Determining sample size for progression criteria for pragmatic pilot RCTs: the hypothesis test strikes back!

BACKGROUND: The current CONSORT guidelines for reporting pilot trials do not recommend hypothesis testing of clinical outcomes on the basis that a pilot trial is under-powered to detect such differences and this is the aim of the main trial. It states that primary evaluation should focus on descriptive analysis of feasibility/process outcomes (e.g. recruitment, adherence, treatment fidelity). Whilst the argument for not testing clinical outcomes is justifiable, the same does not necessarily apply to feasibility/process outcomes, where differences may be large and detectable with small samples. Moreover, there remains much ambiguity around sample size for pilot trials. METHODS: Many pilot trials adopt a 'traffic light' system for evaluating progression to the main trial determined by a set of criteria set up a priori. We construct a hypothesis testing approach for binary feasibility outcomes focused around this system that tests against being in the RED zone (unacceptable outcome) based on an expectation of being in the GREEN zone (acceptable outcome) and choose the sample size to give high power to reject being in the RED zone if the GREEN zone holds true. Pilot point estimates falling in the RED zone will be statistically non-significant and in the GREEN zone will be significant; the AMBER zone designates potentially acceptable outcome and statistical tests may be significant or non-significant. RESULTS: For example, in relation to treatment fidelity, if we assume the upper boundary of the RED zone is 50% and the lower boundary of the GREEN zone is 75% (designating unacceptable and acceptable treatment fidelity, respectively), the sample size required for analysis given 90% power and one-sided 5% alpha would be around n = 34 (intervention group alone). Observed treatment fidelity in the range of 0-17 participants (0-50%) will fall into the RED zone and be statistically non-significant, 18-25 (51-74%) fall into AMBER and may or may not be significant and 26-34 (75-100%) fall into GREEN and will be significant indicating acceptable fidelity. DISCUSSION: In general, several key process outcomes are assessed for progression to a main trial; a composite approach would require appraising the rules of progression across all these outcomes. This methodology provides a formal framework for hypothesis testing and sample size indication around process outcome evaluation for pilot RCTs.

Characteristics and perspectives of night-eating behaviour in a severely obese population.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Night-eating syndrome (NES) can be a feature of severe obesity. NES is a dysfunction of circadian rhythm and is associated with impaired sleep. WHAT THIS STUDY ADDS: Night eaters with severe obesity are more likely to be low in mood and unemployed compared with non-night eaters. Night eaters with severe obesity describe compulsive and uncontrolled eating. Research interest in night-eating syndrome (NES) has grown in recent years in line with increased rates of obesity. This study used a mixed-methods approach to investigate its characteristics in severe obesity. Eighty-one individuals (mean [standard deviation] age 44.6 [11.6] years, [body mass index] 50.0 [10.7] kg m(-2) ; 43% men) from a hospital-based UK obesity clinic were interviewed for NES based on 2003 criteria. Full and partial NES were combined into one night-eating behaviour (NEB) group (n = 31). Demographic and clinical characteristics were compared with those of non-NEB individuals (n = 50). NEB characteristics were also identified through exploratory thematic analysis of interview data. NEB individuals had lower mood (P = 0.01) and were less likely to be employed (P = 0.03). Differences in mean age and reported sleep duration were not significant. Thematic analysis of patient perceptions of NEB highlighted the potential heterogeneity of NEB development: NEB developed in childhood, adolescence and adulthood. Individuals reported long-standing and current sleep difficulties, negative affect and conflictful relationships. Night eating was solitary, compulsive and uncontrolled, and daytime eating patterns were chaotic. Accounts of awareness of night eating were conflicting. Severely obese night eaters are characterized by low mood and lack of employment. Further studies are required to explore behavioural and cognitive influences on night eating in severe obesity.

Treatment of urinary incontinence after stroke in adults.

BACKGROUND: Urinary incontinence can affect 40-60% of people admitted to hospital after a stroke, with 25% still having problems on hospital discharge and 15% remaining incontinent at one year. OBJECTIVES: To determine the optimal methods for treatment of urinary incontinence after stroke in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence and Stroke Groups specialised registers (searched 15 March 2007 and 5 March 2007 respectively), CINAHL (January 1982 to January 2007), national and international trial databases for unpublished data, and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials evaluating the effects of interventions designed to promote continence in people after stroke. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were undertaken by two reviewers working independently. Disagreements were resolved by a third reviewer. MAIN RESULTS: Twelve trials with a total of 724 participants were included in the review. Participants were from a mixture of settings, age groups and phases of stroke recovery. BEHAVIOURAL INTERVENTIONS: Three trials assessed behavioural interventions, such as timed voiding and pelvic floor muscle training. All had small sample sizes and confidence intervals were wide. SPECIALISED PROFESSIONAL INPUT INTERVENTIONS: Two trials assessed variants of professional input interventions. Results tended to favour the intervention groups: in a small trial in early rehabilitation, fewer people had incontinence at discharge from hospital after structured assessment and management than in a control group (1/21 vs. 10/13; RR 0.06, 95% CI 0.01 to 0.43); in the second trial, assessment and management by Continence Nurse Advisors was associated with fewer participants having urinary symptoms (48/89 vs. 38/54; RR 0.77, 95% CI 0.59 to 0.99) and statistically significantly more being satisfied with care. COMPLEMENTARY THERAPY INTERVENTIONS: Three small trials all reported fewer participants with incontinence after acupuncture therapy (overall RR 0.44; 95% 0.23 to 0.86), but there were particular concerns about study quality. PHARMACOTHERAPY AND HORMONAL INTERVENTIONS: There were three small trials that included groups allocated meclofenoxate, oxybutinin or oestrogen. There were no apparent differences other than in the trial of meclofenoxate where fewer participants had urinary symptoms in the active group than in the control group (9/40 vs. 27/40; RR 0.33, 95% CI 0.18 to 0.62). AUTHORS' CONCLUSIONS: Data from the available trials are insufficient to guide continence care of adults after stroke. However, there was suggestive evidence that professional input through structured assessment and management of care and specialist continence nursing may reduce urinary incontinence and related symptoms after stroke. Better quality evidence is required of the range of interventions that have been suggested for continence care after stroke.

Repetitive task training for improving functional ability after stroke.

BACKGROUND: The active practice of task-specific motor activities is a component of current approaches to stroke rehabilitation. OBJECTIVES: To determine if repetitive task training after stroke improves global, upper or lower limb function, and if treatment effects are dependent on the amount, type or timing of practice. SEARCH STRATEGY: We searched the Cochrane Stroke Trials Register (October 2006), The Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro, and OT Seeker (to September 2006), and OT search (to March 2006). We also searched for unpublished/non-English language trials, conference proceedings, combed reference lists, requested information on bulletin boards, and contacted trial authors. SELECTION CRITERIA: Randomised/quasi-randomised trials in adults after stroke, where the intervention was an active motor sequence performed repetitively within a single training session, aimed towards a clear functional goal, and where the amount of practice could be quantified. DATA COLLECTION AND ANALYSIS: Two authors independently screened abstracts, extracted data and appraised trials. Assessment of methodological quality was undertaken for allocation concealment, blinding, loss to follow up and equivalence of treatment. We contacted trial authors for additional information. MAIN RESULTS: Fourteen trials with 17 intervention-control pairs and 659 participants were included. PRIMARY OUTCOMES: results were statistically significant for walking distance (mean difference (MD) 54.6, 95% CI 17.5 to 91.7); walking speed (standardised mean difference (SMD) 0.29, 95% CI 0.04 to 0.53); sit-to-stand (standard effect estimate 0.35, 95% CI 0.13 to 0.56); and of borderline statistical significance for functional ambulation (SMD 0.25, 95% CI 0.00 to 0.51), and global motor function (SMD 0.32, 95% CI -0.01 to 0.66). There were no statistically significant differences for hand/arm function, or sitting balance/reach. SECONDARY OUTCOMES: results were statistically significant for activities of daily living (SMD 0.29, 95% CI 0.07 to 0.51), but not for quality of life or impairment measures. There was no evidence of adverse effects. Follow-up measures were not significant for any outcome at six or twelve months. Treatment effects were not modified by intervention amount or timing, but were modified by intervention type for lower limbs. AUTHORS' CONCLUSIONS: Repetitive task training resulted in modest improvement in lower limb function, but not upper limb function. Training may be sufficient to impact on daily living function. However, there is no evidence that improvements are sustained once training has ended. The review potentially investigates task specificity rather more than repetition. Further research should focus on the type and amount of training, and how to maintain functional gain.

Disease and psychological status in ankylosing spondylitis.

OBJECTIVES: Psychological factors may be important in the assessment and management of ankylosing spondylitis (AS). Our primary objective was to describe associations between disease and psychological status in AS, using AS-specific assessment tools and questionnaires. Our secondary objectives were to identify patient subgroups based on such associations and to determine the stability of the measures over time. METHODS: A total of 110 patients were assessed at 6-monthly intervals up to four times using tools to measure disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI)], psychological [Hospital Anxiety and Depression Questionnaire (HADS), Health Locus of Control-Form C Questionnaire (HLC-C)] and generic health [Short form (SF)-36] status. RESULTS: Eighty-nine participants completed all four assessments. Throughout the study, BASDAI, BASFI and BASMI scores correlated significantly with anxiety, depression, internality and health status, but not with levels of belief in chance or powerful others. Clinically anxious or depressed subgroups had significantly worse BASDAI and BASFI, but not BASMI, scores. BASMI scores were the least closely linked to psychological status. Mean scores for disease, psychological and health status were clinically stable over the 18 months period. CONCLUSIONS: Disease status scores in AS correlated significantly with anxiety, depression, internality and health status. Interpretation of AS disease scores should take an account of psychological status and the choice of measures used. These findings have important potential applications in AS management and monitoring, including the identification of patients for biological therapies.

Ethnic aspects of acute primary angle closure in a UK mulicultural conurbation.

AIM: To investigate the incidence and ethnic distribution of patients with symptomatic acute primary angle closure (APAC) who presented to a UK hospital serving a multicultural conurbation by a population-wide case series investigation. METHODS: Case series chart review of patients aged 30 years and above, who required laser peripheral iridotomy (LPI) for a primary acute angle closure event over a 7-year period. Demographic data for cases were compared to the local resident census data. RESULTS: A total of 46 local residents aged > or =30 years required LPI for APAC. In all, 96% of patients were Caucasian compared to the local resident population of 89% Caucasian. The overall annual APAC rate for Bolton was 4.14 cases per 100 000 population (95% CI 3.03-5.52). The standardised incidence ratio for the South Asian population was 0.78 (95% CI 0.02-4.34) and 26.6 (95% CI 0.67-148.40) for the Chinese population. CONCLUSIONS: APAC incidence in South Asians was similar to that among Caucasians. The incidence of APAC patients treated in this UK department is consistent with international experience. Individuals of Chinese ethnicity were at an enhanced risk of APAC. However, these results should be interpreted with caution, as patient numbers are small.

Levels of the DNA adduct, N7-methyldeoxyguanosine, are associated with increased risk of failure of treatment of cervical intraepithelial neoplasia.

OBJECTIVE: To determine whether exposure to methylating agents was a risk factor for treatment failure in women undergoing colposcopic examination. METHODS: Nine hundred fifty-eight women attending for colposcopic examination after abnormal cervical smear test results were recruited into the study cohort. Information on demographic factors, smoking and other risk factors was obtained and a pre-treatment biopsy was taken and stored at -70 degrees C. After follow-up, cases who had treatment failure of cervical intraepithelial neoplasia (CIN) within 2 years following treatment were identified (n = 77) and matched to women with no treatment failure of CIN in this time period (controls, n = 154). DNA was extracted from the pre-treatment biopsies and levels of N7-methyl-deoxyguanosine (N7-MedG), a marker of exposure to methylating agents, were quantified as the ring-opened form of the base damage by a validated immunoslotblot assay. RESULTS: Sufficient DNA for N7-MedG analysis was extracted from 61 subjects corresponding to 20 matched case control pairs. N7-MedG was detected in cervical DNA with levels ranging from non-detected (<0.1 micromol/mol dG) to 4.83 micromol/mol dG. N7-MedG levels were significantly higher in cases (geometric mean 0.99 micromol/mol dG) than controls (0.33 micromol/mol dG; P = 0.01). There were no associations between N7-MedG levels and HPV or smoking status. Log N7-MedG content, after adjustment for HPV status at time of treatment, was found to be significantly associated with increased risk of treatment failure (OR 5.74, 95% CI 1.05-31.23). CONCLUSIONS: The association between pre-treatment levels of DNA damage induced by methylating agents and subsequent treatment failure implicates methylating agent exposure as a causative factor in treatment failure.

Recurrence of chocolate cysts after laparoscopic ablation.

STUDY OBJECTIVE: To estimate the recurrence rate of chocolate cysts 3 to 12 months after ablative laparoscopic surgery. The secondary outcome measure was the need for a repeat surgical procedure. DESIGN: Prospective cohort study (Canadian Task Force classification II-2). SETTING: Tertiary referral center for laparoscopic treatment of endometriosis. PATIENTS: Seventy-three consecutive women with chocolate cysts larger than 2 cm. INTERVENTION: Laparoscopy at which cyst capsules were vaporized or coagulated with the potassium-titanyl-phosphate (KTP) laser or Bicap bipolar diathermy. MEASUREMENTS AND MAIN RESULTS: There were 96 cysts (23 bilateral) in 73 women (1 patient underwent a two-stage procedure). Their mean diameter was 4.79 cm (range 2-25 cm). The median r-AFS score was 56 (range 22-128), and 55 patients (75.3%) had stage 4 disease. The KTP laser was used in 50 women (68.5%) and bipolar diathermy in 23 (31.5%). At 12 months, 5 patients (6.9%) were lost to follow-up, and 12 had a recurrent cyst. Therefore, the cyst recurrence rate/patient was 16.4% (12/73) and the rate/cyst was 12.5% (12/96). Women who had recurrences were significantly more likely to have bilateral cysts, 7/12 (58.3%), than those with single cysts, 16/61 (26.2%, p =0.032). Bicap bipolar diathermy was associated with a recurrence rate of 20.8% (5/24). The rate in women who had KTP laser ablation was 14.3% (7/49, NS). Eighteen patients had repeat operations (including on recurrent cysts). Therefore the reoperation rate was 24.6% (18/73). No major surgical complications occurred. One woman had a postoperative wound infection after a second procedure to remove an ovary with a recurrent cyst. CONCLUSION: Laparoscopic cyst fenestration followed by capsule ablation is safe and effective treatment for preventing recurrence of chocolate cysts.

Laser laparoscopy for endometriosis and endometriotic cysts.

BACKGROUND: Endometriosis is a common and debilitating condition involving women during their reproductive years. It is characterized by the occurrence of endometrial glands and stroma outside the uterine cavity. Presenting symptoms include chronic nonmenstrual pelvic pain, dysmenorrhea, dyspareunia, and subfertility. The condition is diagnosed at laparoscopy, and operative laparoscopic surgery for endometriosis is also possible. METHODS: This article critically evaluates the evidence for the laparoscopic management of endometriosis and endometriotic cysts. It focuses on laser laparoscopy and reviews the contribution made by the Minimal Access Therapy Training Unit, Guildford, UK, to the treatment of this condition. RESULTS: Few randomized controlled trials have been undertaken to evaluate the surgical management of endometriosis. The studies that have been done show that laparoscopic surgery, including laser laparoscopy, is effective in the management of painful symptoms and subfertility and preventing cyst recurrence. Several of the landmark studies in this area have been carried out in Guildford. CONCLUSION: Laparoscopic surgery is the treatment of choice for patients with endometriosis and endometriotic cysts.

The ovarian endometrioma: why is it so poorly managed? Indicators from an anonymous survey.

As a tertiary referral centre for women with severe endometriosis we see a large number of patients who have endometriotic cysts, and many of these patients have been operated on by gynaecologists elsewhere in the UK. We have been surprised by the variety of approaches to their management. In order to establish the current clinical practices of endometrioma management amongst gynaecologists in the UK, we have carried out an anonymous survey. There appears to be an equal preference for open versus endoscopic surgery, even though there is considerable evidence suggesting that endoscopic surgery is superior. However, the management of endometriomas varies significantly between the two groups. In this article, we have presented the results of our survey and used them as the basis for a debate on the management of endometriomas.

Pregnancy rates following ablative laparoscopic surgery for endometriomas.

BACKGROUND: In this prospective, cohort study we present the cumulative pregnancy rate following ablative laparoscopic surgery in patients with endometriomas. METHODS: The cyst was mobilized, fenestrated, and the capsule treated with the potassium-titanyl-phosphate (KTP) laser or bipolar diathermy. Pre- and post-operative transvaginal ultrasound scans were performed, and a detailed fertility history recorded. RESULTS: There were 39 women (38 intention to treat as a single procedure) who had been trying to conceive for >12 months. The mean age of the patients was 33.8 years (range 20-43), and there were 42 cysts (three bilateral) with a mean diameter of 4.8 cm (range 2-25). The mean revised American Fertility Society score was 64.9 (range 22-124), and 29 (74.4%) patients had stage IV disease. Seven patients (18%) had previously had a live birth, and 17 (43.6%) had undergone assisted conception in the past. The cumulative pregnancy rate was 15/38 (39.5%). The pregnancy rate in patients with stage IV disease was 11/28 (39.3%). There were no major complications. CONCLUSIONS: Our results indicate that laparoscopic cyst fenestration and capsule ablation is a safe and effective treatment for improving fertility.

Long-term follow-up of a controlled trial of laser laparoscopy for pelvic pain.

BACKGROUND AND OBJECTIVES: The purpose of this study was to assess the long-term efficacy of laparoscopic laser surgery in the treatment of painful pelvic endometriosis. METHODS: We conducted a long-term follow-up of 56 patients who had participated in a randomized, double-blind controlled study at a tertiary referral center for the laparoscopic treatment of endometriosis. The patients had pelvic pain, minimal-to-moderate endometriosis, and underwent laser laparoscopy. We asked patients whether they had now achieved satisfactory symptom relief or whether they had received any further medical intervention for their endometriosis. The main outcome measure was continued symptom relief after treatment and subsequent medical history. RESULTS: Of the original 56 patients, we were able to contact 38 (67.9%). The mean (range) time since operation was 73 months. Painful symptoms had recurred in 28/38 (73.7%) patients at some point since their operation. The median (range) time for recurrence was 19.7 (5-60) months. At the time of follow-up, satisfactory symptom relief was reported in 21/38 (55.3%) patients. The remaining 17/38 (44.7%) patients continued to experience painful symptoms, and eight eventually had a hysterectomy. CONCLUSIONS: This study suggests that operative laparoscopy can have long-term benefits for the majority of women with pelvic pain due to endometriosis, but because of the small numbers, this study lacks the power to demonstrate this conclusively.

A study of breast cancers detected in the incident round of the UK NHS Breast Screening Programme: the importance of early detection and treatment of ductal carcinoma in situ.

One hundred and seventy eight cancers detected on incident round screening in the UK National Health Service Breast Screening Programme were reviewed. Critical review of the immediately preceding screening films (from 3 years previously) found abnormalities at the site of the subsequently detected cancer in 93 cases (52%). Forty-eight of these (27% of the total) had microcalcification as the sole abnormality. All of these 48 women had invasive ductal carcinoma and/or ductal carcinoma in situ (DCIS) (including four cases in which DCIS was associated with another type of primary invasive breast cancer). The finding of microcalcification on the previous mammograms at the site of a subsequently detected cancer was a strong predictor for the presence of DCIS (with or without associated invasive disease) (P<0.0001). Of the women with invasive ductal carcinoma, those with microcalcification on previous films were significantly more likely to have intermediate or high grade (grade 2 or 3) tumours than those women without microcalcification on previous films (P=0.0015). Previous films were also read blind by two independent experienced breast radiologists. Cancers were correctly identified by one or both readers in 39 cases. However, 35 of the remaining 139 cases showed microcalcification which was not detected or considered significant by the readers. If only these 139 'true negative' screens are analysed, similar associations are seen between microcalcification on previous films and subsequent finding of DCIS (P=0.03) and between microcalcification on previous films and high grade invasive ductal carcinomas (P=0.015). These findings provide support for the hypothesis that microcalcification seen on previous screening films at the site of a subsequently detected invasive ductal carcinoma represents ductal carcinoma in situ. In this series, 19 of 82 women (23%) with invasive ductal carcinoma in the 'true negative' screen group had microcalcification suggestive of DCIS on mammograms taken, on average, 3 years previously. Significant microcalcification is often overlooked using current detection criteria. Early detection and treatment of DCIS is essential in order to prevent the development of aggressive invasive disease. Revision of the NHSBSP targets for DCIS detection is recommended.

Laparoscopic management of ovarian endometriomas: a critical review of current practice.

Endometriomas are a common cause of gynaecological morbidity, but their aetiology and management remain controversial This review focuses on identifying the evidence from published literature for the laparoscopic management of ovarian endometriomas. A critical appraisal shows that laparoscopic surgery is equivalent to laparotomy. There is no evidence to suggest that one minimal access surgical technique is clearly superior to another. However, this may be related to the inconsistencies in study design. In view of this we describe and justify our own management strategy for dealing with endometriomas.

Does transcervical resection of the endometrium for menorrhagia really avoid hysterectomy? Life table analysis of a large series.

STUDY OBJECTIVE: To determine long-term success and complication rates of transcervical resection of endometrium (TCRE) for menorrhagia. DESIGN: Retrospective audit of a continuous case series with a minimum of 2 and a maximum of 5 years' follow-up (Canadian Task Force classification II-2). SETTING: District general hospital and tertiary referral center for gynecologic endoscopy. PATIENTS: Three hundred eighty consecutive women with menorrhagia. INTERVENTION: TCRE performed as a day case or with overnight stay between August 1988 and December 1992. MEASUREMENTS AND MAIN RESULTS: Complications occurred in 6.8% of patients, with a perforation rate of 3.2%. Life table analysis showed a cumulative hysterectomy rate of 12.4% at 1 year, reaching a plateau of 27.4% after 4 years. The rate at 5 years was higher for women under age 45 years (35%) than for those 45 and over (14.9%, p <0.01, Mantel's test x(2)). Women whose operation was performed by a senior surgeon had a lower cumulative hysterectomy rate (12.6%) than those whose surgery was performed at least in part by trainees (38%, p <0.01, Mantel's text x(2)). There was no significant difference in cumulative hysterectomy rates between women who had uterine fibroids and those who did not. Ninety-six percent of hysterectomies were performed in the first 3 years after initial TCRE. CONCLUSION: Although TCRE for menorrhagia did not avoid hysterectomy in all women, for those considering hysterectomy, it was a conservative procedure with low morbidity and high chance of avoiding the need for major surgery, especially when performed in women over age 45, by an experienced surgeon.

Thermoregulated radiofrequency endometrial ablation.

OBJECTIVE: To test the hypothesis that treating dysfunctional uterine bleeding by automated application of electrothermal energy to the uterine cavity, with precise regional control, might yield results equivalent to those reported for hysteroscopically directed laser and electrosurgical endometrial ablations. MATERIALS AND METHODS: Patients with life style compromising menorrhagia, referred to six gynecologic surgical centers for hysterectomy or endometrial ablation, were admitted to the study if they had normal cervical cytology, a benign endometrial biopsy, no defined cause for their bleeding, and consented to participate in the evaluation of a newly developed Vesta DUB Treatment System. The device consists of a silicone-inflatable electrode carrier to be inserted into the uterine cavity and a controller to monitor and distribute current from a matched electrosurgical generator. Treatment involved a 3-minute or shorter warm-up period and a 4-minute treatment phase. RESULTS: Three- to 24-month follow-up data were available for 187 patients, with a mean follow-up of 14.8 months. The amenorrhea rate was 38%. Bleeding was reduced in 95% of patients. Actuarially, 88 +/- 3% of patients should expect to be free of menorrhagia, dissatisfaction, or need for a second procedure out to 24 months. CONCLUSIONS: The unique regional feed-back control offered by this system causes thorough, evenly distributed, thermal destruction 4-5 mm into the myometrium that reduces bleeding with durability equivalent to published reports of hysteroscopic endometrial ablation.