A comparison of methods for analysing multiple outcome measures in randomised controlled trials using a simulation study

Multiple primary outcomes are sometimes collected and analysed in randomised controlled trials (RCTs), and are used in favour of a single outcome. By collecting multiple primary outcomes, it is possible to fully evaluate the effect that an intervention has for a given disease process. A simple approach to analysing multiple outcomes is to consider each outcome separately, however, this approach does not account for any pairwise correlations between the outcomes. Any cases with missing values must be ignored, unless an additional imputation step is performed. Alternatively, multivariate methods that explicitly model the pairwise correlations between the outcomes may be more efficient when some of the outcomes have missing values. In this paper, we present an overview of relevant methods that can be used to analyse multiple outcome measures in RCTs, including methods based on multivariate multilevel (MM) models. We perform simulation studies to evaluate the bias in the estimates of the intervention effects and the power of detecting true intervention effects observed when using selected methods. Different simulation scenarios were constructed by varying the number of outcomes, the type of outcomes, the degree of correlations between the outcomes and the proportions and mechanisms of missing data. We compare multivariate methods to univariate methods with and without multiple imputation. When there are strong correlations between the outcome measures (ρ > .4), our simulation studies suggest that there are small power gains when using the MM model when compared to analysing the outcome measures separately. In contrast, when there are weak correlations (ρ < .4), the power is reduced when using univariate methods with multiple imputation when compared to analysing the outcome measures separately

Description of complex interventions: analysis of changes in reporting in randomised trials since 2002

BACKGROUND: Inadequate description of non-pharmacological complex interventions in trial publications means that they cannot be replicated or assessed for generalisability. There are published guidelines on how to describe an intervention, such as those from the CONSORT Group. However, there have been few evaluations of whether intervention reporting is improving. METHODS: We aimed to assess whether descriptions of multicomponent, non-pharmacological interventions evaluated in randomised trials are improving. To do so, we chose trials of educational and psychotherapeutic interventions to promote adherence to therapy, and compared those published between 2002 and 2007 (Time-1) with those between 2010 and 2015 (Time-2). These time periods were chosen to concord with the publication in 2008 of the CONSORT extension statement of reporting guidelines for non-pharmacological treatment which included items on intervention description. We assessed 19 items, based on the CONSORT Statement and the more recent Template for Intervention Description and Replication Checklist (TIDieR). Two reviewers independently extracted data. We created a quality score of the eight items we considered key information for replication and assessment of generalisability (setting, provider, recipient, comparator, intervention intensity, how it was conducted, existence of a manual or protocol, and detail of whether there was an assessment of fidelity). Score per item was '1' if reported adequately and '0' if not. RESULTS: Of the eligible trials, 42 were published in Time-1 and 134 published in Time-2. The trials included were published in 112 peer-reviewed journals, 52 of these journals currently require authors to follow the CONSORT Statements, while only one recommended adherence to the TIDieR. Most items of CONSORT and TIDieR were reported by more than half of the trials at both time points. Few trials reported fidelity. A large proportion of the trials did not report the existence of a manual or protocol, or what the comparator group received. We found no statistically significant improvement in the eight-item quality score (Time-1: mean 5.71 (standard deviation (SD) 1.09), Time-2: 5.87 (SD 1.28), p = 0.49). CONCLUSIONS: We found no overall evidence that reporting the specifics of multicomponent, non-pharmacological interventions is improving. Details to replicate interventions remain lacking, impairing best implementation or meaningful further research. Editorial endorsement of reporting checklists needs to be more extensive

How accurate is the ‘Surprise Question’ at identifying patients at the end of life? A systematic review and meta-analysis

Background Clinicians are inaccurate at predicting survival. The ‘Surprise Question’ (SQ) is a screening tool that aims to identify people nearing the end of life. Potentially, its routine use could help identify patients who might benefit from palliative care services. The objective was to assess the accuracy of the SQ by time scale, clinician, and speciality. Methods Searches were completed on Medline, Embase, CINAHL, AMED, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Open Grey literature (all from inception to November 2016). Studies were included if they reported the SQ and were written in English. Quality was assessed using the Newcastle–Ottawa Scale. Results A total of 26 papers were included in the review, of which 22 reported a complete data set. There were 25,718 predictions of survival made in response to the SQ. The c-statistic of the SQ ranged from 0.512 to 0.822. In the meta-analysis, the pooled accuracy level was 74.8% (95% CI 68.6–80.5). There was a negligible difference in timescale of the SQ. Doctors appeared to be more accurate than nurses at recognising people in the last year of life (c-statistic = 0.735 vs. 0.688), and the SQ seemed more accurate in an oncology setting 76.1% (95% CI 69.7–86.3). Conclusions There was a wide degree of accuracy, from poor to reasonable, reported across studies using the SQ. Further work investigating how the SQ could be used alongside other prognostic tools to increase the identification of people who would benefit from palliative care is warranted

A Cross-sectional Questionnaire Study to Gather the Teaching Preferences and Expectations of UK Undergraduate Medical Students For Culinary Medicine Learning

Aim: To determine undergraduate medical students’ teaching preferences and expectations for Culinary Medicine (CM) learning with a view to informing development of a CM course at a UK medical school. Setting: A single, urban UK medical school. Participants :180 undergraduate medical students. Study design: A cross-sectional questionnaire study collecting quantitative and qualitative (free-text) data. Methods and outcome measures: An online questionnaire consisting of 16 questions of various styles (Likert-type, multiple choice and free-text). Quantitative analysis of multiple choice and Likert-type scale questions was conducted. Qualitative thematic analysis was used to analyse the free-text responses and identify themes. Results: Three core themes related to students’ understanding of CM were identified: (1) ‘CM Learning’: students’ perceived relevance of CM knowledge, perceived relevance of CM to healthcare and their expectations for teaching; (2) ‘The Relationship between Food and Health’: links between diet, social factors and health; and (3) ‘Evidence-based Medicine’: students’ perceptions about scientific principles underlying CM. Quantitative analysis revealed that, although 83% of students felt that learning CM is important for their future clinical practice, 56% felt unable to take a dietary history. 73% of students were dissatisfied with the quality, and 78% were dissatisfied with the quantity, of existing medical school teaching understood to be relevant to CM. Topics that students would like to be taught on a CM course included weight management and portion control. Students felt that problem-based style learning would be the most appropriate method for delivering CM teaching. Conclusions: This study revealed that medical students felt their dietary counsulting skills could be improved with further clinically relevant teaching in the undergraduate medical curriculum. Students’ preferences for CM learning have been taken into consideration in the development of a CM course for fifth-year undergraduate students at a UK medical school, which is delivered during their General Practice placement

Interventions for sexual dysfunction following treatments for cancer in women

BACKGROUND: The proportion of people living with and surviving cancer is growing. This has led to increased awareness of the importance of quality of life, including sexual function, in those affected by cancer. Sexual dysfunction is a potential long-term complication of many cancer treatments. This includes treatments that have a direct impact on the pelvic area and genitals, and also treatments that have a more generalised (systemic) impact on sexual function.This is an update of the original Cochrane review published in Issue 4, 2007, on interventions for treating sexual dysfunction following treatments for cancer for men and women. Since publication in 2007, there has been an increase in the number of trials for both men and women and this current review critiques only those for women. A review in press will present those for men. OBJECTIVES: To evaluate the effectiveness of interventions for treating sexual dysfunction in women following treatments for cancer. To assess adverse events associated with interventions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), MEDLINE, EMBASE, PsycINFO, AMED, CINAHL, Dissertation Abstracts and the NHS Research Register. The searches were originally run in January 2007 and we updated these to September 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed the effectiveness of a treatment for sexual dysfunction. The trial participants were women who had developed sexual dysfunction as a consequence of a cancer treatment. We sought evaluations of interventions that were pharmaceutical, mechanical, psychotherapeutic, complementary or that involved physical exercise. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed trial quality. We considered meta-analysis for trials with comparable key characteristics. MAIN RESULTS: Since the original version of this review we have identified 11 new studies in women. The one study identified in the earlier version of this review was excluded in this update as it did not meet our narrower inclusion criteria to include only interventions for the treatment, not prevention, of sexual dysfunction.In total 1509 female participants were randomised across 11 trials. All trials explored interventions following treatment either for gynaecological or breast cancer. Eight trials evaluated a psychotherapeutic or psycho-educational intervention. Two trials evaluated a pharmaceutical intervention and one pelvic floor exercises. All involved heterosexual women. Eight studies were at a high risk of bias as they involved a sample of fewer than 50 participants per trial arm. The trials varied not only in intervention content but in outcome measurements, thereby restricting combined analysis. In the trials evaluating a psychotherapeutic intervention the effect on sexual dysfunction was mixed; in three trials benefit was found for some measures of sexual function and in five trials no benefit was found. Evidence from the other three trials, two on different pharmaceutical applications and one on exercise, differed and was limited by small sample sizes. Only the trial of a pH-balanced vaginal gel found significant improvements in sexual function. The trials of pharmaceutical interventions measured harm: neither reported any. Only one psychological intervention trial reported that no harm occurred because of the intervention; the other trials of psychological support did not measure harm. AUTHORS' CONCLUSIONS: Since the last version of this review, the new studies do not provide clear information on the impact of interventions for sexual dysfunction following treatments for cancer in women. The sexual dysfunction interventions in this review are not representative of the range that is available for women, or of the wider range of cancers in which treatments are known to increase the risk of sexual problems. Further evaluations are needed

Milestones: a mixed methods study of an educational intervention to improve care of the dying

Background: Approximately 460 000 people die annually in England. Three-quarters of these deaths are expected. Health Education England is prioritising upskilling of clinical staff in response to reports of poor care quality in the last days of life in acute hospitals, where almost half of all deaths occur. This study explores the impact of an end-of-life care (EoLC) educational intervention, Milestones, in acute hospital trusts in Greater London. Methods: This is a mixed methods study. Learners completed a questionnaire pre- (n=452), immediately post- (n=488) and 3 to 8 months post- (n=37) intervention. The questionnaire measured learner confidence in EoLC covering the National Health Service adopted ‘Priorities for the Care of the Dying Person’. Paired t-tests were used to determine statistically significant difference in learner confidence pre- and post-intervention. A convenience sample of learners (n=7) and educators (n=5) were recruited to qualitative semi-structured interviews that sought to understand if, how and why Milestones worked. Data were analysed using a thematic approach. Results: A statistically significant increase in learner confidence across all five priorities of care’ was sustained up to 8 months (p<0.001). Interviewees wanted to discuss wider challenges in EoLC related to the organisations and cultural contexts in which they worked. Concerns included balancing hope when decision-making, learning as a multidisciplinary team and emotional impact. Conclusion: The findings suggest that Milestones is a flexible, beneficial resource for teaching EoLC that facilitates enhanced learner engagement. Understanding generated about wider concerns can inform future educational material development, organisational process and research study design

Are multiple primary outcomes analysed appropriately in randomised controlled trials? A review

To review how multiple primary outcomes are currently considered in the analysis of randomised controlled trials. We briefly describe the methods available to safeguard the inferences and to raise awareness of the potential problems caused by multiple outcomes

Mu‐opioid antagonists for opioid‐induced bowel dysfunction in people with cancer and people receiving palliative care

BACKGROUND: Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life. This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care. OBJECTIVES: To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE. MAIN RESULTS: We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm. In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea. The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events. In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence. Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42). AUTHOR'S CONCLUSIONS: In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children