The mean difference between cases’ and control's date of births was 59.27 days (SD 72.26 days), with a minimum difference of 1 day and a maximum of 410 days.Among the suicide cases, 99 (82.5%) were male and 21 (17.5%) were female. The individuals varied in their method of suicide. Overall, 96 individuals died by hanging (80.0%), 19 by gunshot (15.9%), 4 by stabbing (3.3%) and 1 by overdose (0.8%).From March 2006 to July 2010, a total of 498 interviews were carried out with informants in 22 communities across Nunavut. A standardised methodology was used for all the interviews to ensure comparability between cases and controls. For the cases, first-degree relatives (mostly parents) were approached for consent and then interviewed. The living controls were contacted first due to ethical reasons, but were not interviewed. Rather, controls’ relatives and/or friends were interviewed in order to keep the same methodology across both groups.Overall, 498 interviews were conducted to obtain information on 240 individuals (120 cases and 120 controls). The number of informants per case or control was determined by the interviewer, based on the quality of the interviews and the amount of information gathered. For cases, 279 interviews were conducted (an average of 2.3 interviews per case), whereas for controls 219 interviews were carried out (an average of 1.8 interviews per control). Some interviews were carried out with 2 informants present . The majority of interviews were carried out with mothers, siblings, partners and friends of cases and controls .Instruments used in the study measured socio-demographic data, psychopathology, impulsiveness, aggressiveness, history of suicide attempts, family history of psychopathology, development and life trajectory. The selection of these instruments reflected the major risk factors for suicide completion  , 53, 54.qallunaat (white people), pride in Inuit culture, experiences with residential schools, opportunities to hunt and fish, ability to speak English, contact with the government and thoughts for the future of Nunavut among others.The instruments were thoroughly reviewed prior to the fieldwork to ensure that their content was appropriate for the Inuit context. Some items of the Life Trajectory Scale were modified, and others added in order to encompass important aspects of life in Inuit culture, such as experiences with The interviews were followed by a complete review of relevant medical records. For the controls, medical charts were available locally at the community's health centre. The charts for suicide cases in the Qikiqtani region were stored in the Qikiqtani Regional Hospital, while the charts of suicide cases in the Kivalliq and Kitikmeot regions were stored in the health centres of each deceased individual's community. With the available qualitative and quantitative data collected during the interviews and the information from the medical charts, the interviewer was able to determine whether each individual met specific SCID criteria for Axis I and II psychiatric diagnoses. Additionally, with information collected during the interview, the interviewer completed the measures of impulsivity and aggressiveness, history of suicidal behaviour, family antecedents of psychiatric disorders and the individual's life trajectory. Finally, the interviewer wrote a clinical-biographical narrative for each case or control, in which details of the individual's life were summarised. The biographical narrative described the individual's upbringing, familial relationships, academic performance, romantic experiences, interpersonal relationships, occupational life and detailed information about any psychiatric symptoms. This narrative, a copy of the medical records, and the completed set of instruments were sent to the coordinating centre for further processing.At the coordinating centre, the instruments were assessed to ensure completeness. Any discrepancy in information between instruments (or between an instrument and the content of the narrative summary) was identified and resolved by discussion with the interviewer. The narratives were then blinded to the group each individual was in so that cases and controls could not be obviously distinguished . The standardised case narrative, a summary of the medical records, and the final Axis I and II diagnoses were then forwarded to a panel of research collaborators to validate the final Axis I and II diagnoses that were given by the interviewer.The panel was composed of a clinical psychiatrist, a clinical psychologist with research experience and a senior research coordinator with extensive experience with the SCID I and II instruments. A detailed examination of the diagnostic criteria was carried out for each participant, in order to validate or change the diagnoses. This included determining whether the developmental and clinical history, as described by the narrative, supported the clinical diagnoses. DSM-IV-TR criteria were used as the basis for these assessments. An example of a change made by the panel involved replacing an original diagnosis of adjustment disorder with depressed mood by major depressive episode in a situation where the depressive symptoms started just after an important loss, but included consistent suicidal ideation and gestures, sadness, anhedonia, guilt and motor retardation. Particular attention was also paid to diagnoses of substance abuse . Finally, the panel carefully verified Axis II criteria to detect potential overlap with Axis I symptoms, such as items for paranoid personality disorder being endorsed in the presence of a schizophrenia diagnosis. Typically, panel sessions lasted 1.5–2 hours, and 7–10 cases were examined per session .Kappa coefficients were 0.84 for mood disorders, 0.83 for personality disorders, 0.79 for schizophrenia and 0.57 for substance abuse. Among these individuals, 15 had at least 1 Axis I diagnosis (either current or past). Only 7 individuals had 1 or more personality disorder.We carried out 30 interviews with participants from the control group to assess the validity of SCID I and II interviews. This method determines the level of convergence between self-reports and the informant's reports on our measures. Our team members were blinded to the information collected from the proxy-based interviews and carried out identical interviews with 30 controls, rating SCID I and II diagnoses following the same method that had been applied in all interviews. The information collected by these interviews was used only to estimate the validity of the method and was not incorporated into the controls’ files for the study. We calculated the level of agreement between the DSM-IV Axis I and II diagnoses obtained from the proxy-based interviews (the method of the study) and the interviews with the subjects themselves (the “gold standard” assessment) . Overallkappa coefficients demonstrated substantial agreement: 0.82 for mood disorders, 0.79 for substance abuse and 1.0 for schizophrenia.To assess inter-rater reliability, 15 audiotaped psychological autopsy interviews were selected from the McGill Group for Suicide Studies data bank. The interviews selected were conducted by one of the researchers that carried out the interviews in Nunavut, and listened to and re-rated by another interviewer independently. Both the ratings of the original interviewer and the re-rater were assessed. The Overall, the vast majority of individuals approached agreed to participate in the study. No entire family refused to be interviewed, so interviewers were able to collect information on all cases and controls that were approached. In a few families, 1 or 2 members declined to participate because they did not feel comfortable talking about the suicide. Nevertheless, these family members did not oppose the participation of other family members.Only 1 interview out of 498 had to be interrupted because of emotional distress, and therefore only 1 interview remained incomplete. Although several interviews were highly emotional and discussed intensely personal issues, most informants did not have negative reactions. On the contrary, participants of the case group (i.e. relatives or friends of the deceased) often voiced appreciation for the opportunity to talk about their feelings, as they had not received much attention following the suicide. Typically, reactions among the relatives and friends of the control group were neutral. This high level of acceptability for both groups is reassuring. However, it is important to recall that whenever possible the nurse in charge was contacted at the local community health centre prior to the interviews, and so certain potential informants were not contacted based on the nurse in charge's advice. The goal was to identify informants that knew the participant well and would be comfortable answering questions about him or her.The researchers found a high degree of face validity in the instruments used. Some items, however, may have been confounded due to the social context. For instance, the Barratt Impulsivity Scale  items nuThe literature in cultural psychiatry has raised questions about the cross-cultural applicability of conventional diagnostic categories and criteria. In this context, it is significant to note that the informants were able to understand questions related to symptomatology of the Axis I disorders. Particularly core symptoms of major psychiatric syndromes (such as major depression or psychotic conditions) were promptly recognised, and the participants were able to give clear examples. Often, the content of the interviews was confirmed by content of the medical charts. Informants were consistently able to recognise the expression of psychiatric symptoms . Explanations for the occurrence of symptoms, however, were often based on the Inuit cultural background, but this did not prevent recognition of the symptoms as pathological. For example, auditory hallucinations were described in 2 interviews as the revenge of an animal spirit that had been maltreated (according to Inuit tradition) by an Inuit hunter. Nevertheless, informants could identify the symptom as unhealthy and could indicate the point in time that it emerged. Again, these details were corroborated with medical charts. Additionally, unlike what is frequently the case in southern Canadian samples, Inuit informants were remarkably open and direct when describing alcohol and drug use  as well as family violence and abuse. Thus, although the interpretation of a symptom or behaviour might differ from that of Western psychiatry, there was no difficulty in collecting information on signs and symptoms of psychopathology.The majority of informants had positive responses to the interviews. Frequently, informants thanked the researchers for the opportunity to voice their feelings of grief caused by the suicide of a loved one. They mentioned that it was an important part of their healing process. In addition, the fact that the interviewers were “outsiders” was generally viewed as a positive aspect of the study. Since most communities in Nunavut have both a small number of inhabitants and complex networks of relationships, it can be challenging for some people to disclose intimate information. The interview gave people an opportunity to speak openly without fearing any negative repercussions within their family or community.This article describes the adaptation and implementation of the psychological autopsy method to investigate suicide among Inuit in Nunavut. This is the first study in Nunavut to explore suicide with this method. Our initial findings suggest that the psychological autopsy method, as described in this article, was feasible, well accepted and valid. Informants easily understood questions in the interviews and could answer them with detail and accuracy. There were very high rates of participation and minimal instances of interruption during interviews. Interviewers indicated that the informants were comfortable taking part in the interviews, and many informants were openly appreciative of the opportunity to speak about their lost family member or friend.Informants appreciated that interviews were private and confidential. They formed positive a relationship with the interviewer and were reassured by the fact that the interviewer was an “outsider” who did not know people in the community. Some also expressed that the interview helped individuals come to terms with the death and the challenges faced by the deceased before they passed away.Previous studies have reported the therapeutic effect of psychological autopsies , 58–60. The need for research on suicide among Inuit was recognised by the vast majority of informants as well as by health professionals in Nunavut. Overall, the attitude towards the project was positive. Authors have consistently identified the urgent need for effective interventions –63, and As an evaluation of the feasibility and acceptability of the psychological autopsy method in a specific cultural context, the present study has important limitations. There was no standardised assessment to measure the respondents’ reactions to the interviews. In addition, given the length and complexity of the interview process, we were not able to systematically assess informant's reactions to individual interview items. Nevertheless, interviewers and informants both had positive overall perceptions of the interviews. The low number of explicit refusals to participate or interruptions of the interviews themselves also indicated a high level of acceptance. Moreover, the relatively small number of respondents per subject may potentially have limited the amount of information that was collected per case. The inclusion of other sources of information  aimed to minimise this limitation.Inherent limitations in the psychological autopsy method also apply to our study . Some diIn conclusion, indications from this initial evaluation of the study's process and instruments suggest that psychological autopsy is a suitable and valid methodology for suicide studies with Inuit in Nunavut. Additionally informants indicated that they benefited from the psychological autopsy interviews. The method is able to address questions relevant to evidence-based suicide prevention.


There is an urgent need for clinically effective and cost-effective methods to manage antisocial and criminal behaviour in adolescents. Youth conduct disorder is increasingly prevalent in the UK and is associated with a range of negative outcomes. Quantitative systematic reviews carried out for the National Institute for Health and Clinical Excellence have identified multisystemic therapy, an intensive, multimodal, home-based, family intervention for youth with serious antisocial behaviour, as one of the most promising interventions for reducing antisocial or offending behaviour and improving individual and family functioning. Previous international trials of multisystemic therapy have yielded mixed outcomes, and it is questionable to what extent positive US findings can be generalised to a wider UK mental health and juvenile justice context. This paper describes the protocol for the Systemic Therapy for At Risk Teens (START) trial, a multicentre UK-wide randomised controlled trial of multisystemic therapy in antisocial adolescents at high risk of out-of-home placement.The trial is being conducted at 10 sites across the UK. Seven hundred participants and their families will be recruited and randomised on a 1:1 basis to multisystemic therapy or management as usual. Treatments are offered over a period of 3 to 5 months, with follow-up to 18 months post-randomisation. The primary outcome is out-of-home placement at 18 months. Secondary outcomes include offending rates, total service and criminal justice sector costs, and participant well-being and educational outcomes. Data will be gathered from police computer records, the National Pupil Database, and interview and self-report measures administered to adolescents, parents and teachers. Outcomes will be analysed on an intention-to-treat basis, using a logistic regression with random effects for the primary outcome and Cox regressions and linear mixed-effects models for secondary outcomes depending on whether the outcome is time-to-event or continuous.The START trial is a pragmatic national trial of sufficient size to evaluate multisystemic therapy, to inform policymakers, service commissioners, professionals, service users and their families about its potential in the UK. It will also provide data on the clinical and cost-effectiveness of usual services provided to youth with serious antisocial behaviour problems.ISRCTN77132214 This paper describes the protocol for the Systemic Therapy for At Risk Teens (START) trial, a UK evaluation of multisystemic therapy (MST) , an inteThe trial is being conducted at 10 clinical sites across the UK staffed by a team of therapists who have been trained in MST. All sites agreed to participate in a rigorous randomised controlled trial (RCT) as a condition of having a clinical team funded by the UK Department of Health in their locality. Before the launch of the trial, each of the 10 sites providing MST will have been operational in their locality for at least 12 months. This bedding-in period is intended to give each of the sites time to set up local steering groups and raise awareness of their service among referrers , as well as ensuring that the therapists are adhering to the therapeutic model of MST (see below). Each of the sites will join the trial in phases once all of these conditions are met to a satisfactory level, and the research team will then begin its evaluation. The duration of the evaluation is being funded by the Department of Health, Department for Education and Youth Justice Board.The need for an accessible, effective technology to manage antisocial adolescents is widely recognised as urgent ,3. YouthThe most serious youth antisocial behaviour is committed by a very small group of persistent offenders ,9. ThereIn the diagnostic systems developed for classifying mental health disorders of children and adolescents, serious and persistent antisocial behaviour is primarily associated with the diagnosis of conduct disorder (CD). CD is the most common mental health disorder in childhood and adolescence globally, with a lifetime prevalence of approximately 10% . It is tn = 34) of the offending sample, accounted for half (50.1%) of all self-reported offences, with eight times the average victim costs per offender compared with non-persistent offenders . The cumulative cost to services of individuals diagnosed with CD in their teens over a period of about 18 years was estimated, in 1998 values, to be £70,000 [CD and its sequelae place a massive burden on individuals and society, involving not just healthcare services and social care agencies but the family, neighbourhood, schools, police and criminal justice system. Welsh and colleagues  estimate £70,000 .MST is an intensive family- and home-based intervention for young people with serious antisocial behaviour , specifiMST aims to impact on the entire milieu in which the young person operates, by using multiple interventions, in combinations indicated by the clinical picture. The treatment approach integrates theoretical concepts and techniques from systemic and structural family therapy, parent training, marital therapy, supportive therapy related to interpersonal problems, social skills components, social perspective training, behavioural methods  and cognitive therapy techniques . The therapist has an active role as case manager , which includes acting as an advocate to outside agencies. MST has been widely adopted in the US and in other countries including Canada, the Netherlands, Norway, Sweden, Denmark, New Zealand and, most recently, the UK.P <0.0001) across seven studies [P = 0.07) [P = 0.10) [P = 0.05) [Recent, high-quality quantitative systematic reviews conducted for two separate National Institute for Health and Clinical Excellence (NICE) guidelines ,30 have  studies -36,43-46 = 0.07) ,46,47. O = 0.10) ,44,48. A = 0.05) -44,48,49The replicability of the findings from the US in other countries has been mixed. In large trials in Canada  and SwedIn the first RCT of MST to be conducted in the US without the direct involvement of the treatment developers, reoffending rates in the MST group remained high even though the intervention significantly reduced reoffending compared with TAU (66.7% versus 86.7%) . Effect n = 56) or the comprehensive, targeted services delivered by youth offending teams  was more effective in reducing offending and out-of-home placement in an ethnically diverse, urban sample of young people [These three conditions were met with the first UK RCT of MST conducted at the Brandon Centre in London, which evaluated whether MST  rather than the larger population of antisocial youth that are seen across child and youth services  across the UK. The target population and ecological context of the trial is important to consider, as provision of MST in the UK has expanded from one team at the Brandon Centre when the RCT was initiated in 2003 to over 30 teams currently functioning across the country. This expansion is a direct result of a UK government policy decision to help troubled families whose children and young people exhibit truanting and antisocial behaviour.There are several unresolved issues relating to transporting MST to other health and social care systems and jurisdictions, in addition to the obvious issue that the proposed application  is broader than the targeted samples of previous trials (see below). Additionally, in relation to a UK trial at least, the following issues require systematic monitoring: the clinical competences of therapists to practise MST in the light of curriculum differences for psychologists and social workers in the UK and the US; the stronger evidence base of usual services in the UK than TAUs used in previous clinical trials initiated by the developers of MST; differences in the motivation of MST therapists and the research team who were not involved in its development; contextual issues such as differences in national standards with regard to sentencing policy and practice; the need for appropriate measures and sufficient data for examining mediators (mechanisms accounting for the effects of treatment) and moderators  before, during and at the end of treatment; and the need for person-centred statistical analyses to identify typical trajectories of response  traits). It is therefore essential for this major UK trial to include as much detail as possible about the types of YOT and other services made available to young people in the comparator arm, including frequency of contacts with professionals.START is a national RCT to evaluate MST in the UK context. It has been designed as a pragmatic trial that will inform policymakers, commissioners of services and professionals about the potential of MST in the UK context.The primary aim of START is to establish whether MST is more effective than management as usual (MAU) in reducing out-of-home placement in a sample of adolescents at high risk of being removed from their homes because of antisocial behaviour. Secondly, the trial aims to determine whether the provision of MST leads to improved well-being for young people and their families, including improved emotional and behavioural functioning for the young person, closer family relationships, improved parenting skills, improved educational outcomes and reduced offending behaviour. Thirdly, the trial will establish whether MST is cost-effective compared to MAU and results in reduced costs across mental and physical health, criminal justice and educational systems. Finally, in terms of secondary outcomes, the trial will examine the mediators and moderators of treatment change, and determine whether specific groups of young people presenting with antisocial behaviour benefit to a greater or lesser extent from the intervention. Consistent with extant mediational studies of MST trials with a range of juvenile offenders ,50, we wIn addition, we will improve on previous MST trials, which have rarely examined empirically derived moderators of antisocial behaviour, by studying whether treatment outcome is influenced by the onset of participants’ antisocial behaviour, as well as their level of attention deficit hyperactivity disorder (ADHD) symptomatology and CU traits measured at the beginning of the intervention. Early-onset antisocial behaviour, comorbid diagnoses of ADHD and CD, and high levels of CU traits have been associated with greater severity of antisocial behaviour and poorer youth justice outcomes. For example, early-onset antisocial behaviour has been shown to be the best predictor of early arrest (before the age of 13) and, in turn, young people with an early arrest are the most likely to be chronic offenders by the age of 18 ,52. ClinThe START trial is a multicentre pragmatic clinical RCT comparing MST with carefully documented MAU for adolescents meeting criteria for being at high risk of requiring out-of-home placement, specifically when this risk is associated with antisocial behaviour, including conviction as a young offender. Whereas previous US trials of MST for youth antisocial behaviour have exclusively recruited offenders from the juvenile justice system, and European trials in Norway ,60 and SThe study protocol was approved by the London-South East Research Ethics Committee (reference number 09/H1102/55). Research and development approval has also been sought and given for each trial site by the relevant NHS Trust in each geographical area.The study involves each of the 10 MST pilot sites in the UK. Recruitment at each site will take place for 18 months, commencing about 12 months after the inauguration of the programme at each site (sites have begun the programme at different time points), to ensure the embedding of MST at each site before randomisation begins, as described above. At each site, a team of four MST therapists is guided by a supervisor - a doctoral-level  therapist with sound knowledge of the theories underpinning MST and their application, and experience in providing clinical supervision. The MST supervisor conducts weekly group supervision, and one-to-one supervision if needed, of the MST therapists at a site to ensure they are adhering to MST principles in their practice. The supervisor is also involved in the selection of young people referred to the service as suitable for MST (see Recruitment and baseline procedures below).Overall, 700 participants are being recruited, with approximately half of the consecutive qualifying cases being randomised to MST alone, and the other half to MAU. The unit of randomisation is the individual participant.It is estimated that each site will have at least 140 families per year referred for treatment. On the basis of past experience, data from a meta-analysis of previous trials of MST  that was carried out in the course of preparation of the NICE guidelines , and assAssuming that 30% of the MAU arm will have out-of-home placements, this sample size will give 86% power to detect a 10% difference in out-of-home placements (a reduction from 30% to 20%). To take account of within-therapist correlation of outcomes in the MST arm, an intraclass correlation of 0.02 and a total of 30 therapists has been assumed, giving design effects of 1.22 in the MST arm and 1.0 in the MAU arm, and thus reducing the power to 83%.The study design aims to increase generalisability of the findings beyond the group of adolescents under study by using the minimum number of entry criteria. The task of establishing an adolescent target population based on the status of ‘being on the edge of care’ is challenging as, in most contexts, this term covers a heterogeneous group. At the same time, it was recognised that the four referral routes used in the study  often identify young people and families with very similar needs when they have reached a particular crisis point. The nature of the crisis may be associated with the specific service  but the underlying causes in terms of family disorganisation, conflict and stressors, combined with antisocial behaviour by the young person, are similar, and the outcomes in terms of risk of out-of-home placement are common to them.All participants, regardless of referral source, must meet the following general inclusion criteria:● Young person aged 11 to 17 years;● Sufficient family involvement for MST to be applied;● No existing agency involvement that would interfere with MST ;● Displaying antisocial behaviour manifesting as at least one of the following criteria indicating suitability for MST:o Persistent (weekly) and enduring (6 months or longer) violent and aggressive interpersonal behaviour;o A significant risk of harm to self or to others ;o At least one conviction and three warnings, reprimands or convictions in the past 18 months;o Current diagnosis of an externalising disorder and a record of unsuccessful outpatient treatment;o Permanent school exclusion.In addition, participants must meet at least three of the following criteria, which are indicative of risk status and serve as generic indicators of risk sufficient to warrant referral to services:● Excluded from school or at significant risk of exclusion;● High levels of non-attendance at school;● A history of offending, or at significant risk of offending;● Previous episodes on the Child Protection Register;● Previous episodes of being ‘looked after’, that is, placed outside of the home ;● Previous referral to a Family Group Conference ● History of siblings being looked after and taken into local authority care.Guidelines were developed for inclusion depending on the nature of the referral. The specific inclusion criteria for the four agencies and referral paths are briefly summarised in Table The exclusion criteria applied were:● History or current diagnosis of psychosis;● Generalised learning problems  as indicated by intelligence quotient (IQ) below 65;● Identified serious risk of injury or harm to a therapist or researcher;● Presenting issues for which MST has not been empirically validated, in particular, substance abuse in the absence of criminal conduct or sex offending as the sole presenting issue.The recruitment process is fundamental to the success of this large, multisite research trial. In addition to criteria that apply to recruitment for any trial , recruitment for this trial must be especially sensitive to the community context and be based on effective partnerships with referral agencies and strong relationships with the young people and their families. Consequently, the trial team has developed strong collaborative relationships with the MST team at each site to achieve the high levels of accrual necessary to ensure sample comparability and reasonable generalisability.The authors developed a multiple gating procedure for recruitment based partly on the experience of the MST trial conducted at the Brandon Centre . Using tFinally, the research assessor’s (RA) assessment is necessary to confirm the young person’s IQ and psychiatric diagnosis.Multi-agency panels have been put in place at each of the 10 sites, taking referrals from YOTs, CAMHS, social care and education services. These panels identify new cases that meet the eligibility criteria for MST. In addition, the MST team at each site directly takes referrals, as they have become established and connected with other services and referral sources in each of their localities. The decisions made by the multi-agency panels and the MST team constitute the first screen. During the period between establishment of the teams and the start of the trial, each MST team gained experience in screening referrals and educating potential referrers as to what constitutes an appropriate referral to the trial. A standard referral form for each locality is used in liaison with the research team, including specific information pertaining to inclusion and exclusion criteria. This forms the first screen to the trial, focusing on establishing the severity and chronicity of antisocial behaviour.Following acceptance of the referral by the multi-agency panel, a standard initial letter from the clinical team, in the first language of the family, is sent to the parents and separately to the young person if aged 16 or over, informing them about the trial. Recruitment begins with this letter, which is sent to all those identified by a panel and/or MST team to be probably suitable for MST. The letter invites participation, and informs the family and the young person that someone from the MST team (preferably the MST supervisor) will contact them unless they do not wish to participate in the trial. The letter includes material in age-appropriate and culturally appropriate language in the form of a leaflet for both the parents and the young person explaining the trial and what involvement in the trial would mean at that particular site. These information sheets have been constructed and designed with input from young people and their parents or carers who have used MST at the same site to make them as useful and accessible as possible.After 3 to 7 days the family is visited by a member of the MST team to explain what participation might involve and to arrange an appointment at the family home that will include the MST supervisor or therapist, the RA, the young person and his or her primary carer(s). The discussions at this meeting include the identification of an acceptable and credible MAU path  should the young person not be randomised to receive MST.At this meeting, which constitutes the second stage of the multiple screening procedure, the MST therapist identifies possible exclusion criteria, such as a risk of injury or harm to a worker, agency involvement incompatible with participation in the trial, or severe substance dependency. Consent forms are not signed at this appointment because experience has shown that actual take-up of treatment increases dramatically and early drop-outs are reduced if the family feels they have been given adequate time to consider participation.Unless the family expresses a decision not to participate at the time of the visit or within 3 to 7 days after the visit, a telephone contact is made by the RA, offering a research assessment. At this stage the consent form is reviewed. Consent forms signed by both the young person and carer(s) include permission to access the police and correctional databases, remaining in effect for 3 years. For families who sign the consent forms, the RA administers pre-randomisation questionnaires and measures are completed during this contact . The final evaluation for eligibility (the third screen) is made at this second visit.When all the instruments have been completed and eligibility for the trial confirmed, the RA telephones the trial centre to inform the centre of the family’s randomisation details. The randomisation is performed and details communicated to the referrer and family within 24 hours.After consent has been obtained and the baseline assessment has been carried out, a trial identification is assigned. Eligible consenting participants are randomised to MST or MAU on a 1:1 basis by the Trials Unit at University College London using a secure telephone randomisation service that ensures allocation concealment. A computer-generated adaptive minimisation algorithm that incorporates a random element is used with the following stratification factors: treatment centre, gender, age  and age at onset of conduct problems . These strata were selected because previous research has shown that a younger age of onset is associated with poorer prognosis; there is insufficient evidence concerning gender mix, particularly in the older age groups, to ensure that simple randomisation would generate comparable groups. Treatment centre is included in the minimisation stratification to control for differences between centres.To minimise bias that could arise from knowledge of treatment allocation, the following strategies are employed: RAs are blind to treatment allocation; the RA and therapist do not communicate directly  with each other; qualitative interviews, conducted with a subsample of the families by doctoral students trained and supervised by experienced qualitative researchers, are audiotaped and a random sample re-rated by independent raters. The qualitative interviewers are separate from the MST service providers.There are a number of factors that contribute to the unique nature of MST: it addresses the multidetermined nature of severe conduct problems; it sees the caregiver as key to effective behaviour change; it uses the adolescent’s home as the primary site of the intervention; it integrates several evidence-based intervention techniques; it uses a single therapist to deliver multiple modalities of intervention within a singular conceptual framework; and there is rigorous monitoring of adherence to the model, including the use of comprehensive quality assurance and on-going quality improvement system for maintaining standards.MST is a family- and community-based intervention that uses intense contact with a family to understand and address the drivers of a young person’s antisocial behaviour. It targets drivers related to the young person’s individual adjustment, family relationships, school functioning and peer group affiliations. A focus on the caregiver and family is key to the intervention. MST interventions are individualised and highly flexible but are documented in treatment manuals . The pacDespite incorporating a range of modalities, MST is more than just an amalgamation of techniques and approaches, and a focus on the inter-relationship between social, education and healthcare systems is retained. The overarching goals of MST are to give parents the skills and resources needed to address the inevitable difficulties of raising adolescents, and to empower adolescents to cope with familial and extrafamilial problems. Assessment and treatment explore the adolescent’s role in various systems and consider the inter-relationship between these systems. Specific attention is given to strengthening the various systems, and an attempt is made to promote appropriate and responsible behaviour among all family members. MST focuses on current behaviours as opposed to influences from the young person’s past. It seeks to identify, reduce and, if possible, remove behaviours that are of concern to the referring service and the young person’s parent or principal carer. The implementation of MST draws on family members, in contrast to many interventions that define the young person as the ‘identified client’. In addition, collaboration with community agencies is a crucial part of MST. For instance, establishing (or in most cases re-establishing) engagement between the young person, the parent(s) and the school is a critical part of the treatment, and the MST therapist may be in regular contact with teachers. The MST therapist also works in close partnership with the social worker from the YOT or social services, who may have statutory responsibilities for the young person. When considered necessary, the young person is referred to a general practitioner or other medical professional who can assess the young person and prescribe medication.As mentioned above, the MST teams are centrally funded by the Department of Health and had already been operational for approximately 12 to 18 months prior to their participation in the START trial. These factors benefit the RCT in several respects. First, at the start of the trial the clinical teams had already developed relationships with key stakeholders and referrers in their local communities, and multi-agency panels had been in operation to facilitate recruitment. Second, the clinical teams had already had the opportunity to liaise with potential sources of referrals regarding the appropriateness of referrals, and thus to ensure that referral of inappropriate cases is minimised. Third, as the funding of the MST teams is tied to participation in the research trial, the collaboration between the MST clinical teams and the research team to achieve common goals  is maximised. Finally, by the start of the trial, the therapists and supervisors would have been able to develop experience implementing MST; research suggests that mature MST teams are associated with greater adherence of therapists to the MST model. The association between treatment fidelity and outcomes for adolescents has been repeatedly demonstrated in trials of MST ,39,48,50MAU consists of the standard care offered to adolescents and their families who meet eligibility criteria for the trial in each of the sites. This treatment is likely to be diverse and may involve no therapeutic intervention or individual- or family-oriented work. It is likely to be delivered by a wide range of practitioners with different theoretical orientations. The average duration of these interventions is also likely to vary. It is expected that practitioners will be working in line with best practice as specified in relevant Social Care Institute for Excellence and NICE guidance ,30.Based on assessments, the young people in the MAU group receive a tailored range of interventions aimed primarily at preventing reoffending. As in MST, typical interventions are extensive and multicomponent, consistent with the complex mental health needs of this population in the UK . InterveThe key differences between MST and MAU are that MAU interventions are not normally delivered in a family context by a single person. Typically, no overarching model governs the selection of treatments, and there is no set of principles comparable to that of MST to organise the therapies offered. Rather, interventions are likely to be offered on an ‘as needed’ basis by specialist agencies to which the young person is referred. The young people allocated to MAU are likely to receive considerable attention from a range of professionals delivering evidence-based protocols. In a recent RCT comparing MST with usual services provided by YOT, clients typically received around 21 professional appointments over the period that MST was administered ,65. It iFor this reason, MAU interventions in the current trial are carefully monitored using a service use schedule designed specifically for the trial, which records contact with all services , including the number of contacts (and possibly the average duration of contacts). This will give a realistic sense of the level of intensity of MAU in whatever form, and, used in conjunction with the MST arm, will give an indication of shifts in intensity - that is, whether the addition of MST reduces the need for other support. As START is a pragmatic trial involving a number of collaborating services even within each individual site, it was not possible to specify in advance what MAU would constitute.To maximise the clinical validity of the outcome evaluations, assessments are being made across multiple domains using multiple methods and sources.The primary outcome is the proportion of cases assigned to long-term (3 months or longer) out-of-home placements in specialist residential provision, including placement into local authority care, incarceration, long-term hospitalisation and residential schooling, at 18 months following randomisation. The investigators expect this trial to give information on how many children assigned to MAU and MST require specialist residential provision either immediately or during the follow-up period.The number of secondary outcomes is limited to reduce the measurement burden of the study, which was found to be a disincentive to continued participation in the Brandon Centre study . The domObjective secondary outcomes will be collected from reports of offending behaviour based on police computer records, including details of custodial sentences. These measures will be taken at 6-monthly intervals, for the 6 months before randomisation, the 6 months covering the intervention period, and 6-monthly until the 18-month follow-up point. The number of records of offending behaviour (count data) will be obtained and 6-month periods free of any offending behaviour will also be recorded (binary data). Records are obtained from the Police National Computer as well as from the Young Offender Information System database at each site; these records detail information on offences, court appearances, criminal orders, police custody records and arrest rates.Records of school attendance and exclusions will be retrieved from both the local schools themselves and the National Pupil Database to assess educational outcomes.The RA administers pre-testing questionnaires during the initial contact with the young person and family after they have given consent to participate in the trial, prior to group assignment (as described above). Post-testing by the RA is scheduled for 6 months after entry into the study; it is envisaged that this will be a minimum of 2 weeks after the family completes the intervention. Follow-up assessments will be made at 12 and 18 months post-randomisation.Self-report measures of well-being and adjustment, antisocial behaviour, parenting skills and family functioning as well as parental mental health and adjustment are collected.Well-being and adjustment. A general assessment of well-being is taken using the Strengths and Difficulties Questionnaire [ionnaire . Educatiionnaire . Depressionnaire , completAntisocial behaviour. The prevalence and incidence of delinquent behaviour such as vandalism, theft and burglary will be monitored using the Self-Report Delinquency measure [ measure . Noncomp measure . Peer de measure . The inv measure  and is rParenting skills and family functioning. The quality of the parent-adolescent relationship, family functioning and parenting practices will be evaluated using the Family Adaptability and Cohesion Scales [n Scales  and the n Scales . Parentan Scales , and then Scales ,79.Parental mental health and adjustment. A brief assessment of parental mental health will be obtained using the commonly used screening instrument, the General Health Questionnaire-28 [naire-28 .Demographics interview. A bespoke interview (Demographic Interview for Parents) to cover general family information, including parental forensic history, schooling and economic information, has been constructed and will be administered to all parents. Child psychometrics will be obtained from the Wechsler Abbreviated Scale of Intelligence [lligence .Psychiatric screening. Psychiatric disorders will be identified and a psychosis screen provided by the Development and Well-Being Assessment [sessment . This coExperience of MST. Finally, young people and their carer(s) will be interviewed to elicit their views regarding their experience of MST and factors that they perceive had facilitated or inhibited therapeutic change, based on promising qualitative research carried out during the Brandon Centre trial.Health economic analysis will be conducted by the Centre for the Economics of Mental Health at the Institute of Psychiatry, London, to explore the relative costs and cost-effectiveness of MST and MAU. The evaluation will take a broad perspective, including all health, social services, education and voluntary sector services, plus costs to the criminal justice sector, costs resulting from crimes committed, and out-of-pocket expenses to the young people and their families.Data on MST contacts will be collected directly from the pilot schemes to avoid participants revealing their group allocation to the RAs. Data on the use of all other services will be collected in interviews using the Child and Adolescent Service Use Schedule previously used with young people with complex mental health and social care needs -86. The The MST Therapist Adherence Measure-Revised (TAM-R) measures the team’s adherence to the nine MST treatment principles . The TAMThe trial will also evaluate potential moderators that have not been widely explored in previous studies because of sample size constraints, and will consider in particular the role of psychiatric comorbidities including psychopathic traits and ADHD. Young people with high levels of psychopathic traits show a greater likelihood of recidivism , and oneA bespoke fidelity measure has been developed to enable accurate characterisation of the programme components of MST and MAU interventions, the Children and Young People – Resources, Evaluation and Systems Schedule (CYPRESS) . This approach is based on the initiative of the MST developers , who havTo obtain additional information about the experience of MST and being in an RCT of this treatment, the semi-structured interview developed by Tighe and colleagues in the Brandon Centre trial will be used . This 45Interviews will be audio recorded and transcribed verbatim. Transcripts will be analysed using framework analysis, a structured method for analysing themes in data, developed by Ritchie and Spencer , which fThe intention is for the interview to be administered to a random 5% of families across all sites by a person independent of the intervention but not blind to treatment allocation.Follow-up assessments will be conducted at 6, 12 and 18 months post-randomisation. Table All analysis will be according to the intention-to-treat principle. The characteristics of the treatment groups will be described at baseline. Preliminary analysis will investigate the pattern of missing follow-up data.The primary analysis will be a logistic regression with random effects to account for clustering by therapist. The analysis will include centre, number of past convictions, gender, age at onset of criminal behaviour and other risk indicators as fixed effects. The logistic regression will be fitted using generalised estimating equations. A Wald test of the effect of intervention will be used as the primary analysis. As a secondary analysis, tests of interaction will be used to explore whether the intervention differs according to gender, age, presence of a criminal record or referral path. Clustering by therapist will be accounted for by computing robust standard errors .The antisocial behaviour outcome (time to offence) will be analysed using a Cox regression. All other secondary outcomes will be modelled using linear mixed-effects models, with separate treatment effects for the 6-, 12- and 18-month outcomes and an unstructured covariance matrix. The effect of intervention on the 18-month outcome will be tested using a Wald test. Tests of interaction will be performed for all secondary outcomes in which a nominally significant treatment effect is found.It is anticipated that the primary outcome will have very little missing data as these data are obtained independently of the participants. For the secondary outcomes, linear mixed models and Cox regression yield valid inferences when data are missing at random . It is possible that data may be missing not at random, so sensitivity analyses will be conducted to explore the impact of missing data.There is just one primary outcome, so the primary analysis will be conducted at a nominal two-sided significance level of 0.05. There are several secondary outcomes, so caveats will be used when interpreting effects of treatment on secondary outcomes. No formal correction for multiple testing will be used.There is no plan to analyse outcomes by site and it is hoped that TAM-R scores will pick up the variance associated with individual therapists.Although a number of high-quality efficacy studies have demonstrated the success of MST in reducing antisocial behaviour and out-of-home placements in high-risk youth, the replicability of the original findings from the US when MST has been transported internationally has been mixed, especially when field trials have not involved the developers of the programme. Although the evidence from the US suggests that MST is a very promising treatment, the question of whether it will be similarly effective in the UK has not been fully tested. Substantial attention has been paid in past research to treatment transportability and fidelity, but variability in the outcomes of different studies may be due to the comparison conditions not being adequately comparable across studies. The provision for antisocial adolescents in the UK is difficult to compare with that in the US, and expectations of favourable outcomes relative to MAU are not based on comparable investigations. The sole UK study, unlike counterparts in the US, found statistically significant reductions in non-violent criminality only after 18 months following randomisation ; howeverThe research is being conducted across 10 pilot sites, each overseen by a team of therapists who have received specialist training in MST to ensure high-quality delivery of the intervention. As out-of-home placement  in the majority of cases represents an unhelpful outcome for antisocial adolescents, the investigators have chosen to use preservation of the family as the main measure of benefit. As noted above, the rate of out-of-home placement is an important primary outcome, but it is not in every instance an indication of the failure of the system to provide adequate support to the young person and family. Consequently, the authors intend to interpret the information on family preservation in the context of combined information collected from measures of family functioning and home observations to categorise treatment successes and failures regarding out-of-home placement according to pre-assigned criteria. In doing so, it will be possible to capture instances where out-of-home placement is an appropriate outcome and when it is not; for example, instances when there is no out-of-home placement but home observation data and self-report measures suggest that the young person’s situation remains markedly suboptimal.MST aims to reduce the level of offending in the target population, and so offending rates will be used as a key measure to determine whether the intervention is effective. Other possible benefits of MST will also be examined, such as the impact on the young person’s educational progress, his or her mental health and well-being and that of the parents. To address the mediators of improvement, the investigators have taken considerable effort to monitor the effect of MST on parenting and family function. It is anticipated that improvement observed in association with this intervention will be commensurate with the impact that MST has on variables within the family, and for other clinically critical outcomes , to be in line with changes in the purported mediating processes.To assess what the benefits of MST and MAU might be, care will be taken to describe the interventions delivered to both groups in the study accurately, and the investigators will attempt to chart the subjective experience of all stakeholders in the project . The data from the trial will be analysed to determine whether the expected benefit of MST is achieved and whether it represents an economically viable option.The START trial is a pragmatic national RCT that is of sufficient size to evaluate MST in the UK context to inform policymakers, commissioners of services, professionals, service users and their families about the potential of this treatment in the UK. Given the number and geographical spread of sites in the MAU condition, the trial will also provide unprecedented data on the clinical effectiveness and cost-effectiveness of usual services provided to young people with serious antisocial behaviour problems.The START trial intends to recruit a large sample of 700 young people and their families, who will be evaluated repeatedly over a period of 18 months. This will allow their trajectories of adjustment to be mapped over an extended period following the intervention. Moreover, the large sample size, combined with the study design and measurement strategy, will provide for a detailed investigation of mechanisms related to treatment response. The investigators are able to build on earlier studies that have found theoretically consonant mediators ,67-69. FThe investigators will undertake several initiatives that are essential to understanding the impact and cost-effectiveness of MST in the UK. Building on an initial qualitative study of MST in the Brandon Centre trial , young pOngoing. Sites were launched in five phases, once they were well embedded in their local authority and services were familiar with the referral process and eligibility criteria. Recruitment began in February 2010 and recruitment is expected to be complete 18 months after the launch of the last site. Outcome data will be available 18 months post-randomisation of the last participant.ADHD: Attention deficit hyperactivity disorder; CAMHS: Child and adolescent mental health services; CD: Conduct disorder; CI: Confidence interval; CU: Callous-unemotional; CYPRESS: Children and Young People – Resources, Evaluation and Systems Schedule; MAU: Management as usual; MST: Multisystemic therapy; NICE: National Institute for Health and Clinical Excellence; RA: Research assessor; RCT: Randomised controlled trial; SMD: Standardised mean difference; TAM-R: MST Therapist Adherence Measure-Revised; TAU: Treatment as usual; YOT: Youth offending team.The authors declare that they have no competing interests.PFo is Chief Investigator on the START Trial and drafted the manuscript. SBu is Project Coordinator on the trial. PFo, SBu, PFu, SS, IE, and SP will oversee data collection from five pilot sites from the London hub. IG will oversee one pilot site from the Cambridge hub. DC and AK will oversee four pilot sites from the Leeds hub. SBy will carry out the health economic analysis. JW designed and will perform the statistical analysis. RH is Trial Coordinator. All authors participated in the review and revision of the manuscript and approved the final manuscript.