Nicholas R. Parsons

Survey of the quality of experimental design, statistical analysis and reporting of research using animals.

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria.

The Development and Validation of a Self-Administered Quality-of-Life Outcome Measure for Young, Active Patients With Symptomatic Hip Disease: The International Hip Outcome Tool (iHOT-33)

PURPOSE The purpose of this study was to develop a self-administered evaluative tool to measure health-related quality of life in young, active patients with hip disorders. METHODS This outcome measure was developed for active patients (aged 18 to 60 years, Tegner activity level ≥ 4) presenting with a variety of symptomatic hip conditions. This multicenter study recruited patients from international hip arthroscopy and arthroplasty surgeon practices. The outcome was created using a process of item generation (51 patients), item reduction (150 patients), and pretesting (31 patients). The questionnaire was tested for test-retest reliability (123 patients); face, content, and construct validity (51 patients); and responsiveness over a 6-month period in post-arthroscopy patients (27 patients). RESULTS Initially, 146 items were identified. This number was reduced to 60 through item reduction, and the items were categorized into 4 domains: (1) symptoms and functional limitations; (2) sports and recreational physical activities; (3) job-related concerns; and (4) social, emotional, and lifestyle concerns. The items were then formatted using a visual analog scale. Test-retest reliability showed Pearson correlations greater than 0.80 for 33 of the 60 questions. The intraclass correlation statistic was 0.78, and the Cronbach α was .99. Face validity and content validity were ensured during development, and construct validity was shown with a correlation of 0.81 to the Non-Arthritic Hip Score. Responsiveness was shown with a paired t test (P ≤ .01), effect size of 2.0, standardized response mean of 1.7, responsiveness ratio of 6.7, and minimal clinically important difference of 6 points. CONCLUSIONS We have developed a new quality-of-life patient-reported outcome measure, the 33-item International Hip Outcome Tool (iHOT-33). This questionnaire uses a visual analog scale response format designed for computer self-administration by young, active patients with hip pathology. Its development has followed the most rigorous methodology involving a very large number of patients. The iHOT-33 has been shown to be reliable; shows face, content, and construct validity; and is highly responsive to clinical change. In our opinion the iHOT-33 can be used as a primary outcome measure for prospective patient evaluation and randomized clinical trials.

A Short Version of the International Hip Outcome Tool (iHOT-12) for Use in Routine Clinical Practice

PURPOSE The purpose of this study was to develop and validate a shorter version of the 33-item International Hip Outcome Tool (iHOT-33) that could be easily used in routine clinical practice to measure both health-related quality of life and changes after treatment in young, active patients with hip disorders. METHODS A development dataset (104 patients) was explored with forward-selection linear regression analysis to choose a reduced item set for the new scale. This was tested in a validation dataset (1,833 patients) and responsiveness subset (80 patients) to measure agreement between the shorter and longer versions and to test the sensitivity of the shorter instrument to change after treatment. RESULTS Twelve items were chosen for a short version of the International Hip Outcome Tool (iHOT-12). The iHOT-12 showed excellent agreement with the long version (iHOT-33). It captured 95.9% (95% confidence interval, 95.0% to 96.8%) of the variation of the iHOT-33 and showed equivalent sensitivity to change with a standardized effect size of 0.98 (95% confidence interval, 0.67 to 1.28). CONCLUSIONS A short version of the International Hip Outcome Tool (iHOT-12) has been developed. It has very similar characteristics to the original rigorously validated 33-item questionnaire, losing very little information despite being only one-third the length. It is valid, reliable, and responsive to change. We suggest that it be used for initial assessment and postoperative follow-up in routine clinical practice.

Operative versus non-operative treatment for closed, displaced, intra-articular fractures of the calcaneus: randomised controlled trial

Objective To investigate whether surgery by open reduction and internal fixation provides benefit compared with non-operative treatment for displaced, intra-articular calcaneal fractures. Design Pragmatic, multicentre, two arm, parallel group, assessor blinded randomised controlled trial (UK Heel Fracture Trial). Setting 22 tertiary referral hospitals, United Kingdom. Participants 151 patients with acute displaced intra-articular calcaneal fractures randomly allocated to operative (n=73) or non-operative (n=78) treatment. Main outcome measures The primary outcome measure was patient reported Kerr-Atkins score for pain and function (scale 0-100, 100 being the best possible score) at two years after injury. Secondary outcomes were complications; hindfoot pain and function (American Orthopaedic Foot and Ankle Society score); general health (SF-36); quality of life (EQ-5D); clinical examination; walking speed; and gait symmetry. Analysis was by intention to treat. Results 95% follow-up was achieved for the primary outcome (69 in operative group and 74 in non-operative group), and a complete set of secondary outcomes were available for 75% of participants. There was no significant difference in the primary outcome (mean Kerr-Atkins score 69.8 in operative group v 65.7 in non-operative group; adjusted 95% confidence interval of difference −7.1 to 7.0) or in any of the secondary outcomes between treatment groups. Complications and reoperations were more common in those who received operative care (estimated odds ratio 7.5, 95% confidence interval 2.0 to 41.8). Conclusions Operative treatment compared with non-operative care showed no symptomatic or functional advantage after two years in patients with typical displaced intra-articular fractures of the calcaneus, and the risk of complications was higher after surgery. Based on these findings, operative treatment by open reduction and internal fixation is not recommended for these fractures. Trial registration Current Controlled Trials ISRCTN37188541.

The Avon patellofemoral joint replacement: Five-year results from an independent centre.

Between May 1998 and May 2007 we carried out 50 Avon patellofemoral joint replacements in 32 patients with isolated patellofemoral osteoarthritis. There were no revisions in the first five years, giving a cumulative survival of 100% for those with a minimum follow-up of five years. The mean follow-up was 5.3 years (2.1 to 10.2). The median Oxford knee score was 30.5 (interquartile range 22.25 to 42.25). In patients with bilateral replacements the median Euroqol General health score was 50 which was significantly lower than that of 75 in those with a unilateral replacement (p = 0.047). The main complication was progression of disease, which was identified radiologically in 11 knees (22%). This highlights the need for accurate selection of patients. Our findings suggest that the Avon prosthesis survives well and gives a satisfactory functional outcome in the medium term.

Percutaneous fixation with Kirschner wires versus volar locking plate fixation in adults with dorsally displaced fracture of distal radius: randomised controlled trial

Objectives To compare the clinical effectiveness of Kirschner wire fixation with locking plate fixation for patients with a dorsally displaced fracture of the distal radius. Design A multicentre two arm parallel group assessor blind randomised controlled trial with 1:1 treatment allocation. Setting 18 trauma centres in the United Kingdom. Participants 461 adults with a dorsally displaced fracture of the distal radius within 3 cm of the radiocarpal joint that required surgical fixation. Patients were excluded if the surgeon thought that the surface of the wrist joint was so badly displaced it required open reduction. Interventions Kirschner wire fixation: wires are passed through the skin over the dorsal aspect of the distal radius and into the bone to hold the fracture in the correct anatomical position. Locking plate fixation: a locking plate is applied through an incision over the volar (palm) aspect of the wrist and secured to the bone with fixed angle locking screws. Main outcome measures Primary outcome measure: validated patient rated wrist evaluation (PRWE). This rates wrist function in two (equally weighted) sections concerning the patient’s experience of pain and disability to give a score out of 100. Secondary outcomes: disabilities of arm, shoulder, and hand (DASH) score, the EuroQol (EQ-5D), and complications related to the surgery. Results The baseline characteristics of the two groups were well balanced, and over 90% of patients completed follow-up. The wrist function of both groups of patients improved by 12 months. There was no clinically relevant difference in the patient rated wrist score at three, six, or 12 months (difference in favour of the plate group was −1.3, 95% confidence interval −4.5 to 1.8; P=0.40). Nor was there a clinically relevant difference in health related quality of life or the number of complications in each group. Conclusions Contrary to the existing literature, and against the rapidly increasing use of locking plate fixation, this trial found no difference in functional outcome in patients with dorsally displaced fractures of the distal radius treated with Kirschner wires or volar locking plates. Kirschner wire fixation, however, is cheaper and quicker to perform. Trial registration Current Controlled Trials ISCRTN 31379280. UKCRN 8956.

Spatial and Temporal Analysis of the Microbial Community in Slow Sand Filters Used for Treating Horticultural Irrigation Water

ABSTRACT An experimental slow sand filter (SSF) was constructed to study the spatial and temporal structure of a bacterial community suppressive to an oomycete plant pathogen, Phytophthora cryptogea. Passage of water through the mature sand column resulted in complete removal of zoospores of the plant pathogen. To monitor global changes in the microbial community, bacterial and fungal numbers were estimated on selective media, direct viable counts of fungal spores were made, and the ATP content was measured. PCR amplification of 16S rRNA genes and denaturing gradient gel electrophoresis (DGGE) were used to study the dynamics of the bacterial community in detail. The top layer (1 cm) of the SSF column was dominated by a variable and active microbial population, whereas the middle (50 cm) and bottom (80 cm) layers were dominated by less active and diverse bacterial populations. The major changes in the microbial populations occurred during the first week of filter operation, and these populations then remained to the end of the study. Spatial and temporal nonlinear mapping of the DGGE bands provided a useful visual representation of the similarities between SSF samples. According to the DGGE profile, less than 2% of the dominating bands present in the SSF column were represented in the culturable population. Sequence analysis of DGGE bands from all depths of the SSF column indicated that a range of bacteria were present, with 16S rRNA gene sequences similar to groups such as Bacillus megaterium, Cytophaga, Desulfovibrio, Legionella, Rhodococcus rhodochrous, Sphingomonas, and an uncharacterized environmental clone. This study describes the characterization of the performance, and microbial composition, of SSFs used for the treatment of water for use in the horticultural industry. Utilization of naturally suppressive population of microorganisms either directly or by manipulation of the environment in an SSF may provide a more reproducible control method for the future.

A conditional error function approach for subgroup selection in adaptive clinical trials.

Growing interest in personalised medicine and targeted therapies is leading to an increase in the importance of subgroup analyses. If it is planned to view treatment comparisons in both a predefined subgroup and the full population as co-primary analyses, it is important that the statistical analysis controls the familywise type I error rate. Spiessens and Debois (Cont. Clin. Trials, 2010, 31, 647-656) recently proposed an approach specific for this setting, which incorporates an assumption about the correlation based on the known sizes of the different groups, and showed that this is more powerful than generic multiple comparisons procedures such as the Bonferroni correction. If recruitment is slow relative to the length of time taken to observe the outcome, it may be efficient to conduct an interim analysis. In this paper, we propose a new method for an adaptive clinical trial with co-primary analyses in a predefined subgroup and the full population based on the conditional error function principle. The methodology is generic in that we assume test statistics can be taken to be normally distributed rather than making any specific distributional assumptions about individual patient data. In a simulation study, we demonstrate that the new method is more powerful than previously suggested analysis strategies. Furthermore, we show how the method can be extended to situations when the selection is not based on the final but on an early outcome. We use a case study in a targeted therapy in oncology to illustrate the use of the proposed methodology with non-normal outcomes.

Outcome assessment after hip fracture: is EQ-5D the answer?

Objectives To study the measurement properties of a joint specific patient reported outcome measure, a measure of capability and a general health-related quality of life (HRQOL) tool in a large cohort of patients with a hip fracture. Methods Responsiveness and associations between the Oxford Hip Score (a hip specific measure: OHS), ICEpop CAPability (a measure of capability in older people: ICECAP-O) and EuroQol EQ-5D (general health-related quality of life measure: EQ-5D) were assessed using data available from two large prospective studies. The three outcome measures were assessed concurrently at a number of fixed follow-up time-points in a consecutive sequence of patients, allowing direct assessment of change from baseline, inter-measure associations and validity using a range of statistical methods. Results ICECAP-O was not responsive to change. EQ-5D was responsive to change from baseline, with an estimated standardised effect size for the two datasets of 0.676 and 0.644 at six weeks and four weeks respectively; this was almost as responsive to change as OHS (1.14 at four weeks). EQ-5D correlated strongly with OHS; Pearson correlation coefficients were 0.74, 0.77 and 0.70 at baseline, four weeks and four months. EQ-5D is a moderately good predictor of death at 12 months following hip fracture. Furthermore, EQ-5D reported by proxies (relatives and carers) behaves similarly to self-reported scores. Conclusions Our findings suggest that a general HRQOL tool such as EQ-5D could be used to measure outcome for patients recovering from hip fracture, including those with cognitive impairment. Cite this article: Bone Joint Res 2014;3:69–75.

Colourless, directionless, contentionless ROADM architecture using low-loss optical matrix switches

We show a novel colourless, directionless, contentionless add/drop optical node architecture using low-loss NxM optical switches which scales to multiple degrees and removes the need for unnecessary network-wide wavelength assignment restrictions