The Inaccuracy of Patient Recall for COPD Exacerbation Rate Estimation and Its Implications: Results from Central Adjudication.

BACKGROUND: COPD exacerbation incidence rates are often ascertained retrospectively through patient recall and self-reports. We compared exacerbation ascertainment through patient self-reports and single-physician chart review to central adjudication by a committee and explored determinants and consequences of misclassification. METHODS: Self-reported exacerbations (event-based definition) in 409 primary care patients with COPD participating in the International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) cohort were ascertained every 6 months over 3 years. Exacerbations were adjudicated by single experienced physicians and an adjudication committee who had information from patient charts. We assessed the accuracy (sensitivities and specificities) of self-reports and single-physician chart review against a central adjudication committee (AC) (reference standard). We used multinomial logistic regression and bootstrap stability analyses to explore determinants of misclassifications. RESULTS: The AC identified 648 exacerbations, corresponding to an incidence rate of 0.60 ± 0.83 exacerbations/patient-year and a cumulative incidence proportion of 58.9%. Patients self-reported 841 exacerbations (incidence rate, 0.75 ± 1.01; incidence proportion, 59.7%). The sensitivity and specificity of self-reports were 84% and 76%, respectively, those of single-physician chart review were between 89% and 96% and 87% and 99%, respectively. The multinomial regression model and bootstrap selection showed that having experienced more exacerbations was the only factor consistently associated with underreporting and overreporting of exacerbations (underreporters: relative risk ratio [RRR], 2.16; 95% CI, 1.76-2.65 and overreporters: RRR, 1.67; 95% CI, 1.39-2.00). CONCLUSIONS: Patient 6-month recall of exacerbation events are inaccurate. This may lead to inaccurate estimates of incidence measures and underestimation of treatment effects. The use of multiple data sources combined with event adjudication could substantially reduce sample size requirements and possibly cost of studies. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT00706602.

The ADO index as a predictor of two-year mortality in general practice-based chronic obstructive pulmonary disease cohorts.

BACKGROUND: Existing prediction models for mortality in chronic obstructive pulmonary disease (COPD) patients have not yet been validated in primary care, which is where the majority of patients receive care. OBJECTIVES: Our aim was to validate the ADO (age, dyspnoea, airflow obstruction) index as a predictor of 2-year mortality in 2 general practice-based COPD cohorts. METHODS: Six hundred and forty-six patients with COPD with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I-IV were enrolled by their general practitioners and followed for 2 years. The ADO regression equation was used to predict a 2-year risk of all-cause mortality in each patient and this risk was compared with the observed 2-year mortality. Discrimination and calibration were assessed as well as the strength of association between the 15-point ADO score and the observed 2-year all-cause mortality. RESULTS: Fifty-two (8.1%) patients died during the 2-year follow-up period. Discrimination with the ADO index was excellent with an area under the curve of 0.78 [95% confidence interval (CI) 0.71-0.84]. Overall, the predicted and observed risks matched well and visual inspection revealed no important differences between them across 10 risk classes (p = 0.68). The odds ratio for death per point increase according to the ADO index was 1.50 (95% CI 1.31-1.71). CONCLUSIONS: The ADO index showed excellent prediction properties in an out-of-population validation carried out in COPD patients from primary care settings.

Prediction of COPD-specific health-related quality of life in primary care COPD patients: a prospective cohort study.

BACKGROUND: Health-related quality of life (HRQL) is an important patient-reported outcome for chronic obstructive pulmonary disease (COPD). AIM: We developed models predicting chronic respiratory questionnaire (CRQ) dyspnoea, fatigue, emotional function, mastery and overall HRQL at 6 and 24 months using predictors easily available in primary care. METHODS: We used the "least absolute shrinkage and selection operator" (lasso) method to build the models and assessed their predictive performance. RESULTS: were displayed using nomograms. RESULTS: For each domain-specific CRQ outcome, the corresponding score at baseline was the best predictor. Depending on the domain, these predictions could be improved by adding one to six other predictors, such as the other domain-specific CRQ scores, health status and depression score. To predict overall HRQL, fatigue and dyspnoea scores were the best predictors. Predicted and observed values were on average the same, indicating good calibration. Explained variance ranged from 0.23 to 0.58, indicating good discrimination. CONCLUSIONS: To predict COPD-specific HRQL in primary care COPD patients, previous HRQL was the best predictor in our models. Asking patients explicitly about dyspnoea, fatigue, depression and how they cope with COPD provides additional important information about future HRQL whereas FEV1 or other commonly used predictors add little to the prediction of HRQL.

Five comorbidities reflected the health status in patients with chronic obstructive pulmonary disease: the newly developed COMCOLD index.

OBJECTIVE: This study aimed to identify those comorbidities with greatest impact on patient-reported health status in patients with chronic obstructive pulmonary disease (COPD) and to develop a comorbidity index that reflects their combined impact. STUDY DESIGN AND SETTING: We included 408 Swiss and Dutch primary care patients with COPD from the International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) in this cross-sectional analysis. Primary outcome was the Feeling Thermometer, a patient-reported health status instrument. We assessed the impact of comorbidities at five cohort assessment times using multiple linear regression adjusted for FEV1, retaining comorbidities with associations P ≤ 0.1. We developed an index that reflects strength of association of comorbidities with health status. RESULTS: Depression (prevalence: 13.0%; regression coefficient: -9.00; 95% CI: -13.52, -4.48), anxiety (prevalence: 11.8%; regression coefficient: -5.53; 95% CI -10.25, -0.81), peripheral artery disease (prevalence: 6.4%; regression coefficient: -5.02; 95% CI-10.64, 0.60), cerebrovascular disease (prevalence: 8.8%; regression coefficient: -4.57; 95% CI -9.43, 0.29), and symptomatic heart disease (prevalence: 20.3%; regression coefficient: -3.81; 95% CI -7.23, -0.39) were most strongly associated with the Feeling Thermometer. These five comorbidities, weighted, compose the COMorbidities in Chronic Obstructive Lung Disease (COMCOLD) index. CONCLUSION: The COMCOLD index reflects the combined impact of five important comorbidities from patients' perspective and complements existing comorbidity indices that predict death. It may help clinicians focus on comorbidities affecting patients' health status the most.

No association of 25-hydroxyvitamin D with exacerbations in primary care patients with COPD.

BACKGROUND: Cross-sectional studies suggest an association of 25-hydroxyvitamin D with exacerbations in patients with COPD, but longitudinal evidence from cohort studies is scarce. The aim of this study was to assess the association of serum 25-hydroxyvitamin D with exacerbations and mortality in primary care patients with COPD. METHODS: In the main analysis, we included 356 patients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages II-IV, free from exacerbations for ≥ 4 weeks) from a prospective cohort study in Dutch and Swiss primary care settings. We used negative binomial and Cox regression to assess the association of 25-hydroxyvitamin D with (centrally adjudicated) exacerbations and mortality, respectively. RESULTS: Baseline mean ± SD serum 25-hydroxyvitamin D concentration was 15.5 ± 8.9 ng/dL, and 274 patients (77.0%) had 25-hydroxyvitamin D deficiency (< 20 ng/dL). Compared with patients with severe 25-hydroxyvitamin D deficiency (< 10 ng/dL, n = 106 [29.8%]), patients with moderately deficient (10-19.99 ng/dL, n = 168 [47.2%]) and insufficient (20-29.99 ng/dL, n = 58 [16.3%]) concentrations had the same risk for exacerbations (incidence rate ratio, 1.01 [95% CI, 0.77-1.57] vs 1.00 [95% CI, 0.62-1.61], respectively). In patients with desirable concentrations (> 30 ng/dL, n = 24 [6.7%]), the risk was lower, although not significantly (incidence rate ratio, 0.72 [95% CI, 0.37-1.42]). In patients taking vitamin D supplements, using different cutoffs for 25-hydroxyvitamin D or competing risk models did not materially change the results. We did not find a statistically significant association of 25-hydroxyvitamin D concentration with mortality. CONCLUSIONS: This longitudinal study in a real-world COPD population that carefully minimized misclassification of exacerbations and the influence of confounding did not show an association of 25-hydroxyvitamin D with exacerbations and mortality.

All that glitters isn't gold: a survey on acknowledgment of limitations in biomedical studies.

BACKGROUND: Acknowledgment of all serious limitations to research evidence is important for patient care and scientific progress. Formal research on how biomedical authors acknowledge limitations is scarce. OBJECTIVES: To assess the extent to which limitations are acknowledged in biomedical publications explicitly, and implicitly by investigating the use of phrases that express uncertainty, so-called hedges; to assess the association between industry support and the extent of hedging. DESIGN: We analyzed reporting of limitations and use of hedges in 300 biomedical publications published in 30 high and medium -ranked journals in 2007. Hedges were assessed using linguistic software that assigned weights between 1 and 5 to each expression of uncertainty. RESULTS: Twenty-seven percent of publications (81/300) did not mention any limitations, while 73% acknowledged a median of 3 (range 1-8) limitations. Five percent mentioned a limitation in the abstract. After controlling for confounders, publications on industry-supported studies used significantly fewer hedges than publications not so supported (p = 0.028). LIMITATIONS: Detection and classification of limitations was--to some extent--subjective. The weighting scheme used by the hedging detection software has subjective elements. CONCLUSIONS: Reporting of limitations in biomedical publications is probably very incomplete. Transparent reporting of limitations may protect clinicians and guideline committees against overly confident beliefs and decisions and support scientific progress through better design, conduct or analysis of new studies.

Simple functional performance tests and mortality in COPD.

Exercise tests are important to characterise chronic obstructive pulmonary disease patients and predict their prognosis, but are often not available outside of rehabilitation or research settings. Our aim was to assess the predictive performance of the sit-to-stand and handgrip strength tests. The prospective cohort study in Dutch and Swiss primary care settings included a broad spectrum of patients (n=409) with Global Initiative for Chronic Obstructive Lung Disease stages II to IV. To assess the association of the tests with outcomes, we used Cox proportional hazards (mortality), negative binomial (centrally adjudicated exacerbations) and mixed linear regression models (longitudinal health-related quality of life) while adjusting for age, sex and severity of disease. The sit-to-stand test was strongly (adjusted hazard ratio per five more repetitions of 0.58, 95% CI 0.40-0.85; p=0.004) and the handgrip strength test moderately strongly (0.84, 95% CI 0.72-1.00; p=0.04) associated with mortality. Both tests were also significantly associated with health-related quality of life but not with exacerbations. The sit-to-stand test alone was a stronger predictor of 2-year mortality (area under curve 0.78) than body mass index (0.52), forced expiratory volume in 1 s (0.61), dyspnoea (0.63) and handgrip strength (0.62). The sit-to-stand test may close an important gap in the evaluation of exercise capacity and prognosis of chronic obstructive pulmonary disease patients across practice settings.

Validity and reproducibility of a physical activity questionnaire for older adults: questionnaire versus accelerometer for assessing physical activity in older adults.

BACKGROUND: Physical activity (PA) is important in older adults for the maintenance of functional ability. Assessing PA may be difficult. Few PA questionnaires have been compared to activity monitors. We examined reproducibility and validity of the self-administered Longitudinal Ageing Study Amsterdam Physical Activity Questionnaire (LAPAQ) against a triaxial accelerometer (ACTR) (Sensewear(®) Pro) in older adults. METHODS: Participants wore the ACTR continuously for two weeks. After 2 (T [time] = 1) and 4 (T = 2) weeks, participants completed the LAPAQ. Since the LAPAQ asks about 2 weeks' worth of physical activity, the ACTR and LAPAQ coincided at T1. T2 was used to assess the reproducibility of the LAPAQ results only. We calculated Pearson's correlation coefficients (PCC) to examine reproducibility and validity. For visualization, we used scatterplots and Bland-Altman plots. With a receiver operating characteristics (ROC) curve we assessed how well the LAPAQ identifies older adults whose activity level is below official recommendations. RESULTS: A total of 89 persons were included. Of the participants, 48% were men; median age was 73, and median body mass index was 25. The 2-week mean total duration of activity was 2788 (ACTR, T = 1), 2439 (LAPAQ T = 1), and 1994 (LAPAQ T = 2) minutes. As a reference, 2 full weeks contained 20,160 minutes. Reproducibility of the LAPAQ was moderate (PCC 0.68, 95% CI 0.55-0.80). The median difference between LAPAQ at T = 1 and the ACTR (LAPAQ minus ACTR) was -510 minutes and the PCC was 0.25 (95% CI 0.07-0.44). The area under the ROC curve was 0.73 (95% CI 0.59-0.86). CONCLUSION: LAPAQ underestimates PA and seems unsuitable for exact measurement in older adults. However, it may be used to determine if a person's PA level is below the recommended level.

Characteristics of Dutch and Swiss primary care COPD patients - baseline data of the ICE COLD ERIC study.

INTRODUCTION: INTERNATIONAL COLLABORATIVE EFFORT ON CHRONIC OBSTRUCTIVE LUNG DISEASE: Exacerbation Risk Index Cohorts (ICE COLD ERIC) is a prospective cohort study with chronic obstructive pulmonary disease (COPD) patients from Switzerland and The Netherlands designed to develop and validate practical COPD risk indices that predict the clinical course of COPD patients in primary care. This paper describes the characteristics of the cohorts at baseline. MATERIAL AND METHODS: Standardized assessments included lung function, patient history, self-administered questionnaires, exercise capacity, and a venous blood sample for analysis of biomarkers and genetics. RESULTS: A total of 260 Dutch and 151 Swiss patients were included. Median age was 66 years, 57% were male, 38% were current smokers, 55% were former smokers, and 76% had at least one and 40% had two or more comorbidities with cardiovascular disease being the most prevalent one. The use of any pulmonary and cardiovascular drugs was 84% and 66%, respectively. Although lung function results (median forced expiratory volume in 1 second [FEV(1)] was 59% of predicted) were similar across the two cohorts, Swiss patients reported better COPD-specific health-related quality of life (Chronic Respiratory Questionnaire) and had higher exercise capacity. DISCUSSION: COPD patients in the ICE COLD ERIC study represent a wide range of disease severities and the prevalence of multimorbidity is high. The rich variation in these primary care cohorts offers good opportunities to learn more about the clinical course of COPD.

ICE COLD ERIC--International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts--study protocol for an international COPD cohort study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. METHODS/DESIGN: We will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years. DISCUSSION: Despite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov Archive NCT00706602.