Incomplete quality of life data in lung transplant research: comparing cross sectional, repeated measures ANOVA, and multi-level analysis

BACKGROUND: In longitudinal studies on Health Related Quality of Life (HRQL) it frequently occurs that patients have one or more missing forms, which may cause bias, and reduce the sample size. Aims of the present study were to address the problem of missing data in the field of lung transplantation (LgTX) and HRQL, to compare results obtained with different methods of analysis, and to show the value of each type of statistical method used to summarize data. METHODS: Results from cross-sectional analysis, repeated measures on complete cases (ANOVA), and a multi-level analysis were compared. The scores on the dimension 'energy' of the Nottingham Health Profile (NHP) after transplantation were used to illustrate the differences between methods. RESULTS: Compared to repeated measures ANOVA, the cross-sectional and multi-level analysis included more patients, and allowed for a longer period of follow-up. In contrast to the cross sectional analyses, in the complete case analysis, and the multi-level analysis, the correlation between different time points was taken into account. Patterns over time of the three methods were comparable. In general, results from repeated measures ANOVA showed the most favorable energy scores, and results from the multi-level analysis the least favorable. Due to the separate subgroups per time point in the cross-sectional analysis, and the relatively small number of patients in the repeated measures ANOVA, inclusion of predictors was only possible in the multi-level analysis. CONCLUSION: Results obtained with the various methods of analysis differed, indicating some reduction of bias took place. Multi-level analysis is a useful approach to study changes over time in a data set where missing data, to reduce bias, make efficient use of available data, and to include predictors, in studies concerning the effects of LgTX on HRQL

Recruitment failure and futility were the most common reasons for discontinuation of clinical drug trials. Results of a nationwide inception cohort study in the Netherlands

Objectives The objective of the study was to identify the reasons for discontinuation of clinical drug trials and to evaluate whether efficacy-related discontinuations were adequately planned in the trial protocol. Study Design and Setting All clinical drug trials in the Netherlands, reviewed by institutional review boards in 2007, were followed until December 2015. Data were obtained through the database of the Dutch competent authority (Central Committee on Research Involving Human Subjects [CCMO]) and a questionnaire to the principal investigators. Reasons for trial discontinuation were the primary outcome of the study. Three reasons for discontinuation were analyzed separately: all cause, recruitment failure, and efficacy related (when an interim analysis had demonstrated futility or superiority). Among the efficacy-related discontinuations, we examined whether the data monitoring committee, the stopping rule, and the moment of the interim analysis in the trial progress were specified in the trial protocol. Results Of the 574 trials, 102 (17.8%) were discontinued. The most common reasons were recruitment failure (33 of 574; 5.7%) and solely efficacy related (30 of 574; 5.2%). Of the efficacy-related discontinuations, 10 of 30 (33.3%) of the trial protocols reported all three aspects in the trial protocol, and 20 of 30 (66.7%) reported at least one aspect in the trial protocol. Conclusion One out of five clinical drug trials is discontinued before the planned trial end, with recruitment failure and futility as the most common reasons. The target sample size of trials should be feasible, and interim analyses should be adequately described in trial protocols

Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation

BACKGROUND: Inflammation increases during exacerbations of COPD, but only a few studies systematically assessed these changes. Better identification of these changes will increase our knowledge and potentially guide therapy, for instance by helping with quicker distinction of bacterially induced exacerbations from other causes. AIM: To identify which inflammatory parameters increase during COPD exacerbations compared to stable disease, and to compare bacterial and non-bacterial exacerbations. METHODS: In 45 COPD patients (37 male/8 female, 21 current smokers, mean age 65, FEV(1) 52% predicted, pack years 38) sputum was collected during a stable phase and subsequently during an exacerbation. RESULTS: Sputum total cell counts (9.0 versus 7.9 x 10(6)/mL), eosinophils (0.3 versus 0.2 x 10(6)/mL), neutrophils (6.1 versus 5.8 x 10(6)/mL), and lymphocytes (0.07 versus 0.02 x 10(6)/mL) increased significantly during an exacerbation compared to stable disease. A bacterial infection was demonstrated by culture in 8 sputum samples obtained during an exacerbation. These exacerbations had significantly increased sputum total cell and neutrophil counts, leukotriene-B4, myeloperoxidase, interleukin-8 and interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) levels, and were also associated with more systemic inflammation compared to exacerbations without a bacterial infection. Sputum TNF-alpha level during an exacerbation had the best test characteristics to predict a bacterial infection. CONCLUSION: Sputum eosinophil, neutrophil, and lymphocyte counts increase during COPD exacerbations. The increase in systemic inflammation during exacerbations seems to be limited to exacerbations caused by bacterial infections of the lower airways. Sputum TNF-alpha is a candidate marker for predicting airway bacterial infection

End-stage extension of the knee and its influence on tibial tuberosity-trochlear groove distance (TTTG) in asymptomatic volunteers

PURPOSE: Increased tibial tuberosity-trochlear groove distance (TTTG) is one potential correcting parameter in patients suffering from lateral patellar instability. It was hypothesized that end-stage extension of the knee might influence the TTTG distance on MR images. METHODS: Transverse T1-weighted MR images of the knee were acquired at full extension, 15° and 30° flexion of the knee in 30 asymptomatic volunteers. MRI parameters: slice thickness: 3 mm, matrix: 256 × 384, FOV: 150 × 150 mm. Two observers independently measured the TTTG at all positions. RESULTS: Mean TTTG for observer 1 was 15.1 ± 3.2 mm at full extension, 10.0 ± 3.5 mm at 15° flexion and 8.1 ± 3.4 mm at 30° flexion. Mean TTTG for observer 2: 14.8 ± 3.3 mm at full extension, 9.4 ± 3.0 mm at 15° flexion, 8.6 ± 3.4 mm at 30° flexion. Mean values were significantly different (p < 0.001) between full extension and 15° as well as 30° flexion for both observers. Mean values were significantly different (p < 0.001) between 15° and 30° for observer 1, but not for observer 2 (n.s.). Interobserver agreement was very good (intraclass correlation coefficient: 0.87-0.88; p < 0.001). CONCLUSIONS: The TTTG increases significantly at the end-stage extension of the knee. Therefore, the comparability of published TTTG values measured on radiographs, CT and MRI at various flexion/extension angles of the knee are limited. LEVEL OF EVIDENCE: Development of diagnostic criteria in a consecutive series of patients and a universally applied 'gold' standard, Level II