Applying causal mediation methods to clinical trial data: What can we learn about why our interventions (don't) work?

BACKGROUND: Many randomized controlled trials (RCTs) of psychosocial interventions for low back pain (LBP) have been found to have only small effects on disability outcomes. Investigations of the specific mechanisms that may lead to an improvement in outcome have therefore been called for. METHODS: We present an application of the causal inference approach to mediation analysis using the example of a cluster RCT in a primary care population with (sub)acute LBP randomized to either usual GP care (n = 171) or a minimal psychosocial intervention (n = 143). Mediation analysis explored the causal pathway between treatment allocation and disability at 3 months by considering pain catastrophizing, fear-avoidance beliefs, distress and receiving and following advice as potential mediators, all measured at 6 weeks. We have attempted to explain this approach to mediation analysis in a step-by-step manner to help clinical researchers apply this method more easily. RESULTS: In unadjusted mediation analyses, fear-avoidance beliefs were identified as a mediator of treatment on disability, with an indirect effect of -0.30 (95% CI: -0.86, -0.03), although this relationship was found to be non-significant after adjusting for age, gender and baseline scores. This finding supports the trial authors' hypothesis that while fear-avoidance beliefs are important, this intervention may not have targeted them strongly enough to lead to change. CONCLUSION: The use of mediation analysis to identify what factors may be part of the causal pathway between intervention and outcome, regardless of whether the intervention was successful, can provide useful information and insight into how to improve future interventions. SIGNIFICANCE: This study presents a step-by-step approach to mediation analysis using the causal inference framework to investigate why a psychosocial intervention for LBP was unsuccessful. Fear-avoidance beliefs were found to mediate the relationship between treatment and disability, although not when controlling for baseline scores.

Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs.

Disturbed expression of microRNAs (miRNAs) in regulatory T cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. In this study, we have used a microarray approach to comprehensively analyze miRNA expression signatures of both naive Tregs (CD4+CD45RO-CD25++) and memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T cells (Tconvs) derived from peripheral blood of RA patients and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan-based quantitative reverse transcription-PCR. We found a positive correlation between increased expression of miR-451 in T cells of RA patients and disease activity score (DAS28), erythrocyte sedimentation rate levels and serum levels of interleukin-6. Moreover, we found characteristic, disease- and treatment-independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (for example, miR-92a) and a general memory phenotype (for example, miR-21, miR-155). Importantly, the analysis allowed us to define miRNAs that are specifically expressed in both naive and memory Tregs, defining as such miRNA signature characterizing the Treg phenotype (that is, miR-146a, miR-3162, miR-1202, miR-1246 and miR-4281).

Inflammatory bowel disease: a systematic review on the value of diagnostic testing in primary care.

AIM: The clinical presentation of inflammatory bowel disease in primary care represents a diagnostic challenge as its symptoms are heterogeneous and common. To assist the primary care physician, we have summarized the available evidence on diagnostic tests in patients with abdominal symptoms. METHOD: We searched PubMed and Embase and screened references. Studies were selected if the design was a primary diagnostic study. Patients were adults attending with nonacute abdominal symptoms. Tests included clinical assessment, blood or faecal tests or abdominal ultrasonography. Quality assessment using a modified version of the QUADAS tool and data extraction was performed by two reviewers independently. Diagnostic two-by-two tables and pooled estimates of sensitivity and specificity are given. We refrained from pooling when there was considerable clinical or statistical heterogeneity. RESULTS: A total of 24 studies were included. While the diagnostic performance of the individual symptoms was highly variable (range sensitivity 0.0-0.96, specificity 0.09-1.0), the performance of symptom-based classification systems was both more consistent and better (sensitivity 0.65-1.0, specificity 0.17-0.82). Among faecal and blood tests, calprotectin was studied most frequently and showed the best results (sensitivity 0.61-1.0, specificity 0.71-1.0). Statistical pooling for ultrasonography resulted in a sensitivity of 0.73 (0.65-0.80) and a specificity of 0.95 (0.91-0.97). CONCLUSION: Although calprotectin and ultrasonography showed consistent and promising findings, none of the studies was performed in primary care. To assist primary care physicians in diagnostic decision making, we urgently need high quality studies performed in primary care.

Lactose malabsorption and intolerance: a systematic review on the diagnostic value of gastrointestinal symptoms and self-reported milk intolerance.

BACKGROUND: When lactose malabsorption gives rise to symptoms, the result is called 'lactose intolerance'. Although lactose intolerance is often bothersome for patients, once recognized it may be managed by simple dietary adjustments. However, diagnosing lactose intolerance is not straightforward, especially in primary care. AIM: To summarize available evidence on the diagnostic performance of gastrointestinal symptoms and self-reported milk (lactose) intolerance in primary care, and the relationship between lactose malabsorption and intolerance. DATA SOURCES: PubMed, EMBASE and reference screening. STUDY SELECTION: Studies were selected if the design was a primary diagnostic study; the patients were adults consulting because of non-acute abdominal symptoms; the diagnostic test included gastrointestinal symptoms and/or self-reported milk intolerance. A total of 26 primary diagnostic studies were included in the review. DATA EXTRACTION: Quality assessment and data extraction were performed by two reviewers independently. They adhered to the most recent guidelines for conducting a diagnostic review as described in the Cochrane Diagnostic Reviewers' Handbook. RESULTS: The diagnostic performance of diarrhea, abdominal pain, bloating, flatulence and self-reported milk intolerance was highly variable. A non-Caucasian ethnic origin was associated with the presence of lactose malabsorption. Both lactose malabsorbers and lactose absorbers reported symptoms during the lactose hydrogen breath test. CONCLUSION: Our review shows that high-quality studies on the diagnosis of lactose malabsorption and intolerance in primary care are urgently needed. An important prerequisite would be to clearly define the concept of lactose intolerance, as well as how it should be assessed.

Systematic review: accuracy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care.

BACKGROUND: Despite the trend towards making a positive diagnosis of irritable bowel syndrome (IBS), many health care providers approach IBS as a diagnosis of exclusion. AIM: To summarize available evidence on the diagnostic performance of symptom-based IBS criteria in excluding organic diseases, and of individual signs and symptoms in diagnosing IBS and to additionally assess the influence of sources of heterogeneity on diagnostic performance. METHODS: We searched PubMed and EMBASE and screened references. Studies were selected if the design was a primary diagnostic study; the patients were adults consulting because of non-acute abdominal symptoms; the diagnostic test included an externally validated set of IBS criteria, signs, or symptoms. Data extraction and quality assessment were performed by two reviewers independently. The review adhered to the most recent guidelines as described in the Cochrane Diagnostic Reviewers' Handbook. RESULTS: A total of 25 primary diagnostic studies were included in the review. The performance of symptom-based criteria in the exclusion of organic disease was highly variable. Patients fulfilling IBS criteria had, however, a lower risk of organic diseases than those not fulfilling the criteria. CONCLUSIONS: With none of the criteria showing sufficiently homogeneous and favourable results, organic disease cannot be accurately excluded by symptom-based IBS criteria alone. However, the low pre-test probability of organic disease especially among patients who meet symptom-based criteria in primary care argues against exhaustive diagnostic evaluation. We advise validation of the new Rome III criteria in primary care populations.

Lumbar supports for prevention and treatment of low back pain.

BACKGROUND: Lumbar supports are used in the treatment of low-back pain patients, to prevent the onset of low-back pain (primary prevention) or to prevent recurrences of a low-back pain episode (secondary prevention). OBJECTIVES: To assess the effects of lumbar supports for prevention and treatment of non-specific low-back pain. SEARCH STRATEGY: We updated the search in the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL to December 2006. We also screened references given in relevant reviews and identified trials, and contacted experts to identify additional RCTs. SELECTION CRITERIA: Randomized controlled trials that reported on any type of lumbar supports as preventive or therapeutic intervention for non-specific low-back pain. DATA COLLECTION AND ANALYSIS: One review author generated the electronic search. Two review authors independently identified trials that met the inclusion criteria. One review author extracted data on the study population, interventions, and final results. The methodological quality and the clinical relevance were independently assessed by two review authors. Because it was not possible to perform a quantitative analysis, we performed a qualitative analysis in which the strength of evidence on the effectiveness of lumbar supports was classified as strong, moderate, limited, conflicting, or no evidence. MAIN RESULTS: Seven preventive studies (14,437 people) and eight treatment studies (1361 people) were included in this updated review. Overall, the methodological quality of the studies was rather low. Only five of the fifteen studies met 50% or more of the internal validity items. There was moderate evidence that lumbar supports are not more effective than no intervention or training in preventing low-back pain, and conflicting evidence whether lumbar supports are effective supplements to other preventive interventions. It is still unclear if lumbar supports are more effective than no or other interventions for the treatment of low-back pain. AUTHORS' CONCLUSIONS: There is moderate evidence that lumbar supports are not more effective than no intervention or training in preventing low-back pain, and conflicting evidence whether they are effective supplements to other preventive interventions. It remains unclear whether lumbar supports are more effective than no or other interventions for treating low-back pain. There is still a need for high quality randomized trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realization of an adequate compliance. Special attention should be paid to different outcome measures, types of patients and types of lumbar support.

Individual patient education for low back pain.

BACKGROUND: While many different types of patient education are widely used, the effect of individual patient education for low-back pain (LBP) has not yet been systematically reviewed. OBJECTIVES: To determine whether individual patient education is effective in the treatment of non-specific low-back pain and which type is most effective. SEARCH STRATEGY: A computerized literature search of MEDLINE (1966 to July 2006), EMBASE (1988 to July 2006), CINAHL (1982 to July 2006), PsycINFO (1984 to July 2006), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2) was performed. References cited in the identified articles were screened. SELECTION CRITERIA: Studies were selected if the design was a randomised controlled trial; if patients experienced LBP; if the type of intervention concerned individual patient education, and if the publication was written in English, German, or Dutch. DATA COLLECTION AND ANALYSIS: The methodological quality was independently assessed by two review authors. Articles that met at least 50% of the quality criteria were considered high quality. Main outcome measures were pain intensity, global measure of improvement, back pain-specific functional status, return-to-work, and generic functional status. Analysis comprised a qualitative analysis. Evidence was classified as strong, moderate, limited, conflicting or no evidence. MAIN RESULTS: Of the 24 studies included in this review, 14 (58%) were of high quality. Individual patient education was compared with no intervention in 12 studies; with non-educational interventions in 11 studies; and with other individual educational interventions in eight studies. Results showed that for patients with subacute LBP, there is strong evidence that an individual 2.5 hour oral educational session is more effective on short-term and long-term return-to-work than no intervention. Educational interventions that were less intensive were not more effective than no intervention. Furthermore, there is strong evidence that individual education for patients with (sub)acute LBP is as effective as non-educational interventions on long-term pain and global improvement and that for chronic patients, individual education is less effective for back pain-specific function when compared to more intensive interventions. Comparison of different types of individual education did not show significant differences. AUTHORS' CONCLUSIONS: For patients with acute or subacute LBP, intensive patient education seems to be effective. For patients with chronic LBP, the effectiveness of individual education is still unclear.

WITHDRAWN: Lumbar supports for prevention and treatment of low-back pain.

BACKGROUND: Lumbar supports are used in the treatment of low back pain patients to make the impairment and disability vanish or decrease. Lumbar supports are also used to prevent the onset of low back pain (primary prevention) or to prevent recurrences of a low back pain episode (secondary prevention). OBJECTIVES: The objective of this systematic review was to assess the effects of lumbar supports for prevention and treatment of non-specific low back pain. SEARCH STRATEGY: We searched the Medline, Cinahl and Current Contents databases and the Cochrane Controlled Trials Register up to September 1999, and the Embase database up to September 1998. We also screened references given in relevant reviews and identified controlled trials, and used Science Citation Index to identify additional controlled trials. SELECTION CRITERIA: Controlled clinical trials that reported on any type of lumbar supports as preventive or therapeutic intervention for non-specific low back pain were included. DATA COLLECTION AND ANALYSIS: One author extracted data from the trials considering characteristics of the study population, characteristics of the interventions and the final results for each outcome measure. The author compared these findings to data regarding the same characteristics of the same studies published already in other reviews. The methodological quality was independently assessed by two authors. Because it was not possible to perform a quantitative analysis, a qualitative meta-analysis was performed in which the strength of evidence on the effectiveness of lumbar supports was classified as being strong, moderate, limited or conflicting, and no evidence. MAIN RESULTS: Five randomized and two nonrandomized controlled preventive trials and six randomized therapeutic trials were included in our review. Overall the methodological quality of the studies included in our review was rather low. Only four of the thirteen studies scored positive on 50% or more of the the internal validity items. There was moderate evidence that for primary prevention lumbar supports are not more effective than other types of treatment or no intervention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, while it is still unclear if lumbar supports are more effective than other interventions for treatment of low back pain. AUTHORS' CONCLUSIONS: There is still a need for high quality randomised trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realisation of an adequate compliance.

Feasibility of lumbar supports for home care workers with low back pain.

The aims of this study were to assess the compliance of home care workers with low back pain (LBP) in using a lumbar support, to establish the benefit experienced from the support, and to determine the predictive factors for that compliance and benefit. Only home care workers who had LBP at the start of the study or who had experienced at least two episodes of LBP in the 12 months prior to the study could apply for participation. The study consisted of two phases. In phase I (the first week of the study), workers used the lumbar support each working day. In phase II (the following 6 months), subjects were instructed to use the lumbar support only on those working days when they experienced LBP. Weekly questionnaires were used to measure compliance; monthly questionnaires were used to measure the benefit experienced. Fifty-nine workers participated in the study. Overall, they scored their perceived benefit from the lumbar support as 7 on a scale of 0-10, and 61-81% of the workers were compliant. Multiple linear regression analysis showed that the best predictor for experienced benefit is the degree of confidence in expected pain reduction due to the lumbar support, measured after phase I (R(2) = 0.70). Multiple logistic analysis showed that the best predictor for compliance is the extent to which subjects consider they can influence their own health status (R(2) = 0.49). Because both the benefit experienced and the compliance rate were substantial, the use of lumbar supports by home care workers with LBP seems feasible. However, we cannot recommend extensive use of lumbar supports in home care workers with LBP based solely on the results of the present study. First, there is a clear need for a randomized clinical trial on this topic.

Lumbar supports for prevention and treatment of low back pain: a systematic review within the framework of the Cochrane Back Review Group.

STUDY DESIGN: A systematic review of randomized and nonrandomized controlled trials. SUMMARY OF BACKGROUND DATA: Lumbar supports are used in the treatment of low back pain, but also to prevent the onset (primary prevention) or recurrences of a low back pain episode (secondary prevention). OBJECTIVES: To assess the effects of lumbar sup-ports for prevention and treatment of nonspecific low back pain. METHODS: The Medline, Cinahl, and Current Contents databases; the Cochrane Controlled Trials Register up to September 1999; and the Embase database up to September 1998 were all searched. References of identified trials and systematic reviews were reviewed and the Science Citation Index used to identify additional trials. Methodologic quality assessment and data extraction were performed by two reviewers independently. A quantitative analysis was performed in which the strength of evidence was classified as strong, moderate, limited or conflicting, and no evidence. RESULTS: Five randomized and two nonrandomized preventive trials and six randomized therapeutic trials were included in the review. Only 4 of the 13 studies were of high quality. There was moderate evidence that lumbar supports are not effective for primary prevention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, whereas it is still unclear whether lumbar supports are more effective than other interventions for treatment of low back pain. CONCLUSIONS: There continues to be a need for high quality randomized trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realization of adequate compliance.

Lumbar supports for prevention and treatment of low back pain.

BACKGROUND: Lumbar supports are used in the treatment of low back pain patients to make the impairment and disability vanish or decrease. Lumbar supports are also used to prevent the onset of low back pain (primary prevention) or to prevent recurrences of a low back pain episode (secondary prevention). OBJECTIVES: The objective of this systematic review was to assess the effects of lumbar supports for prevention and treatment of non-specific low back pain. SEARCH STRATEGY: We searched the Medline, Cinahl and Current Contents databases and the Cochrane Controlled Trials Register up to September 1999, and the Embase database up to September 1998. We also screened references given in relevant reviews and identified controlled trials, and used Science Citation Index to identify additional controlled trials. SELECTION CRITERIA: Controlled clinical trials that reported on any type of lumbar supports as preventive or therapeutic intervention for non-specific low back pain were included. DATA COLLECTION AND ANALYSIS: One reviewer extracted data from the trials considering characteristics of the study population, characteristics of the interventions and the final results for each outcome measure. The reviewer compared these findings to data regarding the same characteristics of the same studies published already in other reviews. The methodological quality was independently assessed by two reviewers. Because it was not possible to perform a quantitative analysis, a qualitative meta-analysis was performed in which the strength of evidence on the effectiveness of lumbar supports was classified as being strong, moderate, limited or conflicting, and no evidence. MAIN RESULTS: Five randomized and two nonrandomized controlled preventive trials and six randomized therapeutic trials were included in our review. Overall the methodological quality of the studies included in our review was rather low. Only four of the thirteen studies scored positive on 50% or more of the the internal validity items. There was moderate evidence that for primary prevention lumbar supports are not more effective than other types of treatment or no intervention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, while it is still unclear if lumbar supports are more effective than other interventions for treatment of low back pain. REVIEWER'S CONCLUSIONS: There is still a need for high quality randomised trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realisation of an adequate compliance.