Working together to deliver stratified medicine research effectively.

INTRODUCTION OR BACKGROUND: Stratified medicine is an important area of research across all clinical specialties, with far reaching impact in many spheres. Despite recently formulated global policy and research programmes, major challenges for delivering stratified medicine studies persist. Across the globe, clinical research infrastructures have been setup to facilitate high quality clinical research. SOURCES OF DATA: This article reviews the literature and summarizes views collated from a workshop held by the UK Pharmacogenetics and Stratified Medicine Network and the NIHR Clinical Research Network in November 2016. AREAS OF AGREEMENT: Stratified medicine is an important area of clinical research and health policy, benefitting from substantial international, cross-sector investment and has the potential to transform patient care. However there are significant challenges to the delivery of stratified medicine studies. AREAS OF CONTROVERSY: Complex methodology and lack of consistency of definition and agreement on key approaches to the design, regulation and delivery of research contribute to these challenges and would benefit from greater focus. GROWING POINTS: Effective partnership and development of consistent approaches to the key factors relating to stratified medicine research is required to help overcome these challenges. AREAS TIMELY FOR DEVELOPING RESEARCH: This paper examines the critical contribution clinical research networks can make to the delivery of national (and international) initiatives in the field of stratified medicine. Importantly, it examines the position of clinical research in stratified medicine at a time when pressures on the clinical and social services are mounting.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

The use of behavioural change techniques in the treatment of paediatric obesity: qualitative evaluation of parental perspectives on treatment.

BACKGROUND: Treatment for childhood obesity is characterized by nonattendance and widespread failure to achieve weight maintenance. The use of behavioural change methods is suggested for engaging families in changing lifestyles. Qualitative methods may improve understanding of patient perceptions, thus improving treatment. The present study aimed to explore the thoughts and feelings of parents whose children had undertaken dietetic consultations either employing behavioural change techniques or delivered by dietitians with no formal training in these techniques. METHODS: The study used purposive sampling, interviewing 17 parents of children attending 6-month outpatient treatments for obesity (body mass index > 98 th percentile). Parent's perceptions of the dietetic treatment were explored by in-depth interviews and analysed using Framework methods. RESULTS: Parents who had taken part in the behavioural change techniques applauded the process, finding it child-friendly and talked of 'forming a partnership'. Conversely, standard care treatment was less well received. Developing a rapport with the dietitian was significant for the parents in their perception of a positive experience. CONCLUSIONS: The present study may help inform future treatments for childhood obesity by providing insights into the aspects of treatment and approaches applauded by parents. It highlights the possible value of use of behavioural change skills by dietitians to engage with families of obese children.

Parents' journey through treatment for their child's obesity: a qualitative study.

BACKGROUND: Treatment for childhood obesity is characterised by patient non-attendance and drop-out, and widespread failure to achieve weight maintenance. Qualitative methods may improve our understanding of patient perceptions and so improve treatment for childhood obesity. AIM: To provide insight into the perceptions of parents of obese children as they "journey" from pre-treatment to end of treatment. METHODS: We used purposive sampling and studied 17 parents of children (mean (SD) age 8.4 (2.1) years) attending 6-month outpatient treatments for obesity (BMI>98th percentile). Parent's perceptions were explored by in-depth interviews, analysed using Framework methods. RESULTS: Parents were characterised as being unaware of their child's weight, in denial or actively seeking treatment. Parents were consistently motivated to enter treatment due to perceived benefits to their child's self-esteem or quality of life, and weight outcomes appeared typically less important. During treatment parents felt there was a lack of support for lifestyle changes outside the clinic, and noted that members of the extended family often undermined or failed to support lifestyle changes. Parents generally felt that treatment should have continued beyond 6 months and that it had provided benefits to their child's well-being, self-esteem and quality of life, and this is what motivated many to remain engaged with treatment. DISCUSSION: This study may help inform future treatments for childhood obesity by providing insights into the aspects of treatment of greatest importance to parents. Future treatments may need to consider providing greater support for lifestyle changes within the extended family, and may need to focus more on psycho-social outcomes.

Low-dose aspirin for in vitro fertilisation.

BACKGROUND: Low-dose aspirin is sometimes used to improve the outcome in women undergoing in vitro fertilisation, despite inconsistent evidence of efficacy and the potential risk of significant side affects. The most appropriate time to commence aspirin therapy and length of treatment required is also still to be determined. OBJECTIVES: To determine the effectiveness of low-dose aspirin for improving the outcome of in vitro fertilisation and intracytoplasmic sperm injection treatment cycles. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (April 2007), MEDLINE (1966 to March 2007) and EMBASE (1980 to March 2007) databases using the following research terms: "(aspirin OR acetylsalicylic acid) AND (in-vitro fertilisation OR intracytoplasmic sperm injection)" combined with the Cochrane Menstrual Disorders and Subfertility Group's search strategy for identifying randomised controlled trials for reports which appeared to describe randomised controlled trials of low-dose aspirin for women undergoing in vitro fertilisation. SELECTION CRITERIA: Prospective randomised controlled trials, published or unpublished, which addressed the objectives of the review. Quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies to include in the review, extracted data and assessed trial quality. MAIN RESULTS: The searches identified nine trials which were eligible for inclusion in the review, including a total of 1449 participants. No significant differences were found between the treatment and control groups for any of the outcomes assessed. Only two studies (involving 401 participants) investigated the effect of low-dose aspirin on live birth rate, and no significant difference was found between the treatment and control groups (RR 0.94, 95% CI 0.63 to 1.39). No significant difference was found in clinical pregnancy rate between treatment and control groups, based on results from 1240 participants in seven studies (RR 1.09, 95% CI 0.83 to 1.43). No data were reported on adverse events related to aspirin treatment in any of the included studies. AUTHORS' CONCLUSIONS: Use of low-dose aspirin for women undergoing in vitro fertilisation cannot currently be recommended due to lack of adequate trial data. There is a need for randomised controlled trials investigating the use of low-dose aspirin for different patient groups undergoing in vitro fertilisation. We used control group data from the largest trial included in this review to determine that a sample size of 350 women in each group would be required in order to demonstrate a 10% improvement from the use of aspirin with 80% power at the 5% significance level. Until evidence from appropriately powered trials is available, this treatment can not be recommended.

Protein substitute for children and adults with phenylketonuria.

BACKGROUND: Phenylketonuria is an inherited disease characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase. The aim of treatment is to lower blood phenylalanine concentrations to prevent developmental delay. Current treatment is based on a low phenylalanine diet in combination with a protein substitute (mixtures of amino acids free from or low in phenylalanine). Guidance regarding the dosage and distribution of this protein substitute, over a 24-hour period, is unclear and there is variation in recommendation between treatment centres. OBJECTIVES: To assess in children and adults with phenylketonuria, who are adhering to a low phenylalanine diet, the benefits and adverse effects of protein substitute, its dosage and distribution of dose. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also contacted manufacturers of the phenylalanine-free and low phenylalanine protein substitutes for any data from published and unpublished randomised controlled trials. Date of the most recent search of the Group's Trials Register: August 2005. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing: any dose of protein substitute with no protein substitute; an alternative dosage; or the same dose, but given as frequent small doses throughout the day compared with the same total daily dose given as larger boluses less frequently. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed trial quality. MAIN RESULTS: The searches identified 20 trials, of which one, including a total of 28 participants, was eligible for inclusion in the review. This was a two-phase trial, with only phase one being a randomised controlled trial. As data from both phases were combined in the analysis presented in the published paper, we are currently unable to include any data from the randomised controlled trial in the analysis of this review. AUTHORS' CONCLUSIONS: No conclusions could be made about the short- or long-term use of protein substitute in phenylketonuria due to the lack of adequate trial data. A randomised controlled trial is needed to investigate the use of protein substitute in phenylketonuria. Until further evidence is available current practice in the use of protein substitute should continue to be observed and monitored with care.

Reliability of calculating body mass index centile.

OBJECTIVE: Body mass index (BMI) centile is recommended for assessing body fatness in children. We compared the reliability of two methods of deriving BMI centile. METHOD: A total of 42 dietitians calculated the BMI centiles of six children, half using the Cole Calculator (a slide rule) and half calculating by hand and plotting on the BMI centile chart. RESULTS: The centile chart method was more reliable than the Cole Calculator, probably due to its greater familiarity.

Dietary treatment for familial hypercholesterolaemia.

BACKGROUND: Familial hypercholesterolaemia is an inherited disorder characterised by a raised blood cholesterol, the presence of xanthomatosis and premature ischaemic heart disease. The aim of treatment is the reduction of blood LDL cholesterol concentrations in order to reduce the risk of ischaemic heart disease. Current treatment is based on a cholesterol lowering diet alone or in combination with drug therapy. Many of the drugs found to be effective in treating adults with this disease are not licensed for use in children, therefore diet is the main treatment of children with familial hypercholesterolaemia. In addition to the cholesterol-lowering diet, several other dietary interventions have been suggested and consensus has yet to be reached on the most appropriate dietary treatment for children and adults with familial hypercholesterolaemia. OBJECTIVES: To examine the evidence that in children and adults with familial hypercholesterolaemia, a cholesterol lowering diet is more effective at lowering cholesterol and reducing incidence of ischaemic heart disease than no intervention or than other dietary interventions. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register, a specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Additional studies were identified from handsearching the Journal of Inherited Metabolic Disease (from inception, 1978 to 2000) and from the reference lists of identified studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), both published and unpublished, where a cholesterol lowering diet in children and adults with familial hypercholesterolaemia has been compared to other forms of dietary treatment or to no dietary intervention. Trials which include patients with familial hypercholesterolaemia alongside patients with non-familial hypercholesterolaemia were only included if the group of familial patients was well defined and the results for these patients were available. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial eligibility and methodological quality and one reviewer extracted the data, with independent verification of data extraction by a colleague. MAIN RESULTS: Only short term outcomes could be assessed in this review due to the length of the five eligible studies. Compliance to treatment, quality of life, mortality and evidence of ischaemic or atheromatous disease were not assessed in the studies identified. No differences were found between the cholesterol-lowering diet and all other diets for all of the short term outcomes assessed. REVIEWER'S CONCLUSIONS: No conclusions can be made about the effectiveness of the cholesterol-lowering diet, or any of the other dietary interventions suggested for familial hypercholesterolaemia, due to the lack of adequate data. A large, parallel, randomised controlled trial is needed to investigate the effectiveness of the cholesterol-lowering diet and other dietary interventions for FH. It is also possible that data from trials including subjects with both familial and non-familial hypercholesterolaemia could alter the results of future updates of this review and until further evidence is available current dietary treatment of FH should continue to be observed and monitored with care.

Reliability of percentage ideal weight for height.

AIMS: To assess the reliability of percentage ideal weight for height (%WFH) as a measure in children. METHODS: Forty two dietitians calculated %WFH of six children. Eleven of the 42 repeated the calculations. RESULTS: Interexaminer estimates varied by 16.5 to 40 percentage points (mean 27.8). Intraexaminer variability was also large. CONCLUSIONS: %WFH is an unreliable measure of nutritional status.

Oral protein calorie supplementation for children with chronic disease.

BACKGROUND: Growth failure and poor nutritional status are common features in children with chronic diseases due to reduced appetite, malabsorption and increased nutritional requirements associated with some diseases. The provision of oral protein calorie supplements is one of a number of interventions used to improve nutritional status in these children. The use of these products, which are expensive, may be associated with a number of adverse effects, for example, they may effect development of normal eating behaviour patterns or lead to unpleasant symptoms such as vomiting and diarrhoea. OBJECTIVES: To examine the evidence that in children with chronic disease, oral protein calorie supplements alter daily nutrient intake, nutritional indices, survival and quality of life and are associated with adverse effects, for example diarrhoea, vomiting, reduced appetite, glucose intolerance, bloating and eating behaviour problems. SEARCH STRATEGY: All publications describing RCTs of the use of oral protein calorie supplements in children with chronic diseases were identified through comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. The companies which market oral protein calorie supplements were also contacted. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing use of oral protein calorie supplements for at least one month to increase calorie intake with existing conventional therapy, which may include nutritional advice on how to improve nutritional intake from food or no specific intervention, in children with chronic disease. DATA COLLECTION AND ANALYSIS: The following outcomes were assessed: indices of nutrition and growth, anthropometric measures of body composition, calorie and nutrient intake (total, from oral protein calorie supplements and from food), eating behaviour, compliance, quality of life, specific adverse effects and disease severity scores, and mortality. MAIN RESULTS: Three trials have been identified as being suitable for inclusion in the review and we are awaiting further data from one of these trials. All of these trials were carried out in children with cystic fibrosis. Few statistical differences could be found between the treatment and control groups apart from change in total fat intake at three months (weighted mean difference 69.20 [95% CI 11.05, 127.35]). However, this was based on the results of only one, small study. No trials have been identified which assess the effectiveness of oral protein calorie supplements in children with other chronic diseases. REVIEWER'S CONCLUSIONS: Oral protein calorie supplements are widely used to improve the nutritional status of children with a number of chronic diseases. We have only been able to identify a small number of trials assessing these products in children with cystic fibrosis and have been unable to draw any conclusions based on the limited data extracted from these. We therefore recommend that a series of large, randomised controlled trials are undertaken investigating the use of these products in children with different chronic diseases. Until further data are available, we would suggest that these products are only used with caution.

Dietary interventions for phenylketonuria.

BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap however the diet is very restrictive and unpalatable and can be difficult to follow. Whether the diet can be relaxed or discontinued during adolescence or should be continued for life remains a contraversial issue which we aim to address in this review. OBJECTIVES: To assess the effects of a phenylalanine restricted diet commenced early in life for patients with phenylketonuria. To assess the possible adverse effects of relaxation or termination of the diet on intelligence, neuropsychological outcomes and mortality, and to assess the effect on growth, nutritional status and eating behaviour and quality of life. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register which is a specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Additional studies were identified from handsearching the Journal of Inherited Metabolic Disease (from inception, 1978 to 1998). The manufacturers of dietary products for phenylketonuria were also contacted. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised controlled trials comparing a phenylalanine restricted diet to either relaxation or termination of dietary restrictions in patients with phenylketonuria. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Four studies were included in this review including a total of 251 patients. Few statistically significant differences were found between treatment and comparison groups for any of the outcomes apart from for blood phenylalanine level and intelligence quotient. Blood phenylalanine levels were significantly lower in those subjects with phenylketonuria following a phenylalanine restricted diet compared to those on a less restricted or relaxed diet (weighted mean difference at three months -672.203, 95% Confidence interval (CI) -813.799 to - 530.608). Intelligence quotient was significantly higher in subjects who continued on the phenylalanine restricted diet compared to those who terminated the diet (weighted mean difference after 12 months -5.00, 95% CI -9.595 to -0.405). However this is based on the results of only one study. REVIEWER'S CONCLUSIONS: The results of non-randomised studies have concluded that a phenylalanine restricted diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcome. No randomised controlled trials have assessed the effect of a phenylalanine restricted diet versus no dietary restrictions from diagnosis. In view of evidence from non-randomised studies, such a trial would now be unethical and it is recommended that phenylalanine restricted diet should be commenced at the time of diagnosis. There is uncertainty about the precise level of phenylalanine restriction and when, if ever, the diet should be relaxed. These questions should be addressed by randomised controlled trials with careful consideration given to which patients to include.

Tyrosine supplementation for phenylketonuria.

BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap however the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in PKU. Therefore, this review aims to assess the efficasy of tyrosine supplementation for phenylketonuria. OBJECTIVES: To assess the effects of tyrosine supplementation alongside or instead of phenylalanine restricted diet for patients with phenylketonuria who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of phenylalanine restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register which is a specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Additional studies were identified from handsearching the Journal of Inherited Metabolic Disease (from inception, 1978, to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudo-randomised trials investigating the use of tyrosine supplementation versus placebo in patients with phenylketonuria in addition to, or instead of, a phenylalanine restricted diet. Patients treated for maternal phenylketonuria were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Two trials were included with a total of 47 patients. The blood tyrosine concentrations were significantly higher in the patients receiving tyrosine supplements than those in the placebo group (weighted mean difference 22.526, 95% Confidence interval (CI) 12.182 - 32.870). No significant differences were found between any of the other outcomes measured. REVIEWER'S CONCLUSIONS: From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide further evidence.