Primary endpoint discrepancies were found in one in ten clinical drug trials. Results of an inception cohort study.

OBJECTIVE: To identify the occurrence and determinants of protocol-publication discrepancies in clinical drug trials. STUDY DESIGN AND SETTING: All published clinical drug trials reviewed by the Dutch institutional review boards in 2007 were analyzed. Discrepancies between trial protocols and publications were measured among key reporting aspects. We evaluated the association of trial characteristics with discrepancies in primary endpoints by calculating the risk ratio (RR) and 95% confidence interval (CI). RESULTS: Of the 334 published trials, 32 (9.6%) had a protocol/publication discrepancy in the primary endpoints. Among the subgroup of randomized controlled trials (RCTs; N = 204), 12 (5.9%) had a discrepancy in the primary endpoint. Investigator-initiated trials with and without industry (co-) funding were associated with having discrepancies in the primary endpoints compared with industry-sponsored trials (RR 3.7; 95% CI 1.4-9.9 and RR 4.4; 95% CI 2.0-9.5, respectively). Furthermore, other than phase 1-4 trials (vs. phase 1; RR 4.6; 95% CI 1.1-19.3), multicenter trials were also conducted outside the European Union (vs. single center; RR 0.2; 95% CI 0.1-0.6), not prospectively registered trials (RR 3.3; 95% CI 1.5-7.5), non-RCTs (vs. superiority RCT; RR 2.4; 95% CI 1.2-4.8) and, among the RCTs, crossover compared with a parallel group design (RR 3.7; 95% CI 1.1-12.3) were significantly associated with having discrepancies in the primary endpoints. CONCLUSIONS: Improvement in completeness of reporting is still needed, especially among investigator-initiated trials and non-RCTs. To eliminate undisclosed discrepancies, trial protocols should be available in the public domain at the same time when the trial is published.

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.

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials.

The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

Occurrence and determinants of selective reporting of clinical drug trials: design of an inception cohort study.

INTRODUCTION: Responsible conduct of research implies that results of clinical trials should be completely and adequately reported. This article describes the design of a cohort study that aims to investigate the occurrence and the determinants of selective reporting in an inception cohort of all clinical drug trials that were reviewed by the Dutch Institutional Review Boards (IRBs) in 2007. It also describes the characteristics of the study cohort. METHODS AND ANALYSIS: In 2007, Dutch IRBs reviewed 622 clinical drug trials. For each trial, we assessed the stages of progress. We discriminated five intermediate stages and five definite stages. Intermediate stages of progress are: approved by an IRB; started inclusion; completed as planned; terminated early; published as article. The definite stages of progress are: rejected by an IRB; never started inclusion; not published as article; completely reported; selectively reported. We will use univariate and multivariate Cox regression models to identify trial characteristics associated with non-publication. We will identify seven trial-specific discrepancy items, including the objectives, inclusion and exclusion criteria, end points, sample size, additional analyses, type of population analysis and sponsor acknowledgement. The percentage of trials with discrepancies between the protocol and the publication will be scored. We will investigate the association between trial characteristics and the occurrence of discrepancies. ETHICS AND DISSEMINATION: No IRB-approval is required for this study. Access to confidential research protocols was provided by the Central Committee on Research Involving Human Subjects. We plan to finish data collection in June 2015, and expect to complete data cleaning, analysis and manuscript preparation within the next 3 months. Hence, a first draft of an article containing the results is expected before the end of October 2015.

[Review of multicentre clinical trials is simplified; more trial centres are approved in the first assessment round]. / Toetsing multicentrisch onderzoek is vereenvoudigd.

The CCMO (the Dutch Central Committee on Research Involving Human Subjects) has evaluated the External Review Directive. This new directive for multicentre clinical trials reduces the administrative burden in approving medical research involving human subjects. The number of trial centres approved in the primary decision has increased. However, it still takes quite some time before a study actually starts. The boards of directors of the participating trial centres play an important role in further streamlining the process.

[Patient safety in clinical intervention research]. / Patiëntveiligheid bij klinisch interventieonderzoek.

In clinical intervention research, the monitoring of patient safety is essential. In December 2009, a symposium on the role of the different parties involved was organised. Research starts with a robust protocol with a section dealing with interim decision-making and procedures for reporting during the research. After the approval by an accredited Ethics Committee, the responsibility for the patient safety primarily lies with the investigators and sponsor (in the case of investigator-initiated research generally the Institutional Board of Directors). In addition, the appointment of a Data and Safety Monitoring Committee (DSMC) has become more frequent during recent years. This committee monitors the safety of patients by means of evaluation of interim results and advises the sponsor accordingly. The decision process concerning premature ending is a clinical decision, which should not exclusively be based on exceeding a statistical limit. The focus of the DSMC should be on safety issues; only in exceptional cases should a trial be discontinued because of clear efficacy, or the lack of it.

Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells.

Reactive oxygen species (ROS) present in cigarette smoke (CS) are thought to contribute to the development of COPD. Although CS-ROS can hardly enter airway epithelial cells, and certainly not the circulation, systemic levels of ROS have been found to be elevated in COPD patients. We hypothesize that lipophilic components present in CS can enter airway epithelial cells and increase intracellular ROS production by disturbing mitochondrial function. Different airway epithelial cells were exposed to CS extract (CSE), hexane-treated CSE (CSE without lipophilic components), gaseous-phase CS, and water-filtered CS (gaseous-phase CS without ROS). Mitochondrial membrane potential (Deltapsi(m)) and ATP levels were assessed using the bronchial epithelial cell line Beas-2b. ROS generation measured directly by DCF fluorescence and indirectly by measuring free thiol groups (-SH) upon exposure to CS was assessed using lung alveolar epithelial cells devoid of functional mitochondria (A549-rho0), with normal A549 cells serving as controls. In Beas-2b cells, CSE (4 h) caused a dose-dependent decrease in Deltapsi(m) and ATP levels, whereas hexane-treated CSE did not. DCF fluorescence in A549 cells increased in response to CSE, whereas this was not the case in A549-rho0 cells. Exposure of A549 cells to CS resulted in a rapid decrease in free -SH, whereas exposure to ROS-depleted CS only resulted in a delayed decrease. This delayed decrease was less pronounced in A549-rho0 cells. Lipophilic components in CS disturb mitochondrial function, which contributes to increased intracellular generation of ROS. Our results are of importance in understanding the systemic effects of smoking observed in patients with COPD.

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.

Cross-sectional assessment of daily physical activity in chronic obstructive pulmonary disease lung transplant patients.

BACKGROUND: Information about daily physical activity of chronic obstructive pulmonary disease (COPD) lung transplant patients is relevant for evaluation of the functional recovery of physical capacity after lung transplantation. The objective of this study was to cross-sectionally assess daily physical activity, pulmonary function, physical fitness, fear of physical activity and motivation to exercise in COPD patients who were lung transplant candidates and lung transplant recipients. METHODS: Fifteen COPD lung transplant candidates (5 men and 10 women, mean age 53 years, forced expiratory volume in 1 second [FEV(1)] 20% predicted) and 47 recipients (18 men and 29 women, mean age 55 years, FEV(1) 93% predicted, 39 bilateral and 8 unilateral transplants) were enrolled in this observational study. Daily physical activity was measured using a pedometer (Digiwalker SW-200) and the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH). Physical fitness was measured by the sit-to-stand test and the arm curl test. Fear of physical activity and motivation to exercise were measured by the Tampa Scale for Kinesiophobia-Dutch version Questionnaire and the Exercise Self-Regulation Questionnaire. RESULTS: Mean (+/-SD) number of steps per day in lung transplant recipients was higher compared with transplant candidates: 6,642 (+/-2,886) and 1,407 (+/-1,166), respectively (p < 0.05). Number of steps per day correlated significantly with FEV(1) (r = 0.32, p = 0.03) and lower body strength (r = 0.45, p = 0.002) in lung transplant recipients. There was no significant difference in daily physical activity, physical fitness, fear and motivation between bi- and unilateral transplant recipients. CONCLUSION: Our data suggest that lung transplantation improves daily physical activity, lower body strength and FEV(1).

Depressive symptoms as predictors of mortality in patients with COPD.

OBJECTIVE: Prognostic studies of mortality in patients with COPD have mostly focused on physiologic variables, with little attention to depressive symptoms. This stands in sharp contrast to the attention that depressive symptoms have been given in the outcomes of patients with other chronic health conditions. The present study investigated the independent association of depressive symptoms in stable patients with COPD with all-cause mortality. METHODS: The baseline characteristics of 121 COPD patients (78 men and 43 women; mean [+/- SD] age, 61.5 +/- 9.1 years; and mean FEV(1), 36.9 +/- 15.5% predicted) were collected on hospital admission to a pulmonary rehabilitation center. The data included demographic variables, body mass index (BMI), post-bronchodilator therapy FEV(1), and Wpeak (peak workload [Wpeak]). Depressive symptoms were assessed using the Beck depression inventory. The vital status was ascertained using municipal registrations. In 8.5 years of follow-up, 76 deaths occurred (mortality rate, 63%). Survival time ranged from 88 days to 8.5 years (median survival time, 5.3 years). The Cox proportional hazard model was used to quantify the association of the baseline characteristics (ie, age, sex, marital status, smoking behavior, FEV(1), BMI, Wpeak, and depressive symptoms) with mortality. RESULTS: Depressive symptoms (odds ratio [OR], 1.93; 95% confidence interval [CI], 1.12 to 3.33) were associated with mortality in patients with COPD, independent of other factors including male sex (OR, 1.73; 95% CI, 1.03 to 2.92), older age (OR, 1.05; 95% CI, 1.02 to 1.08), and lower Wpeak (OR, 0.98; 95% CI, 0.97 to 0.99). CONCLUSIONS: This study provides evidence that depressive symptoms assessed in stable patients with COPD are associated with their subsequent all-cause mortality.

Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations.

Systemic corticosteroids and additional short-acting beta2-agonists are commonly used in exacerbations of chronic obstructive pulmonary disease (COPD). In this double-blind study, the combination of a high-dose inhaled corticosteroid with a rapid-onset long-acting beta2-agonist was evaluated in the treatment of out-patient COPD exacerbations. The primary aim was to compare 14-day treatment effects of budesonide/formoterol to placebo on sputum eosinophils and, secondarily, on other indices of inflammation, forced expiratory flow in one second (FEV(1)), symptoms, health status, and adverse events. Forty-five patients not using steroids (37 male, 21/24 current/ex smoker, median packyears 38, age 65 years, FEV(1) 61% predicted), experiencing a COPD exacerbation, were treated at home with budesonide/formoterol (320/9 microg 4 times daily), prednisolone (30 mg daily), or placebo for 14 days. Sputum eosinophils were significantly reduced by budesonide/formoterol (-57%) compared to placebo (+24%) (p = 0.01). Budesonide/formoterol reduced total symptom scores significantly (p = 0.01) compared to placebo. The increase in FEV(1) by 2 weeks of treatment with budesonide/formoterol (125 ml) was not significantly different from that of placebo (43 ml) (p = 0.07). Budesonide/ formoterol treatment did not suppress morning serum cortisol compared to placebo (-16%; p = 0.50). In conclusion, budesonide/formoterol reduces sputum eosinophils and improves symptoms in the treatment of out-patient COPD exacerbations.

FVC to slow inspiratory vital capacity ratio: a potential marker for small airways obstruction.

BACKGROUND: The ratio of FVC to slow inspiratory vital capacity (SVC) has been reported to reflect small airways obstruction, but its validity as such is still unclear. The aim of this study was to assess the applicability of the FVC/SVC ratio as a marker of small airways function in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX), which is a disorder in which predominantly small airways obstruction causes progressive airflow limitation. METHODS: The FVC/SVC ratio was analyzed both cross-sectionally and longitudinally in 39 patients (26 men) with BOS after bilateral LTX (median age, 47 years; interquartile range [IQR], 35 to 54 years), and 36 bilateral lung transplant recipients without BOS (14 men; median age, 46 years; IQR, 41 to 53 years). RESULTS: The FVC/SVC ratio decreased significantly during follow-up in patients with BOS stages 1 and 2, by 2.2% and 4.4%, respectively, from baseline (p < 0.001). This decrease was not significantly associated with the decrease in FEV(1). The FVC/SVC ratio increased, though not significantly, in the group in which BOS did not develop by 1.1%, which is a significant difference from the average fall of 4.4% in the group in which BOS developed. CONCLUSIONS: Significant, yet small decreases in FVC/SVC ratio occur in patients in whom BOS develops, independent from changes in FEV(1). At a group level, FVC/SVC ratio is able to detect small airways changes. These results merit prospective studies to determine the sensitivity of FVC/SVC ratio to quantifying small airways dysfunction at an individual level and in other airway diseases.

Cyclosporin A-induced oxidative stress is not the consequence of an increase in mitochondrial membrane potential.

Cyclosporin A induces closure of the mitochondrial permeability transition pore. We aimed to investigate whether this closure results in concomitant increases in mitochondrial membrane potential (DeltaPsim) and the production of reactive oxygen species. Fluorescent probes were used to assess DeltaPsim (JC-1, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide), reactive oxygen species [DCF, 5- (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester] and [Ca2+][Fluo-3, glycine N-[4-[6-[(acetyloxy)methoxy]-2,7-dichloro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-(acetyloxy)methyl ester] in human kidney cells (HK-2 cells) and in a line of human small cell carcinoma cells (GLC4 cells), because these do not express cyclosporin A-sensitive P-glycoprotein. We used transfected GLC4 cells expressing P-glycoprotein as control for GLC4 cells. NIM811 (N-methyl-4-isoleucine-cyclosporin) and PSC833 (SDZ-PSC833) were applied as selective mitochondrial permeability transition pore and P-glycoprotein blockers, respectively. To study the effect of cyclosporin A on mitochondrial function, we isolated mitochondria from fresh pig livers. Cyclosporin A and PSC833 induced a more than two-fold increase in JC-1 fluorescence in HK-2 cells, whereas NIM811 had no effect. None of the three substances induced a significant increase in JC-1 fluorescence in GLC4 cells. Despite this, cyclosporin A, NIM811 and PSC833 induced a 1.5-fold increase in DCF fluorescence (P<0.05) and a two-fold increase in Fluo-3 fluorescence (P<0.05). Studies in isolated mitochondria showed that blockage of mitochondrial permeability transition pores by cyclosporin A affected neither DeltaPsim, ATP synthesis, nor respiration rate. The mitochondrial permeability transition pore blockers cyclosporin A and NIM811, but also the non-mitochondrial permeability transition pore blocker PSC833, induced comparable degrees of reactive oxygen species production and cytosolic [Ca2+]. Neither mitochondria, effects on P-glycoprotein nor inhibition of calcineurin therefore play a role in cyclosporin A-induced oxidative stress and disturbed Ca2+ homeostasis.

Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis.

Increased lung cell apoptosis and necrosis occur in patients with chronic obstructive pulmonary disease (COPD). Mitochondria are crucially involved in the regulation of these cell death processes. Cigarette smoke is the main risk factor for development of COPD. We hypothesized that cigarette smoke disturbs mitochondrial function, thereby decreasing the capacity of mitochondria for ATP synthesis, leading to cellular necrosis. This hypothesis was tested in both human bronchial epithelial cells and isolated mitochondria. Cigarette smoke extract exposure resulted in a dose-dependent inhibition of complex I and II activities. This inhibition was accompanied by decreases in mitochondrial membrane potential, mitochondrial oxygen consumption, and production of ATP. Cigarette smoke extract abolished the staurosporin-induced caspase-3 and -7 activities and induced a switch from epithelial cell apoptosis into necrosis. Cigarette smoke induced mitochondrial dysfunction, with compounds of cigarette smoke acting as blocking agents of the mitochondrial respiratory chain; loss of ATP generation leading to cellular necrosis instead of apoptosis is a new pathophysiological concept of COPD development.

Changes in personal control as a predictor of quality of life after pulmonary rehabilitation.

OBJECTIVE: Perceptions of mastery and self-efficacy may be related to better outcomes in pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). This study examined (1) whether patients with COPD improved during a rehabilitation programme with respect to quality of life (QoL) and perceptions of self-efficacy and mastery, and (2) whether increased perceptions of mastery and self-efficacy contributed to a higher QoL after rehabilitation. METHODS: Thirty-nine consecutive COPD patients (aged 60.5 +/- 9.0) were included from a rehabilitation centre and completed self-report questionnaires assessing symptoms, QoL, and perceptions of personal control. RESULTS: COPD patients improved during rehabilitation in overall QoL and self-efficacy, although no significant changes were found in QoL domains and mastery. Changes in self-efficacy during rehabilitation contributed to the explanation of the social and psychological functioning QoL domains. CONCLUSION: Even in seriously impaired COPD patients in advanced stages of illness, positive changes in self-efficacy and overall well-being can be established during rehabilitation. Changes in self-efficacy were related to a better QoL, suggesting the importance of personal control in the adjustment to COPD. PRACTICE IMPLICATIONS: Focussing more explicitly on the enhancement of perceptions of personal control in COPD patients may be an important aim of pulmonary rehabilitation.

The relationship between self-efficacy and self-reported physical functioning in chronic obstructive pulmonary disease and chronic heart failure.

In this study, the authors investigated whether self-reported physical functioning of patients with chronic obstructive pulmonary disease (COPD) and chronic systolic heart failure (CHF) was primarily explained by illness-specific differences related to diagnosis or whether more generic factors also contributed to their physical functioning. Consecutive patients with COPD (n = 56; mean age = 67.8, SD = 8.5) and CHF (n = 65; mean age = 60.0, SD = 10.2)from the outpatient clinics of a university hospital and a general hospital completed a self-report questionnaire, including the Rand-36 Health Survey, Cantril's ladder, the Mastery scale, the Perceived Health Competence Scale, and the Self-efficacy scale. COPD patients scored significantly worse in self-reported physical and psychological functioning and perceived health competence than did patients with CHF Regression analysis revealed that both the diagnosis and the illness severity contributed to self-reported physical functioning, although self-efficacy explained the main part of physical functioning. Therefore, important aims in the treatment of patients with COPD and CHF should be not only improving physical functioning but also enhancing self-efficacy.

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.

Stress, psychological distress, and coping in patients on the waiting list for lung transplantation: an exploratory study.

Little information is available in literature on quality of life, stress and coping during the period patients are waiting for lung transplantation. This study explored potential stressful events that patients experience during the waiting period assessed the level of anxiety and depression and explored the use of coping strategies. Cross sectional analysis were performed. Between 3 and 27 months the number of patients that participated varied between 70 and 21. Measurements took place every 3 months until 27 months after waiting list placement. Instruments were the State Trait Anxiety Inventory, the Self-rating Depression Scale (SDS)-Zung and questions concerning stress and coping. Feeling tension caused by 'having to wear a beeper', and 'being afraid that the transplantation will come too late' were identified as important stress factors. Patients on the waiting list experienced more anxiety and depression, compared to the general population. The longer patients had been on the waiting list, the more anxiety and depression they experienced. Positive coping strategies like 'trying to relax' were more frequently used than negative ones like 'taking sedatives'. Stress, anxiety, and depression occur frequently in waiting list patients.

Consequences of chronic obstructive pulmonary disease and chronic heart failure: the relationship between objective and subjective health.

This study investigates whether the relationship between objective health parameters and general health perceptions was mediated by symptoms of dyspnoea and physical functioning in patients with chronic obstructive pulmonary disease (COPD) and patients with chronic heart failure (CHF). The different health parameters were organised according to Wilson and Cleary's conceptual model of patient outcomes (Wilson & Cleary (1995). Journal of the American Medical Association, 273, 59-65). Second, we investigated whether perceptions of personal control were related to the health parameters in the model. Consecutive patients with COPD and CHF were included from the outpatient clinics of a university hospital and a general hospital, and from a rehabilitation centre, all in the Netherlands. Ninety-five COPD patients (aged 65.0+/-9.3; forced expiratory volume in 1s (FEV1)<70%) were included and compared with 90 CHF patients (aged 59.6+/-10.0; left ventricular ejection fraction (LVEF)<45%). The relationship between objective health parameters (FEV1 or LVEF) and subjective health (self-reported physical functioning) was not mediated by symptoms of dyspnoea. FEV1 or LVEF and symptoms of dyspnoea were independently related to self-reported physical functioning, which was directly related to general health perceptions. Perceived health competence was related to symptoms of dyspnoea and general health perceptions in patients with either COPD or CHF. Although patients with COPD reported lower levels in all self-reported health parameters in the model than the patients with CHF, this study showed that the relations between the health parameters in the model were comparable for COPD and CHF patients.