Validation of an instrument to measure quality of life in British children with inflammatory bowel disease.

OBJECTIVE: To validate IMPACT-III (UK), a health-related quality of life (HRQoL) instrument, in British children with inflammatory bowel disease (IBD). PATIENTS AND METHODS: One hundred six children and parents were invited to participate. IMPACT-III (UK) was validated by inspection by health professionals and children to assess face and content validity, factor analysis to determine optimum domain structure, use of Cronbach alpha coefficients to test internal reliability, ANOVA to assess discriminant validity, correlation with the Child Health Questionnaire to assess concurrent validity, and use of intraclass correlation coefficients to assess test-retest reliability. The independent samples t test was used to measure differences between sexes and age groups, and between paper and computerised versions of IMPACT-III (UK). RESULTS: IMPACT-III (UK) had good face and content validity. The most robust factor solution was a 5-domain structure: body image, embarrassment, energy, IBD symptoms, and worries/concerns about IBD, all of which demonstrated good internal reliability (α = 0.74-0.88). Discriminant validity was demonstrated by significant (P  < 0.05, P < 0.01) differences in HRQoL scores between the severe, moderate, and inactive/mild symptom severity groups for the embarrassment scale (63.7 vs 81.0 vs 81.2), IBD symptom scale (45.0 vs 64.2 vs 80.6), and the energy scale (46.4 vs 62.1 vs 77.7). Concurrent validity of IMPACT-III (UK) with comparable domains of the Child Health Questionnaire was confirmed. Test-retest reliability was confirmed with good intraclass correlation coefficients of 0.66 to 0.84. Paper and computer versions of IMPACT-III (UK) collected comparable scores, and there were no differences between the sexes and age groups. CONCLUSIONS: IMPACT-III (UK) appears to be a useful tool to measure HRQoL in British children with IBD.

Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Enteral nutrition for maintenance of remission in Crohn's disease.

BACKGROUND: Prevention of relapse is a major issue in the management of Crohn's disease. Corticosteroids and 5-ASA preparations are not effective for the maintenance of remission. Methotrexate, infliximab, 6-mercaptopurine and its prodrug, azathioprine may be effective in maintaining remission, but these drugs may cause significant adverse events. OBJECTIVES: To conduct a systematic review to evaluate the efficacy of enteral nutrition for the maintenance of remission in Crohn's disease. SEARCH STRATEGY: MEDLINE (1966 to January 2007), EMBASE (1984 to January 2007) the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 4, 2006) and the IBD/FBD Review Group Specialized Trials Register were searched. The articles cited in each publication were hand searched. SELECTION CRITERIA: Randomised controlled trials which compared enteral nutrition with no intervention, placebo or with any other intervention were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodological quality of included studies were independently performed by two authors. The main outcome measure was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Odds ratios and 95% confidence intervals were calculated for dichotomous outcomes. MAIN RESULTS: Two studies were identified that met the inclusion criteria and were included in the review. Statistical pooling of the results of these studies was not possible because the control interventions, and the way outcomes were assessed differed greatly between the two studies. In one study (Takagi 2006), patients who received half of their total daily calorie requirements as elemental diet and the remaining half by normal diet had a significantly lower relapse rate compared to patients who received unrestricted normal diet (9 of 26 versus 16 of 25; OR 0.3, 95% CI 0.09 to 0.94). In the other study (Verma 2001), elemental and polymeric feeds (providing between 35 and 50% of patients' pretrial calorie intake in addition to unrestricted normal food) were equally effective for maintenance of remission and allowing withdrawal of steroid therapy (8 of 19 versus 6 of 14; OR 0.97, 95% CI 0.24 to 3.92). AUTHORS' CONCLUSIONS: The available evidence suggests that supplementary enteral nutritional may be effective for maintenance of remission in Crohn's disease. Whilst larger studies are needed to confirm these findings, enteral nutritional supplementation could be considered as an alternative or as an adjunct to maintenance drug therapy in Crohn's disease.

Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis.

BACKGROUND: Anti-TNF-alpha agents have been shown to be effective for the induction of remission in Crohn's disease. The role of TNF-alpha blocking agents in ulcerative colitis is, however, unclear and recent studies have yielded conflicting results. OBJECTIVES: To evaluate the efficacy of TNF-alpha antibody for induction of remission in ulcerative colitis, and to determine adverse events associated with TNF-alpha antibody treatment. SEARCH STRATEGY: We searched MEDLINE (1966 to 2005), EMBASE (1984 to 2005), the Cochrane Central Register of Controlled Trials (Issue 3, 2004) and the IBD/FBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication. SELECTION CRITERIA: Only randomised controlled trials in which patients with active ulcerative colitis (defined by a combination of clinical, radiographic, endoscopic and histologic criteria) were randomly allocated to receive a TNF-alpha blocking agent in the treatment arm, and to receive placebo or another treatment in the comparison arm were included. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodological quality of each study were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. The main outcome measure was the occurrence of remission as defined by the primary studies. Other endpoints were clinical, histological or endoscopic improvement as defined by the primary studies; improvement in quality of life as measured by a validated quality of life tool and the occurrence of adverse events. MAIN RESULTS: Seven randomised controlled trials were identified that satisfied the inclusion criteria. In patients with moderate to severe ulcerative colitis whose disease was refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab (three intravenous infusions at 0, 2, and 6 weeks) was more effective than placebo in inducing clinical remission (Relative Risk (RR) 3.22, 95% CI 2.18 to 4.76); inducing endoscopic remission (RR 1.88, 95% CI 1.54 to 2.28); and in inducing clinical response (RR 1.99, 95% CI 1.65 to 2.41) at 8 weeks. A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44, 95% CI 0.22 to 0.87). AUTHORS' CONCLUSIONS: In patients with moderate to severe ulcerative colitis whose disease is refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab is effective in inducing clinical remission, inducing clinical response, promoting mucosal healing, and reducing the need for colectomy at least in the short term. Serious adverse events attributable to infliximab were not common in the included studies but physicians should be aware of and be prepared to deal with potential adverse events such as anaphylactic reactions and infections.

Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease.

BACKGROUND: Prevention of relapses is a major issue in the management of Crohn's disease. Corticosteroids, the mainstay of treatment of acute exacerbations are not effective in the maintenance of remission and its chronic use is limited by numerous adverse events. A number of randomised controlled trials comparing various 5-ASA agents with either placebo or other drugs have had conflicting results. OBJECTIVES: To conduct a systematic review to evaluate the efficacy of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn's disease. SEARCH STRATEGY: We searched MEDLINE (1966 to January 2004), EMBASE (1984-January 2004), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 1, 2004) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication. SELECTION CRITERIA: We included randomised controlled trials which compared oral 5-ASA agents with either placebo or sulphasalazine, with treatment durations of at least 6 months. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of methodological quality of each study were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. The main outcome measure was the occurrence of relapse as defined by the primary studies. Odds ratios of relapse rates and their 95% confidence intervals were calculated. MAIN RESULTS: 5-ASA VERSUS PLACEBO. In the main analysis, we used as the denominator the total number of patients randomised. We assumed that participants who dropped out of the study, and on whom there was no post withdrawal information, had relapsed during the study period. Using the fixed effects model, the odds ratio for 6 studies where participants were followed up for 12 months was 1.00 (95%CI, 0.80 to 1.24). Using the random effects model in a sensitivity analysis had little effect on the results with an OR of 0.93 (95% CI, 0.65 to 1.33). For the seventh study where follow up was for 24 months, the odds ratio was 0.98; 95% CI, 0.51 to 1.90. In further sensitivity analyses, we analysed only participants who completed the study and ignored the dropouts. The odds ratio (fixed effects model) for the 6 studies where follow up was for 12 months was 0.74 (95% CI, 0.57 to 0.96), but using the random effects model, the OR was 0.68 (95% CI 0.45 to 1.02). The OR for the seventh study where follow up was for 24 months (Gendre 1993a), was 0.86; 95% CI, 0.42 to 1.78. 5-ASA VERSUS SULPHASALAZINE. We did not find any study that satisfied the inclusion criteria. AUTHORS' CONCLUSIONS: We found no evidence in this review to suggest that 5-ASA preparations are superior to placebo for the maintenance of medically-induced remission in patients with Crohn's disease. Therefore it appears that additional randomised trials of this regime are not justified.

Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease may be refractory to conventional treatments such as corticosteroids, enteral nutrition and immuno-suppressive agents. A number of patients with the disease may also become steroid-dependent leading to increased risk of developing steroid-related adverse effects. Recent studies suggest that TNF-a blocking agents may be effective in inducing remission in Crohn's disease. OBJECTIVES: To conduct a systematic review to evaluate the effectiveness of TNF-a blocking agents in inducing remission in patients with active Crohn's disease. SEARCH STRATEGY: We searched MEDLINE (1966-June 2003), EMBASE (1984-June 2003), the Cochrane Central Register of Controlled Trials from the Cochrane Library (Issue 2, 2003) and the IBD Review Group Specialized Trials Register. We hand-searched the articles cited in each publication obtained. SELECTION CRITERIA: We included only randomised controlled trials in which patients with active Crohn's disease (defined by a validated Crohn's disease activity index) were randomly allocated to receive a TNF-a blocking agent in the treatment arm, or to receive placebo or another treatment in the comparison arm. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of the methodological quality of each trial were independently performed by two reviewers. Any disagreement among reviewers was resolved by consensus. Outcome measures reported in the primary studies included clinical remission, clinical response and changes in disease activity index. MAIN RESULTS: Ten studies were identified of which 4 met the inclusion criteria. The included studies either differed in the type of TNF-a blocking agent used or in the way outcomes were assessed to such an extent that we considered it inappropriate to combine the data statistically. There is evidence from one randomised controlled trial that suggests that a single intravenous infusion of the monoclonal antibody cA2, infliximab, may be effective for induction of remission in Crohn's disease. There was no difference in response rates among infliximab doses of 5, 10 or 20 mg/kg. The results of two other trials suggested that CDP571, the genetically engineered human TNF monoclonal antibody, may also be effective in reducing disease activity index at 2 weeks after an infusion. We did not find any evidence to support the use of etanercept in Crohn's disease. REVIEWER'S CONCLUSIONS: Evidence from one randomized controlled trial suggests that a single infusion of infliximab may be effective for induction of remission in Crohn's disease. Based on this study, we can recommend a dose of 5 mg/kg. There is also some evidence that CDP571 may be effective in inducing remission in Crohn's disease. We did not find any evidence that supports the use of etanercept in Crohn's disease. The period of follow up for the patients in these studies was probably too short to allow adequate assessment of recently reported serious adverse effects such as tuberculosis and lymphoma.

The effects of anti-TNF-α treatment with adalimumab on growth in children with Crohn's disease (CD).

INTRODUCTION: Adalimumab is used to treat children with Crohn's disease (CD), but the effects of adalimumab on growth in CD have not been studied. AIM: To study growth and disease activity over 12 months (6 months prior to (T-6), baseline (T0) and for 6 months following (T+6) adalimumab). SUBJECTS AND METHODS: Growth and treatment details of 36 children (M: 22) who started adalimumab at a median (10th, 90th) age of 14.7 years (11.3, 16.8) were reviewed. RESULTS: Of 36 cases, 28 (78%) went into remission. Overall 42% of children showed catch up growth, which was more likely in: (i) those who achieved remission (median change in height SDS (ΔHtSDS) increased from -0.2 (-0.9, 1.0) at T0 to 0.2 (-0.6, 1.6) at T+6, (p=0.007)), (ii) in those who were on immunosuppression ΔHtSDS increased from -0.2 (-0.9, 1.0) at T0 to 0.1 (-0.8, 1.3) at T+6, (p=0.03) and (iii) in those whose indication for using adalimumab therapy was an allergic reaction to infliximab, median ΔHtSDS increased significantly from -0.3 (-0.9, 1.0) at T0 to 0.3 (-0.5, 1.6) at T+6, (p=0.02). Median ΔHtSDS also increased from -0.4 (-0.8, 0.7) at T0 to 0.0 (-0.6, 1.6) at T+6, (p=0.04) in 15 children who were on prednisolone therapy when starting adalimumab. CONCLUSION: Clinical response to adalimumab therapy is associated with an improvement in linear growth in a proportion of children with CD. Improved growth is more likely in patients entering remission and on immunosuppression but is not solely due to a steroid sparing effect.

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease.

BACKGROUND: Adalimumab is efficacious therapy for adults with Crohn's disease (CD). AIM: To summarise the United Kingdom and Republic of Ireland paediatric adalimumab experience. METHODS: British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) members with Inflammatory Bowel Disease (IBD) patients <18 years old commencing adalimumab with at least 4 weeks follow-up. Patient demographics and details of treatment were then collected. Response and remission was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI)/Physicians Global Assessment (PGA). RESULTS: Seventy-two patients [70 CD, 1 ulcerative colitis (UC), 1 IBD unclassified (IBDU)] from 19 paediatric-centres received adalimumab at a median age of 14.8 (IQR 3.1, range 6.1-17.8) years; 66/70 CD (94%) had previously received infliximab. A dose of 80 mg then 40 mg was used for induction in 41(59%) and 40 mg fortnightly for maintenance in 61 (90%). Remission rates were 24%, 58% and 41% at 1, 6 and 12 months, respectively. Overall 43 (61%) went into remission at some point, with 24 (35%) requiring escalation of therapy. Remission rates were higher in those on concomitant immunosuppression cf. those not on immunosuppression [34/46 (74%) vs. 9/24 (37%), respectively, (χ(2) 8.8, P=0.003)]. There were 15 adverse events (21%) including four (6%) serious adverse events with two sepsis related deaths in patients who were also on immunosuppression and home parenteral nutrition (3% mortality rate). CONCLUSIONS: Adalimumab is useful in treatment of refractory paediatric patients with a remission rate of 61%. This treatment benefit should be balanced against side effects, including in this study a 3% mortality rate.

Review article: the evidence base for interventions used to maintain remission in Crohn's disease.

BACKGROUND: Crohn's disease is characterised by recurrent flare-ups alternating with periods of remission. A number of interventions are currently used in clinical practice to try and maintain remission in Crohn's disease but the evidence base for some of them may be questionable. AIM: To review the available evidence on interventions, which are currently used to maintain remission in Crohn's disease. METHODS: The Cochrane Library and Medline (Pubmed) were searched for level 1 evidence on specific interventions. Search terms included 'Crohn's disease or synonyms', 'remission or synonyms' and the names of specific interventions. RESULTS: Azathioprine, infliximab and adalimumab are effective at maintaining remission in Crohn's disease. Natalizumab is also effective, but there are concerns about its potential association with progressive multifocal leukoencephalopathy. Long-term enteral nutritional supplementation, enteric-coated omega-3 fatty acids and intramuscular methotrexate may also be effective but the evidence for these is based on relatively small studies. The available evidence does not support the use of oral 5-aminosalicylates agents, corticosteroids, anti-mycobacterial agents, probiotics or ciclosporin as maintenance therapy in Crohn's disease. CONCLUSION: A better understanding of the evidence base of existing interventions could result in the use of treatments, which are more likely to lead to improved patient outcomes.

Communicating the benefits and harms of treatments.

Although various measures can be used to describe the benefits and harms of treatments, not all of these clearly show the benefits or otherwise of treatments in a clinically useful way. Relative risk and relative risk reduction are commonly used to describe the results of studies, but they are of limited clinical usefulness as they do not take baseline risks into account and tend to exaggerate the results of studies. Absolute risk measures such as the number needed to treat (NNT) and the number needed to harm (NNH) allow risk to be expressed in a much more clinically relevant way. The absolute risk measures reflect baseline risk and more accurately indicate the magnitude of the treatment effect. However, because they vary according to the baseline risk of the population, they are of limited generalisability, and the published NNT of a treatment in one population cannot be directly applied to another population with a different baseline risk. There are, however, a number of simple methods which can allow us to estimate NNTs or NNHs for our own patients based on published data. The benefits of a treatment (expressed as the NNT) and the harms of the treatment (expressed as the NNH) can be combined into a single ratio called the likelihood of being helped or harmed (LHH). LHH can be adjusted for individual patients by taking account of their own values and unique circumstances.

Crohn's disease: current treatment options.

There is no known cure for Crohn's disease (CD), but a better understanding of the evidence base of both established treatments (such as enteral nutrition, corticosteroids, 5-aminosalicylates and immunosuppressive agents) and emerging treatments (such as the anti-tumour necrosis factor-alpha (anti-TNF-alpha) agents, infliximab and adalimumab) provides opportunities to improve and maintain the quality of life for children with the disease. This article provides an overview of the evidence base of current medical treatments that are used to induce and maintain remission in CD. Exclusive enteral nutrition is recommended as the first line of treatment for the induction of remission in paediatric CD. Corticosteroids are also effective for inducing remission but may be associated with significant adverse events. Patients with chronically active CD may benefit from immunosuppressive agents such as azathioprine and methotrexate. Infliximab is effective for inducing remission in patients who continue to have significant active disease despite the use of conventional treatments. Adalimumab may be indicated for patients who develop a severe allergic reaction to infliximab or those who initially respond to infliximab but subsequently lose their response. Treatments that have been shown to be effective for the maintenance of remission include azathioprine, methotrexate, infliximab and adalimumab. Recent evidence also suggests that long-term enteral nutritional supplementation with patients taking about half of their daily calorie requirements as enteral nutrition may be an effective strategy for the maintenance of remission in CD. The available evidence does not support the use of corticosteroids or 5-aminosalicylates as maintenance therapy for CD.

Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis.

OBJECTIVES: To assess whether vitamin D supplementation in infancy reduces the risk of type 1 diabetes in later life. METHODS: This was a systematic review and meta-analysis using Medline, Embase, Cinahl, Cochrane Central Register of Controlled Trials and reference lists of retrieved articles. The main outcome measure was development of type 1 diabetes. Controlled trials and observational studies that had assessed the effect of vitamin D supplementation on risk of developing type 1 diabetes were included in the analysis. RESULTS: Five observational studies (four case-control studies and one cohort study) met the inclusion criteria; no randomised controlled trials were found. Meta-analysis of data from the case-control studies showed that the risk of type 1 diabetes was significantly reduced in infants who were supplemented with vitamin D compared to those who were not supplemented (pooled odds ratio 0.71, 95% CI 0.60 to 0.84). The result of the cohort study was in agreement with that of the meta-analysis. There was also some evidence of a dose-response effect, with those using higher amounts of vitamin D being at lower risk of developing type 1 diabetes. Finally, there was a suggestion that the timing of supplementation might also be important for the subsequent development of type 1 diabetes. CONCLUSION: Vitamin D supplementation in early childhood may offer protection against the development of type 1 diabetes. The evidence for this is based on observational studies. Adequately powered, randomised controlled trials with long periods of follow-up are needed to establish causality and the best formulation, dose, duration and period of supplementation.

Systematic review: tolerable amount of gluten for people with coeliac disease.

BACKGROUND: The threshold amount of gluten in 'gluten-free' products that can be tolerated by people with coeliac disease is unclear. AIM: To investigate the threshold amount of gluten and the threshold concentration of gluten in food products that can be tolerated by people with coeliac disease. DESIGN: Systematic review of studies published between 1966 and May 2007. METHODS: The data sources used were MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and reference lists of retrieved articles. We included studies that evaluated the amount of dietary gluten or the concentrations of gluten in food products that can be tolerated by people with coeliac disease whatever their design, method or language of publication. RESULTS: Thirteen studies (three randomized controlled, one cohort, two crossover, and seven cross-sectional) met the inclusion criteria. The daily amount of tolerable gluten varied widely between studies. Whilst some patients tolerated an average of 34-36 mg of gluten per day, other patients who consumed about 10 mg of gluten per day developed mucosal abnormalities. The effect of the consumption of 'gluten-free' products with different degrees of gluten contamination was also inconsistent. CONCLUSIONS: The amount of tolerable gluten varies among people with coeliac disease. Although there is no evidence to suggest a single definitive threshold, a daily gluten intake of <10 mg is unlikely to cause significant histological abnormalities.

Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies.

BACKGROUND: Coeliac disease (CD) is a disorder that may depend on genetic, immunological, and environmental factors. Recent observational studies suggest that breast feeding may prevent the development of CD. AIM: To evaluate articles that compared effects of breast feeding on risk of CD. METHODS: Systematic review and meta-analysis of observational studies published between 1966 and June 2004 that examined the association between breast feeding and the development of CD. RESULTS: Six case-control studies met the inclusion criteria. With the exception of one small study, all the included studies found an association between increasing duration of breast feeding and decreased risk of developing CD. Meta-analysis showed that the risk of CD was significantly reduced in infants who were breast feeding at the time of gluten introduction (pooled odds ratio 0.48, 95% CI 0.40 to 0.59) compared with infants who were not breast feeding during this period. CONCLUSIONS: Breast feeding may offer protection against the development of CD. Breast feeding during the introduction of dietary gluten, and increasing duration of breast feeding were associated with reduced risk of developing CD. It is, however, not clear from the primary studies whether breast feeding delays the onset of symptoms or provides a permanent protection against the disease. Long term prospective cohort studies are required to investigate further the relation between breast feeding and CD.

Principles of evidence based medicine.

Health care professionals are increasingly required to base clinical decisions on the best available evidence. Evidence based medicine (EBM) is a systematic approach to clinical problem solving which allows the integration of the best available research evidence with clinical expertise and patient values. This paper explains the concept of EBM and introduces the five step EBM model: formulation of answerable clinical questions; searching for evidence; critical appraisal; applicability of evidence; evaluation of performance. Subsequent articles will focus on the principles and critical appraisal of randomised controlled trials, systematic reviews, and meta-analyses, and provide a practical demonstration of the five step EBM model using a real life clinical scenario.

Understanding randomised controlled trials.

The hierarchy of evidence in assessing the effectiveness of interventions or treatments is explained, and the gold standard for evaluating the effectiveness of interventions, the randomised controlled trial, is discussed. Issues that need to be considered during the critical appraisal of randomised controlled trials, such as assessing the validity of trial methodology and the magnitude and precision of the treatment effect, and deciding on the applicability of research results, are discussed. Important terminologies such as randomisation, allocation concealment, blinding, intention to treat, p values, and confidence intervals are explained.

Understanding systematic reviews and meta-analysis.

This review covers the basic principles of systematic reviews and meta-analyses. The problems associated with traditional narrative reviews are discussed, as is the role of systematic reviews in limiting bias associated with the assembly, critical appraisal, and synthesis of studies addressing specific clinical questions. Important issues that need to be considered when appraising a systematic review or meta-analysis are outlined, and some of the terms used in the reporting of systematic reviews and meta-analyses--such as odds ratio, relative risk, confidence interval, and the forest plot--are introduced.

Evidence in practice.

A clinical scenario is used to illustrate how the principles outlined in the previous articles in the series could be applied to help improve patient care. A practical demonstration of the art of formulating answerable clinical questions, finding evidence, critically appraising evidence, and putting evidence into practice is provided. The importance of integrating evidence with patient's preferences, and taking account of issues such as availability of interventions, costs, and so on is discussed. Finally, some of the issues involved in the development of evidence based policies within clinical teams are outlined.

Understanding measures of treatment effect in clinical trials.

Evidence based medicine implies that healthcare professionals are expected to base their practice on the best available evidence. This means that we should acquire the necessary skills for appraising the medical literature, including the ability to understand and interpret the results of published articles. This article discusses in a simple, practical, 'non-statistician' fashion some of the important outcome measures used to report clinical trials comparing different treatments or interventions. Absolute and relative risk measures are explained, and their merits and demerits discussed. The article aims to encourage healthcare professionals to appreciate the use and misuse of these outcome measures and to empower them to calculate these measures themselves when, as is frequently the case, the authors of some original articles fail to present their results in a more clinically friendly format.