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In addition cheap betnovate 20gm without a prescription acne 5 benzoyl peroxide cream, HeLP was delivered as designed in all intervention schools with very high levels of engagement buy betnovate 20gm amex acne like rash on face, as was also seen in the exploratory trial betnovate 20gm free shipping acne 30 years old male. The findings from the process evaluation allow us to be confident that the difference in results between the exploratory and the definitive trial are not due to scale-up issues of delivery generic 20gm betnovate fast delivery acne quitting smoking. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 101 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION AND CONCLUSIONS differential effect of the intervention between the two cohorts on the primary outcome, indicating that this logistical requirement did not affect the overall findings, and our follow-up rates at 18 and 24 months were similar across both trials. Understanding the lack of effectiveness Conducting health promotion interventions within schools has the obvious potential advantage of being able to reach virtually all children. The behaviours that underlie the development of obesity and overweight in children and adolescents result from a complex interaction of individual, family and social factors. This is particularly relevant for children of primary school age, as their ability to influence their diet and activity is directly limited by decisions made by their parents/carers, as well as being affected by wider social influences. We therefore aimed to develop an intervention that would influence not only the children themselves, but also their parents and the school environment, as we felt that this would have a higher likelihood of being effective. Our review of existing evidence suggested that multifaceted interventions were more likely to be effective when they addressed both diet and exercise, were of significant duration and involved the family, although the strength of these conclusions was limited owing to the paucity of existing high-quality studies. We were also aware that a common reason for failure in health promotion programmes is a failure to persuade the target group to participate and to stay involved, so strategies to achieve engagement by children, parents and schools were fundamental in the design of both the intervention and the trial. In addition, for public health interventions to have an impact, they need to be deliverable without disrupting normal activities and at an affordable cost. We therefore worked closely with children from the target age group, parents, teachers and education advisors at all stages of the design. We assessed the extent to which children, parents and teachers actually engaged with the programme using prespecified criteria for engagement, as well as conducting focus groups with children and interviews with parents and teachers. The results suggested very high levels of engagement across all socioeconomic groups and considerable enthusiasm for the programme. We succeeded in achieving extremely high levels of participation: only 34 out of 1371 children opted out of the trial and only 80 out of 1324 who started the study were lost to follow-up, and hence > 94% of children provided anthropometric data at 2 years and we have accelerometry data at 18 months post baseline on 84% of children (3 weekdays and 1 weekend day). The lack of any effect of the intervention on our primary outcome measure is particularly disappointing given the high levels of engagement and that the programme was developed with substantial stakeholder involvement and reflected the current best evidence regarding techniques to change behaviour. There is a number of potential explanations: we recognise the importance of wider family and social factors in driving health behaviours, which may limit the potential effects of interventions that are delivered primarily at the level of the individual. We are also aware that although the increase in overweight among children is perceived by policy-makers as constituting a major threat to health, it is less clear whether or not parents share this view. It has been repeatedly reported that a large proportion of parents of overweight children perceive their children as being of normal weight. However, it may be the case that the HeLP messages regarding diet 102 NIHR Journals Library www. We chose to target children aged 9–10 years for the intervention on the basis of our early pilot work. Broadly speaking, our initial development work showed that younger children were keen to engage but did not appear to successfully absorb the messages such that they engaged their parents with them, while older children were less easy to engage. However, it is the case that, at this age, the ability of children to actually influence their own diet and activity may be limited, as, inevitably, most decisions will be made by their parents. Parental involvement in obesity prevention programmes has been frequently cited as one of the key characteristics associated with behaviour change, and throughout the programme there were activities specifically aimed at engaging parents across the socioeconomic spectrum. Our data showed that > 50% of parents attended at least one parental engagement event, and three-quarters either attended an event or signed support for their child on the goal-setting sheet. Although it is possible to engage children (and assess their levels of engagement) in school-based programmes, the lack of direct contact with parents means that parental engagement is more difficult to achieve and assess. Many parents reported (in questionnaire responses and interview) that they had made changes at a family level and gave examples of how they were supporting their child, but this was only a subset of all of the parents involved. We consider it unlikely that school-based obesity prevention programmes will ever be of sufficient intensity to affect the family environment, and more direct approaches would be required. We were mindful from the outset that the programme should complement educational activities (by meeting national curriculum objectives) and not be a burden to teachers. It is possible that, although the external delivery of the majority of programme activities (by sport and dance groups, actors and the HeLP co-ordinators) was welcomed by teachers and children, this delivery mode meant that the programme was probably not embedded across the school and hence could not systematically affect the school environment. Our development and early piloting work suggested that a more intensive intervention with greater parental involvement in the programme would be less acceptable or unfeasible for schools, suggesting that those planning future obesity prevention interventions may need to consider new approaches and settings if they are seeking to affect family behaviours and the home environment. Trial strengths and limitations There are well-recognised potential sources of bias associated with cluster RCTs,33 including recruitment bias, performance bias and detection bias. We tried to reduce the likelihood of these biases by recruiting schools and children and collecting baseline measures before the known allocation of schools to intervention or control (to reduce differential take-up); by capturing evidence of changes in school policies around food or physical activity through school completion of a checklist at the beginning of the trial and at 18 months (see Appendix 16); and by using assessors blinded to allocation to measure the anthropometric outcomes. The primary outcome for the trial was based on measures taken when the children had transferred to secondary school, and hence secondary schools included children from both the intervention and the control groups. No child revealed their group allocation to the blinded assessor at 24-month follow-up. However, it should be noted that although the MLQ and FIQ were completed before the group allocation at baseline and at 12 and 18 months, respectively, the children were aware of their group allocation, as shown in Figure 1. Sample size calculations, which allowed for the anticipated level of clustering as estimated from the 28 138, exploratory trial and NCMP data, suggested that we needed measures from approximately 760 children at 24 months to detect a 0. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 103 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION AND CONCLUSIONS approximately 35–40 children, to complete the study and so, allowing for a 20% loss to follow-up at 24 months, we sought to recruit 32 schools to allow for both school-level and child-level dropouts. Few eligible children (34/1371) opted out of the study and we achieved follow-up rates of between 84% and 96% for all outcome measures, and hence there is a very low risk of attrition bias. Reviews and recent studies of school-based obesity prevention and management trials in children have 459139, , , highlighted low participation, differential dropout and loss to follow-up rates. The HeLP trial, therefore, has one of the most complete follow-up rates and physical activity compliance of recent obesity prevention trials for children in this age group. We attribute this to the relational approach that we took in the trial delivery, as well as to the stakeholder involvement we had in developing the intervention and the trial design. In other respects, the schools that participated in the trial are representative of Devon, and the anthropometric data from the children are broadly similar to the Devon NCMP Year 6 data. The one exception is that, although the included schools reflected the proportion of children with English as an additional language typical for Devon (2. A further strength of this trial was its robust process evaluation involving qualitative and quantitative data and its prespecified logic model and mediating variables questionnaire to understand whether or not HeLP was working in the way it was intended, with the qualitative data being analysed prior to the outcome result being known. We acknowledge that this is a weak assessment of engagement and does not capture engagement with the messages of the programme. The low response rate (25%) from parents to the questionnaire about HeLP, which formed part of the process evaluation, limits the strength of these data and also suggests that the sample interviewed (who were recruited from responders to the questionnaire) is unlikely to be representative of all parents. This suggests that the qualitative data from parents cannot be considered as representative of all parents receiving the programme. However, the children recruited for the process evaluation were representative of the overall sample, and all Year 5 teachers were interviewed. Research recommendations The disappointing results of this study and other recent well-designed, UK-based trials suggest to us that it is unlikely that affordable, school-based interventions that are inherently time-limited can achieve clinically meaningful change in weight status/anthropometric outcomes in a single targeted age group. This view is reinforced by other research using data from the NCMP that suggested that there was no consistent school effect on childhood obesity. This suggests that researchers should consider whether or not other age groups offer greater possibilities for affecting behaviour. It is possible that older children, who have a greater degree of autonomy, if engaged, may be more able to make changes in their behaviour. It has also been suggested that pregnant women and parents of very young children may be more amenable to adopting health messages.

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Contrasting but complementary classifcation – a disease code is combined with profles of health research a description of the research purpose – indicat- spending order betnovate 20 gm free shipping acne 5 pocket jeans, United Kingdom ing that there is a common understanding of C004–F004 order betnovate 20gm mastercard skin care in your 20s. Te Ireland buy 20 gm betnovate overnight delivery acne jensen boots, 2009–2010 next step in reconciling diferent schemes could A generic betnovate 20 gm acne hormonal imbalance. Medical research organizations take one of two directions: either agreement to 50 adopt the same system, or reliance on computer sofware to translate and map the current variety 40 of classifcation systems to a common standard 30 (71). Te best approach will be the one that most easily achieves the main goal, which is to assure 20 transparency and accountability in research funding (70). Despite the impor- Type of research study tance of good accounting in research, the evaluation Wellcome Trust Medical Research Council of both need and cost are underdeveloped skills. Funding for TB operational research illus- trates the challenge of assessing need. National health departments able expenditure (budget) for TB operational 50 research has been set at US$ 80 million annually, calculated as 1% of the expenditure of national 40 TB control programmes (72). Against this arbi- 30 trary spending target, which is far lower than that for any other area of TB research, the avail- 20 able funds totalled 76% of assessed need. Tis is a higher percentage than for any other area of 10 research (Fig. Te danger here is to con- 0 clude that the need for operational research has 1 largely been satisfed. While the Global Plan to Type of research study Stop TB has successfully highlighted the need to England Scotland invest in R&D for technology, a more objective method is needed for calculating the TB opera- Types of research: 1, underpinning; 2, etiology; 3, preven- tional research budget, especially in light of the tion; 4, detection and diagnosis; 5, treatment development; widely-held view that too little efort is devoted 6, treatment evaluation; 7, disease management; 8, health systems and services (Box 2. Note: For each of the four organizations, percentages sum to On the question of costing, the calculation of 100%. Adapted, by permission of the publisher, from the UK Clinical It refers to the indirect costs that are harder to Research Collaboration (69). Research institutions 106 Chapter 4 Building research systems for universal health coverage Building research institutions Fig. Global expenditures and budget gap in tuberculosis R&D by and networks research category, 2010 Te Global Health Trials network has expressed a view of capacity-building that is shared by other health research networks (Box 4. In the con- text of research networks, “capacity” is seen as the establishment of a community of researchers based in lower-income countries who can devise and validate methods and operational tools for improving health, and who share local and global solutions to make pragmatic and locally- led development possible (79). Putting the spotlight on collaboration between lower-income countries does not mean neglecting the traditional links through R&D, research and development. Reproduced, by permission of the publisher, from Treatment research studies of each group differs from that Action Group (73). For instance, clinical trials in poorer countries have focused largely on communicable rather in low- and middle-income countries have the than noncommunicable diseases. In contrast, task of persuading external donors to contribute researchers in richer countries have enormous to indirect costs, and also to align their research expertise in studying noncommunicable dis- priorities in contributing to direct costs. Their expertise will be in demand as the these problems were confronted – and solved – by need for research on these diseases continues to the International Centre for Diarrhoeal Diseases rise worldwide (79). Solutions were found, in part by adopting a transparent approach to fnancial monitoring Defning and implementing and evaluation. ICDDR,B explicitly defned and norms and standards measured activities, outputs and outcomes in the areas of research, clinical services, teaching, and Codes of practice for the responsible conduct management and operations. Developing research networks Initiative to Strengthen Health Research Capacity in Africa (ISHReCA) ISHReCA (ishreca. ISHReCA aims to expand research capacity in four ways: (i) it provides a platform for African health researchers to discuss ways of building sustainable capacity for health research in Africa; (ii) it promotes an African-led agenda for health research, negotiating with funders and partners concerning support for, and harmonization of, research initiatives; (iii) it advocates for increased commitment to research by national governments and civil society, emphasizing the translation of research into policy and practice; and (iv) it seeks novel ways to garner regional and international support for health research in Africa. African Network for Drugs and Diagnostics Innovation (ANDI) Launched in 2008, ANDI (www. To realize this vision, ANDI is building capacity that supports pharmaceutical research, development and manufacturing to improve access to medicines. Specific activities include the development of a portfolio of high-quality, pan-African pharmaceutical R&D innovation projects, project coordination and management, including intellectual property management. Vital to ANDI are more than 30 African institutions which are recognized as research centres of excel- lence and are committed to sharing expertise, knowledge, research equipment and facilities (61, 78). Global Health Trials Global Health Trials (globalhealthtrials. An e-learning centre offers short courses, seminars and a library. Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) North–south research collaboration, such as that fostered by the European and Developing Countries Clinical Trials Partnership (www. The EDCTP 14-country partnership works to “accelerate the development of new or improved drugs, vaccines, microbicides and diagnostics against HIV/AIDS, tuberculosis and malaria, with a focus on phase II and III clinical trials in sub-Saharan Africa”. An offshoot of EDCTP, PanACEA is a network of 11 linked clinical trial sites in six African countries, supported by European research organizations and pharmaceutical companies. The initial aim of the network was to investigate the role of moxifloxacin in reducing treatment durations for TB. However, PanACEA has a wider ambition – to establish collaboration rather than competition as a driving force in the conduct of high-quality clinical and regulatory trials. Research for Health Africa (R4HA) The goal of R4HA (www. The NEPAD Agency and COHRED, financially supported by the Ministry of Foreign Affairs of the Netherlands, work with Mozambique, Senegal and Tanzania to strengthen the governance of research for health in these countries. Country focused activi- ties are complemented by cross-country learning and exchange opportunities. At the same time, in 2011, a group of 14 West African countries launched a four-year project dedicated to strengthening health research systems. An assessment of research for health in this group of West African countries identified Guinea- Bissau, Liberia, Mali and Sierra Leone as most in need of support. WAHO and COHRED help to build the research systems in these countries based on action plans they have defined themselves. How to prevent and treat syphilis: an operational research network connecting six countries Two million pregnant women are infected with syphilis each year. More than half transmit the infection to newborn children, resulting in premature births, stillbirths and underweight babies. Syphilis also augments sexual and mother-to-child transmis- sion of HIV. However, syphilis is easily diagnosed and treated, and congenital syphilis is preventable. Point-of-care diagnostic tests and treatment with penicillin each cost less than US$ 1. The London School of Hygiene & Tropical Medicine coordinated a three-year, multicountry implementation research project to determine the feasibility and cost–efectiveness of using simple diagnostic tests and same-day treatment in prenatal and high-risk populations in low- and middle-income countries (80). More than 150 000 individuals were screened in six countries. Interventions were introduced through existing services, so there was no need for new infrastructure. Numbers screened and population focus by country China > 5000 screened Population focus: prenatal and high Zambia risk > 12 000 screened Population focus: integration into PMTCT programmes Uganda for HIV > 13 000 screened Population focus: integration into PMTCT programmes for HIV Peru > 17 000 screened Population focus: Brazil United Republic prenatal > 45 000 screened of Tanzania Population focus: > 58 000 screened remote and indigenous Population focus: communities prenatal and high risk Initial preparatory work – including making sure that screening was culturally acceptable – was critical to the success of the project. In China, female sex workers were trained to speak to other female sex workers and encourage them to take up screening. In a seventh country, Haiti, traditional healers were educated about the signs and symptoms of syphilis, which enabled them to refer patients to health clinics. Ministries of health were consulted about what evidence they would need before considering a change of policy. A baseline survey of services and barriers aided the design of specifc interventions to overcome obstacles and to measure increase in coverage. Health ministries were given regular updates which provided a sense of ownership and facilitated policy change. From stafng to equipment, emphasis was placed on establishing systems that could be sustained.

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Molecular as aloofness and rigidity buy 20gm betnovate acne dark spots, (b)diminished pragmatic language studies implicated a paternally imprinted disease locus that and speech abilities cheap 20 gm betnovate free shipping acne images, (c)fewer quality friendships order betnovate 20gm acne keloidalis nuchae surgery, and (d) escapes X-inactivation in distal Xp22 buy discount betnovate 20 gm line acne solutions. This paternal decreased scores on a number of specific cognitive measures imprinting could explain why karyotypically normal males (107–109). Two more affected individuals, thereby enabling extension of more XO autistic individuals have recently been reported, typically small autism pedigrees. Understanding the bound- one with a maternally derived X (102)and the other with aries and nature of the BAP may also help our efforts to an X of unknown origin (Wassink et al. Rett syndrome, considered to be a subtype of repetitive behaviors, or cognitive deficits)that may map on PDD, is a disorder occurring only in girls that is character- to separate genes that together cause the full syndrome of ized by mental retardation, loss of speech, and stereotypic autism. This approach to disaggregating complex pheno- hand movements after 1 to 2 years of normal development. Clearly, clarification of the genetically rele- expression (1). The evidence from sex chromosome abnormalities and from X-linked dis- RELATED DISORDERS orders with phenotypic similarities, however, suggests that such pessimism is premature, and that the X and Y chromo- Autism is characterized by dysfunction in three symptom somes should continue to be a focus of attention in autism. As autism is a heterogene- BROADER AUTISM PHENOTYPE ous, genetically complex disorder, it may be that each of these domains has unique, independent genetic determi- In addition to describing the hereditary basis of autism, nants. Studying disorders that resemble these individual do- family and twin studies have demonstrated, in nonautistic mains, therefore, may provide insight into their etiology in 558 Neuropsychopharmacology: The Fifth Generation of Progress autism. There are also related disorders, such as tuberous some Abnormalities). Additional research related to social sclerosis, and domains of investigation, such as immunoge- deficits that may have relevance to autism comes from stud- netics, that may provide insight into autism. For example, nematode worms that lack receptors for neuropeptide Y become strik- Disorders of Language ingly isolated in situations where they would normally con- gregate with other worms (118). Genetic variability in re- Specific language impairment (SLI)is a disorder character- ceptors for oxytocin/vasopressin in mice and other rodents ized by isolated impairment of language skills, and may is also associated with clear variability in social behavior be characterized by grammatical impairment, word finding (119). Thus, though there is significant evolutionary dis- difficulties, or an underlying perceptual deficit (111). Conversely, an increased rate of autistic disorder Tuberous Sclerosis has recently been found in siblings of children with SLI (112). Tying this in to chromosome 7, an association study Tuberous sclerosis complex (TSC)is a neurocutaneous dis- found significant associations between two 7q31 genetic order characterized by benign tumors affecting numerous markers and a group of SLI trios (113). Also, a family has organs, most commonly the brain, eyes, skin, kidneys, and been identified with a severe speech and language disorder heart (120), with a population prevalence estimated at 1/ characterized by deficits in grammar, expressive language, 10,000 (121). The occurrence of autism and other behav- articulation, and coordination of orofacial musculature ioral and psychiatric disturbances in the context of TSC has (114). A genome-wide screen of this three-generation pedi- long been recognized (122). Clinic-based and epidemiologic studies of autism in TSC suggest that up to 25% of individ- gree found a maximum LOD score of 6. These findings, therefore, may to 3% of autistic individuals will have TSC (124), though represent localizations of heritable components of the au- this rate approaches 10% for autistic individuals with seizure tism phenotype and are of particular interest given the evi- disorders (24,123). TSC2 is located on chromosome 16p13 and codes for the protein Disorders of Repetitive and Stereotyped tuberin, whereas TSC1 is located on 9q34 and codes for Behaviors the protein hamartin. Dysfunction of tuberin may led some to wonder whether these disorders have etiologic result in constitutive activation of RAP1, a protein that mechanisms in common. Therefore, we examined caudate volumes tion of a variety of cell types. Hamartin is one of the proteins in an MRI study of autistic children and found enlargement for which tuberin acts as a cytosolic chaperone. Other than of the caudate that was correlated to ritualistic, stereotyped an ill-defined role in tumor suppression, the function of behaviors but not to social or communication deficits (17). Approximately two- In an earlier family study, we reported higher familial aggre- thirds of TSC cases are sporadic and one-third familial. Half gation of autism and the BAP in families ascertained of the familial cases and 75% to 80% of sporadic cases arise through a Kanner proband (more severe ritualistic behavior) from mutations of TSC2, with the remainder attributed to versus more broadly defined (DSM, third edition, revised) TSC1. Two studies have shown that TSC due to TSC2 probands (117). Findings such as these suggest that traits mutations is more likely to be associated with either mental such as stereotypies or ritualistic behavior may have unique retardation or intellectual impairment than TSC due to genetic determinants that, when combined with genes that TSC1 mutations (127,128). Despite the strong association give rise to other traits such as language or communication between TSC and autism, however, the mechanistic link deficits, could give rise to the syndrome of autism. Autism in the context of TSC may arise directly from the TSC mutations, from the tubers they produce, or from some other as yet Disorders of Social Activity undiscovered mechanism. One group, for example, has re- Examples of disorders that involve significant social deficits ported an association between the presence of temporal lobe include Turner syndrome and the fragile X syndrome, both tubers and autism (129), though this finding has not been of which have been discussed above (see Other Sex Chromo- replicated (24). Chapter 41: The Molecular and Cellular Genetics of Autism 559 Immunogenetics individuals with familial autism–related traits as 'affected' may increase the prevalence of extended pedigrees and reveal A number of investigators have suggested that some cases patterns of segregation within those pedigrees beyond what of autism may be attributable to interactions between infec- is seen for autism itself. Segregation of such traits (and their tions, the immune system, and genetic factors (130). Sub- underlying genetic diatheses), however, will only be de- jects with autism have been shown to have deficits in the tected if extended pedigrees are sought to begin with. A number and function of various immune cell subtypes further benefit to using the BAP is that it enables us to (131–136). A series of investigations, therefore, performed diagnose parents, and possibly siblings, of ASPs as well. The samples in these studies genetically related to autism. The BAP conceptualizes ulation control group as opposed to a parent-based test. Nonetheless, the authors report consistently significant Those subjects who exceed severity thresholds on these mea- findings that await replication by others. These measures also indicate, however, family members who are very unaffected, and therefore discordant, with their autistic siblings. If the traits FUTURE DIRECTIONS measured by the BAP truly reflect underlying genetic diathe- ses toward autism, one would expect reduced allele sharing Alternative Sampling Designs between DSPs at susceptibility loci as opposed to the excess As noted above, all of the genome-wide linkage screens per- allele sharing expected in ASPs (141). This is in part due to the diffi- retically, it may require far fewer sibling pairs than the ASP culty of gathering extended autism pedigrees. Risch and Zhang (142) because the mode of inheritance for autism is unknown, estimated that DSP analysis may provide the same power many researchers appear to be more comfortable with the to detect disease genes as the ASP method with a sample simple 'model-free' linkage analysis methods available for 10- to 40-fold smaller. The primary disadvantage of the ASP data than with the more complicated methods required DSP method is that DSPs are difficult to find, and require for the analysis of general pedigree structures. Yet, limiting an extensive screening effort to identify enough pairs. Microarray Technology The optimal pedigree structure for the detection of link- age depends on the true, underlying genetic model for the DNA chip microarray technology, which enables the simul- trait, which in this case is unknown. Large, multiplex pedi- taneous analysis of tens of thousands of DNA or RNA se- grees, for example, are optimal when a trait is transmitted quences, may be of significant benefit to autism research in as a rare dominant but tend to be uninformative if the two primary domains. First, an important focus of the cur- trait is a common recessive. Furthermore, an ASP data set rent effort to sequence the human genome is the identifica- contains only two primary pieces of information—the tion of single nucleotide polymorphisms (SNPs)(143). The to detect linkage under all possible modes of transmission hope, therefore, is that DNA SNP chips will be used to may be similarly limited. It could be argued, therefore, that rapidly screen a dense marker map, thereby enabling the precisely because the mode of inheritance for autism is un- performance of genome-wide association studies (145). Im- known, the optimal strategy would be to ascertain all types plementation of DNA chips for this purpose awaits the de- of potentially informative pedigree structures.

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