Interpreting the results of patient reported outcome measures in clinical trials: The clinician's perspective

This article deals with the problem of interpreting health-related quality of life (HRQL) outcomes in clinical trials. First, we will briefly describe how dichotomization and item response theory can facilitate interpretation. Based on examples from the medical literature for the interpretation of HRQL scores we will show that dichotomies may help clinicians understand information provided by HRQL instruments in RCTs. They can choose thresholds to calculate proportions of patients benefiting based on absolute scores or change scores. For example, clinicians interpreting clinical trial results could consider the difference in the proportion of patients who achieve a mean score of 50 before and after an intervention on a scale from 1 to 100. For the change score approach, they could consider the proportion of patients who have changed by a score of 5 or more. Finally, they can calculate the proportion of patients benefiting and transform these numbers into a number needed to treat or natural frequencies. Second, we will describe in more detail an approach to the interpretation of HRQL scores based on the minimal important difference (MID) and proportions. The MID is the smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important, either beneficial or harmful, and that would lead the patient or clinician to consider a change in the management. Any change in management will depend on the downsides, including cost and inconvenience, associated with the intervention. Investigators can help with the interpretation of HRQL scores by determining the MID of an HRQL instrument and provide mean differences in relation to the MID. For instance, for an MID of 0.5 on a seven point scale investigators could provide the mean change on the instrument as well as the proportion of patients with scores greater than the MID. Thus, there are several steps investigators can take to facilitate this process to help bringing HRQL information closer to the bedside

Interval exercise versus continuous exercise in patients with moderate to severe chronic obstructive pulmonary disease – study protocol for a randomised controlled trial [ISRCTN11611768]

BACKGROUND: Physical exercise has become a cornerstone of management of chronic obstructive pulmonary disease (COPD) because it leads to clinically relevant improvements of exercise capacity and health-related quality of life (HRQL). Despite the scarcity of randomised trials directly comparing exercise protocols, current guidelines recommend high intensity continuous exercise for lower extremities as the probably most effective exercise modality. However, for patients admitted to inpatient respiratory rehabilitation programmes, it is often difficult to initiate such an exercise programme because they are severely limited by dyspnoea and leg fatigue and therefore unable to perform continuous exercise at higher intensities and for periods longer than 30 minutes. Interval exercise may be an attractive alternative for these COPD patients because it allows high intensity exercise with recovery periods. The aim of this study is to assess if interval exercise compared to high intensity continuous exercise is not of inferior effectiveness in terms of HRQL and exercise capacity improvements but associated with better exercise tolerance in patients with moderate to severe COPD at the beginning of a respiratory rehabilitation. METHODS/DESIGN: We will assign patients with moderately severe to severe COPD to either continuous exercise or interval exercise using a stratified randomisation. Patients will follow 12–15 exercise sessions during a comprehensive inpatient respiratory rehabilitation. Primary end point for effectiveness is HRQL as measured by the Chronic Respiratory Questionnaire (CRQ) two weeks after the end of rehabilitation and secondary endpoints include additional clinical outcomes such as functional exercise capacity, other HRQL measures, patients' experience of physical exercise as well as physiological measures of the effects of physical exercise such as cardiopulmonary exercise testing. Including expected drop-outs, we will need 52 patients per group to show differences corresponding to the minimal clinically important difference of the CRQ. Outcome assessors and investigators involved in data analysis will be blinded to group assignment until analyses have been carried out. DISCUSSION: Clinicians and the scientific community need evidence on the benefits and tolerance of exercise protocols available in clinical practice. The proposed trial will provide important and needed data on interval and continuous exercise for decision making in clinical practice

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

The methodological quality of systematic reviews comparing temporomandibular joint disorder surgical and non-surgical treatment

<p>Abstract</p> <p>Background</p> <p>Temporomandibular joint disorders (TMJD) are multifactor, complex clinical problems affecting approximately 60–70% of the general population, with considerable controversy about the most effective treatment. For example, reports claim success rates of 70% and 83% for non-surgical and surgical treatment, whereas other reports claim success rates of 40% to 70% for self-improvement without treatment. Therefore, the purpose of this study was to (1) identify systematic reviews comparing temporomandibular joint disorder surgical and non-surgical treatment, (2) evaluate their methodological quality, and (3) evaluate the evidence grade within the systematic reviews.</p> <p>Methods</p> <p>A search strategy was developed and implemented for MEDLINE, Cochrane Library, LILACS, and Brazilian Dentistry Bibliography databases. Inclusion criteria were: systematic reviews (± meta-analysis) comparing surgical and non-surgical TMJD treatment, published in English, Spanish, Portuguese, Italian, or German between the years 1966 and 2007(up to July). Exclusion criteria were: <it>in vitro </it>or animal studies; narrative reviews or editorials or editorial letters; and articles published in other languages. Two investigators independently selected and evaluated systematic reviews. Three different instruments (AMSTAR, OQAQ and CASP) were used to evaluate methodological quality, and the results averaged. The GRADE instrument was used to evaluate the evidence grade within the reviews.</p> <p>Results</p> <p>The search strategy identified 211 reports; of which 2 were systematic reviews meeting inclusion criteria. The first review met 23.5 ± 6.0% and the second met 77.5 ± 12.8% of the methodological quality criteria (mean ± sd). In these systematic reviews between 9 and 15% of the trials were graded as high quality, and 2 and 8% of the total number of patients were involved in these studies.</p> <p>Conclusion</p> <p>The results indicate that in spite of the widespread impact of TMJD, and the multitude of potential interventions, clinicians have expended sparse attention to systematically implementing clinical trial methodology that would improve validity and reliability of outcome measures. With some 20 years of knowledge of evidence-based healthcare, the meager attention to these issues begins to raise ethical issues about TMJD trial conduct and clinical care.</p

The effects of pulmonary rehabilitation in patients with non-cystic fibrosis bronchiectasis: protocol for a randomised controlled trial

BACKGROUND: Non-cystic fibrosis bronchiectasis is characterised by sputum production, exercise limitation and recurrent infections. Although pulmonary rehabilitation is advocated for this patient group, its effects are unclear. The aims of this study are to determine the short and long term effects of pulmonary rehabilitation on exercise capacity, cough, quality of life and the incidence of acute pulmonary exacerbations. METHODS/DESIGN: This randomised controlled trial aims to recruit 64 patients with bronchiectasis from three tertiary institutions. Participants will be randomly allocated to the intervention group (supervised, twice weekly exercise training with regular review of airway clearance therapy) or a control group (twice weekly telephone support). Measurements will be taken at baseline, immediately following the intervention and at six and 12 months following the intervention period by a blinded assessor. Exercise capacity will be measured using the incremental shuttle walk test and the six-minute walk test. Quality of life and health status will be measured using the Chronic Respiratory Questionnaire, Leicester Cough Questionnaire, Assessment of Quality of Life Questionnaire and the Hospital Anxiety and Depression Scale. The rate of hospitalisation will be captured as well as the incidence of acute pulmonary exacerbations using a daily symptom diary. DISCUSSION: Results from this study will help to determine the efficacy of supervised twice-weekly pulmonary rehabilitation upon exercise capacity and quality of life in patients with bronchiectasis and will contribute to clinical practice guidelines for physiotherapists in the management of this population. TRIAL REGISTRATION: This study protocol is registered with ClinicalTrials.gov (NCT00885521)

Clinical practice guidelines within the Southern African development community: a descriptive study of the quality of guideline development and concordance with best evidence for five priority diseases

<p>Abstract</p> <p>Background</p> <p>Reducing the burden of disease relies on availability of evidence-based clinical practice guidelines (CPGs). There is limited data on availability, quality and content of guidelines within the Southern African Development Community (SADC). This evaluation aims to address this gap in knowledge and provide recommendations for regional guideline development.</p> <p>Methods</p> <p>We prioritised five diseases: HIV in adults, malaria in children and adults, pre-eclampsia, diarrhoea in children and hypertension in primary care. A comprehensive electronic search to locate guidelines was conducted between June and October 2010 and augmented with email contact with SADC Ministries of Health. Independent reviewers used the AGREE II tool to score six quality domains reporting the guideline development process. Alignment of the evidence-base of the guidelines was evaluated by comparing their content with key recommendations from accepted reference guidelines, identified with a content expert, and percentage scores were calculated.</p> <p>Findings</p> <p>We identified 30 guidelines from 13 countries, publication dates ranging from 2003-2010. Overall the '<it>scope and purpose' </it>and '<it>clarity and presentation' </it>domains of the AGREE II instrument scored highest, median 58%(range 19-92) and 83%(range 17-100) respectively. '<it>Stakeholder involvement' </it>followed with median 39%(range 6-75). '<it>Applicability'</it>, '<it>rigour of development' </it>and '<it>editorial independence' </it>scored poorly, all below 25%. Alignment with evidence was variable across member states, the lowest scores occurring in older guidelines or where the guideline being evaluated was part of broader primary healthcare CPG rather than a disease-specific guideline.</p> <p>Conclusion</p> <p>This review identified quality gaps and variable alignment with best evidence in available guidelines within SADC for five priority diseases. Future guideline development processes within SADC should better adhere to global reporting norms requiring broader consultation of stakeholders and transparency of process. A regional guideline support committee could harness local capacity to support context appropriate guideline development.</p

Defining the minimal important difference for the visual analogue scale assessing dyspnea in patients with malignant pleural effusions

BACKGROUND: The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established. METHODS: Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale. FINDINGS: The mean decrease in VASD in patients with a MPE reporting a 'small but just worthwhile decrease' in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml. INTERPRETATION: The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies

Genetic Ancestry-Smoking Interactions and Lung Function in African Americans: A Cohort Study

Background: Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans. Methodology/Principal Findings: We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV1) per pack-year of smoking (-5.7 ml FEV1/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV1/ smoking pack-year) (interaction P value = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV1 decline in Health ABC and independently replicated in CARDIA. Conclusions/Significance: African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking. © 2012 Aldrich et al

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals

Background - The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods - We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results - Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions - When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research “Mistra”. LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950–230607