Method/design
Design
Open, prospective and multi-centre validating and updating scales study. Patient recruitment started in February 2015 and will last until Dec 31th, 2016. The patients will be followed for 5 years since their recruitment.
Standards of Reporting adhere to the SPIRIT 2013 Statement for protocols.
Setting
Primary Care Centres, from Vigo Health Authority (Galicia, Spain) and from Balearic Islands Health Authority (Balearic Islands, Spain). Through these centres, doctors/nurses potentially willing to participate were identified during national and international scientific meetings, both in Spain (Aragón, Canarias, Cataluña) and other European countries (Croatia, Bulgaria, Macedonia, Germany and Romania). Subsequently, General Practitioners (GPs) and/or Nurses were invited and informed by e-mail about the description of the background and objectives of the study, as well as the implications of their participation. There are 36 health centres involved.
Study sites can be found in authors affiliations.
Subjects
Patients diagnosed with COPD. The eligibility criteria for those studied were similar to those used in the original derivation of the models.
Inclusion criteria
a)
patients with a moderate-severe obstruction, defined by a FEV1 lower than 80 % of the expected post-bronchodilator FEV in the presence of a FEV1 quotient/forced vital capacity (FVC) lower than 70 %, diagnosed with COPD
b)
patients in a stable phase of COPD, clinically defined as at least 6 weeks since the last exacerbation
c)
acceptance to participate in the study by providing written informed consent.
Exclusion criteria
a)
patients diagnosed with cystic fibrosis, or bronchiectasis that is clinically significant or of a different origin to COPD (tuberculosis, childhood infections, immunodeficiencies, and severe cognitive or mobility impairment)
b)
patients diagnosed with a severe chronic disease, besides COPD (active malignancy, AIDS, heart failure, severe kidney or liver failure, etc.).
Sample size
A validation study has a specific goal: quantifying the performance of an existing model in other data. Sample size requirements for validation studies are not well understood, and there is a dearth of empirical evidence to guide investigators. In some cases it is possible to choose sample size on statistical grounds. We will focus on the precision and accuracy of the performance measures in the new data.
To analyse the ROC curve for each index and the corresponding AUC, the size of the sample was calculated using pROC package, free software available at
https://cran.r-project.org/. The formula used was:
power.roc.test (auc = 0.75, sig.level = 0.05, power = 0.9, kappa = 8).
The selected parameters considered were: a) mortality estimated in 3 years to be 12.5 % [
14], which is a proportion of 1 exitus for every eight patients; b) 30 % of the patients belong to subgroups A, C and D of the GOLD classification [
9], although there are discrepancies in this proportion according to the study; c) the lowest AUC described for the different indices is 0.75 [
15,
17]; and d) Type I error has been set at 5 % and the power of the study at 90 %.
Under these assumptions, 477 patients need to be recruited, of which 30 % should belong to groups A, C and D, with the number of patients in group A = number in group B = number in group C = 133 (15 deaths and 118 living after 3 years). Moreover, 10 % are added for patients expected to be in group B and a further 10 % for losses to the study. This figure will also be adequate for the total number of patients, but not for those in group B. Currently, there is no published prevalence for the GesEPOC 2014 phenotypes, therefore, these subgroups cannot be estimated.
Patient recruitment
The healthcare professionals identified potentially eligible cases, within their quota of assigned patients, through electronic medical records review (10 per professional). Those patients who are diagnosed with COPD will be included, provided that they fulfil the inclusion criteria as explained previously. After obtaining the informed consent, patients will be incorporated in the study if they have already been correctly diagnosed with COPD. The results of a test taken in the last 6 months during a stable phase will be considered valid; if the last test was more than 6 months ago, a new spirometry test will have to be taken. The study personnel will assess whether the patients have COPD stage II–IV using portable and hand-held spirometry. For our purpose, we will determine postbronchodilator FEV1 and Forced Vital Capacity as a measure for airflow obstruction. Ten minutes before measuring lung function, patients will inhale two puffs of 100 μg salbutamol through a spacer. Once a diagnosis is established, the severity of the obstruction is classified in relation to the post-bronchodilator FEV1 value, expressed as a percentage of the expected level.
The undertaking of the spirometry test and its interpretation will be the responsibility of specially trained staff, who has taken an accredited and tutored theoretical and practical course.
Outcome variables
Survival (time to event) without exacerbation will be assessed during 5 years since patient recruitment. In addition, mortality (time to event) from all causes and those specifically due to respiratory causes will be analysed as health outcome at the end of the study. Data source will be EMR and death registry data if needed. Blind assessment of the outcome to be predicted is not feasible.
Exacerbations are defined as any sustained increase in respiratory symptoms (dyspnoea, cough and/or expectoration) that require modification of the usual treatment and/or hospital care -visit to the Emergency Room or admission- (for the BODEx index), as well as the exacerbations identified at the PC emergencies department (but without changing subsequent treatment). In this definition, admissions for pneumonia, pulmonary embolism and other causes of complications in COPD are not included.
Predictors
Assessment of predictors is done by GPs/nurses at baseline, without knowledge of the participant’s outcome, following the indices (ADO, BODEx, DOSE) definition. Formulas to calculate them are available in Additional file
1: Table S1.
They will be recorded in a specific database along with detailed patient history: date of birth, sex, height, weight, and body mass index. The spirometry test will be carried out according to protocol recommendations and the date of the first spirometric diagnosis of COPD will be recorded. Dyspnoea will be assessed according to the scale proposed by the British Medical Research Council for the ADO and BODEx indices. Associated diseases will be evaluated using the Charlson Comorbidity Index and COMCOLD, and the presence of other relevant illnesses, not included in Charlson, will be recorded, such as myopathy, osteoporosis, obstructive sleep apnoea-hypopnoea syndrome, and anxiety and depression disorders. The COPD Assessment Test (CAT) questionnaire will be used to assess the impact of COPD on the daily life and welfare of the patient, and its results will be used for categorisation according to the revised 2011 GOLD classification. Participating patients will be asked about tobacco consumption (packets/year), alcohol consumption (yes/no, units/week), physical exercise (Physical Activity Questionnaire short form (IPAQ), daily physical activity intense/moderate/low), current respiratory pharmacological treatment (in the stable phase), influenza and pneumococcal vaccine status, having received advice about their lifestyle and evaluation of the social support of the patient. The patient will be classified in accordance with the phenotypes defined by the
GesEPOC [
17].
The number of exacerbations in the previous years will be counted, in accordance with each index definition.
The ADO and modified ADO (from 0 to 14) indices, the BODEx index, DOSE index, Charlson index, COMCOLD index and the combined assessment of the GOLD score using the four possible models will be automatically calculated when introducing the variables that make up the computerised database.
For clinical monitoring of the patient, but not included in the prognosis model, a laboratory analysis must be carried out and should include: haemogram, determination of alpha-1-antitrypsin levels (if they have never been determined), IgE and eosinophilia in sputum, as minor criteria of GesEPOC. Moreover, if it is an initial diagnosis, a chest radiograph will be requested. An electrocardiogram will be required if pulmonary hypertension or Stages III or IV of the GOLD classification are suspected [
6].
Independent variables in the follow-up
The follow-up will be undertaken by clinical visits every 6 months. When the patient cannot make the appointment, follow-up will be by telephone interview or a review of the EMR. Information about the date of clinical exacerbations, admissions, visits to the emergency department (primary care or hospital) and mortality will be obtained by a review of the patient’s medical record, contact with the patient’s family and/or passive follow-up (from hospital and mortality records). Survival will be evaluated after 5 years. If cases are referred to a second care level, any specialist care appointments will be recorded.
Adverse events and dropouts during follow-up will be recorded, with the reason for them.
Participant time line
At enrolment, a clinical assessment is performed for all the patients by appropriately trained study personnel. Participants are asked to perform spirometry and complete the study questionnaires (Table
1). Participants are also requested a laboratory analysis and chest radiograph if needed following the GOLD guideline. Every 6 months, their exacerbations will be count up.
Table 1
Participants time line
Planning |
WHAT |
Design | x | | | |
Galician Ethics Committee approval | x | | | |
Other nodes Ethics Committees | x | x | | |
Funding | x | x | | |
Web-page design and pilot study | x | | | |
WHO (nodes) | | | | |
Galicia | x | | | |
Balearic Islands | x | | | |
Recruitment |
WHAT | | | | |
Spirometry | | x | | |
Clinical assesment | | x | | |
MRC | | x | | |
CAT | | x | | |
IPAQ | | x | | |
Laboratory analysis (optional) | | x | | |
Chest radiography (optional) | | x | | |
WHO (nodes) | | | | |
Galicia | | x | | |
Balearic Islands | | x | | |
Aragon | | x | | |
Canary Islands | | x | | |
Catalonia | | x | | |
Bulgaria | | | x | |
Croatia | | x | | |
Germany | | | x | |
Macedonia | | | x | |
Romania | | | x | |
FOLLOW-UP |
WHAT | | | | |
Exacerbations (type and number) | | x | x | x |
Mortality and morbidity outcome | | x | x | x |
In terms of the level of additional risk posed by diagnostic/monitoring procedures as compared to normal clinical practice, these will be performed in accordance with the terms of the treatment guidelines [
1] in any Member State concerned.
Data analysis
The analyst will identify incomplete data and communicate it to the relevant professional for the particular patient. Appropriate test and statistical treatment (multiple imputations) of lost values will be performed.
To assess the discriminatory capacity of the different indices studied (ADO, BODEx and DOSE), logistic regression models and Cox proportional hazard models will be constructed. Initially, the possible non-linear effect of the indices will be studied by using Structured Additive Regression (STAR) models with penalised splines. Subsequently, we will assess different aspects of the regression models: discrimination, calibration and diagnostic precision. For calibration, the Brier score will be used, together with the Hosmer–Lemeshow test for goodness of fit and graphs of the non-parametric estimates of the association between the expected frequencies and those found for the model. To determine the discrimination of the models, ROC curves (and the corresponding AUC) will be calculated. For survival models, the time-dependent ROC will be estimated, as well as its graphical representation. Diagnostic precision will be calculated as the proportion of patients classified incorrectly. For this purpose, the classification rule shall be as follows: each patient will be classified as belonging to the group for which the predicted probability is higher. To correct against optimism, bootstrap techniques will be used.
Discussion
COPD in Europe affects between 4 and 10 % of adults and causes between 200,000 and 300,000 deaths annually. Moreover, associated healthcare costs are estimated at around 10,000 million Euros. The European Platform of Public Health Organizations (EPHA) recommended that COPD research should be included among the priority objectives included in Horizon 2020. Moreover, strategy B3 of the European Innovation Partnership on Active and Healthy Aging prioritised COPD among the chronic diseases requiring research.
The Research Agenda for General Practice/Family Medicine [
30] of the European General Practice Research Network (EGPRN) established recommendations both for objectives and methodologies coherent with Family Medicine as defined by World Organization of National Colleges, Academies and Associations of General Practitioners/Family Physicians (WONCA). This agenda has been translated by members of our research team to orientate the research strategy in PC in Spain. The Research Agenda highlights that the evidence on predictive values of all kinds of findings, test or prognostic indices in primary care settings is scarce. Many tests have not been formally evaluated in primary care; different prevalence settings are then used, with more or less selected populations, and often result in unrealistically high prevalence estimates for chronic disease. This is problematic as these results are then used to conclude that GPs are not good at detecting disease and many articles then recommend indices for prognosis in unselected populations or to identify patients to be treated.
In this context, a prospective cohort like that of
PROEPOC/COPD provides good opportunities for learning about the clinical course of COPD in a PC population, which represents all patients with COPD, from the mildest to the most severe cases. Considering the characteristics of the initial cohort, and the higher survival expected in a primary care setting, ADO and BODEx recalibration may be necessary, as had to be done to combine the cohorts of international studies [
15]. The International Primary Care Respiratory Group (IPCRG) set up the Uncovering and Noting Long-term Outcomes in COPD and asthma to enhance Knowledge (UNLOCK) cohort [
31]. Kruis [
32] evaluated the external validity of 6 large pharmaceutically-sponsored COPD studies (LPCS) and compared them to the characteristics of the patients in 7 database registers that constitute the UNLOCK cohort: between 53 and 84 % of the patients treated in primary care did not fulfil the inclusion criteria of the cohorts recruited in the hospital setting.
In this study, prognostic indices (ADO, BODEx and DOSE) will be assessed for COPD, in different subgroups of patients. Therefore, it will influence the functioning of the health system, because the classification of COPD patients will individualize preventative activities and/or treatments indicated for each patient, modify referral procedures between general family practitioners-nursing staff and specialty-primary care and improve knowledge/self-management of the disease by patients themselves and their families.
The good technical quality of the information obtained is essential for the results of the study to be valid and to reduce variability. Standardization of protocols, including web-page form were sent to the researchers, reviewed and translated in each country by the node leaders. Group reunions are planned during EGPRN meetings, twice per year. The study protocol was presented and reviewed at Barcelona meeting, 11st May, 2014. Later, three reunions were organized (Heraklion, Timisoara and Edirne). The project was presented at UNLOCK board during Singapore IPCRG meeting in 2015. For quality control, the following procedures will be in place throughout the different stages of the study in each node: daily calibration of spirometers; automation of filter variables and forms; computer-based administration of questionnaires; accreditation of the training of the nursing staff in spirometry; updating of clinical knowledge about COPD, data monitoring three times per year. An international workshop about spirometry was organized during WONCA Istanbul meeting in 2015 and web seminars will be scheduled (one per year).
TRIPOD Group [
33] encourages complete and transparent reporting reflecting study design and conduct, and even enter the study in registers that accommodate observational studies such as ISRCTN. We try to help readers submitting the TRIPOD reporting template as Additional file
1: Table S2.
The information gathered will allow research into COPD and make communication easier between family practitioners, nursing staff, pneumologists and other professionals, supporting a multi-disciplinary approach to the treatment of these patients. Both GOLD and the phenotypes recently presented in the updated
GesEPOC have this same orientation. Soriano [
34] compared the different groups of combined assessment and the predictive validity of the old and new GOLD methodologies, speculating that there may be a higher percentage of type B COPD in primary care and, therefore, the need for a longer follow-up period. The
GesEPOC 2014 uses prognostic indices (BODEx, with 5 as the cut-off threshold) to refer patients [
17].
The UNLOCK cohort has demonstrated the superiority of DOSE over ADO. However, in a primary care-based cohort, no study in a European setting has included the BODEx index in the comparative analysis. The main aim of the present study, and one of its contributions to this debate, is to undertake a comparative analysis among these indices and with DOSE, in the same patients and with common recruitment criteria. Moreover, the PROEPOC/COPD study gives priority to issues about preventative and/or therapeutic actions usually managed by the patient and by primary care professionals that should be tackled in that setting.
The usefulness of these indices will be determined by their application in primary care [
35] and the possibility of personalized treatment, as has been established for a considerable time for cardiovascular diseases. Multi-dimensional scales are tools that should be analysed and used in relation to these guidelines [
36].
Acknowledgment
Collaborator researchers of the PROEPOC/COPD study group:
Abalde-Castro, Luz. Teis Health Centre, Vigo, Spain.
Ares-Vila, Sara. Teis Health Centre, Vigo, Spain.
Bernardez-Peña, Lorena N. Pintor Colmeiro Health Centre, Vigo, Spain.
Bozhinovska, Elizabeta. Poliklinika Dr. Beti, Bitola, Macedonia
Budiu, Ioana. Cabinet Medical de Medicina Familiei, Timisoara, Romania.
Bundó Vidiella, Magdalena. Mataró 7 (Ronda Prim) Health Centre. Institut Universitari d’Investigació en Atenció Primaria Jordi Gol (IDIAP Jordi Gol). Mataró, Spain.
Clemente-Jimenez, L. Pirineos Health Centre, Huesca. Spain.
Coma Carbó, Rosa M. Mataró 6 (Ronda Gatassa) Health Centre. Institut Universitari d’Investigació en Atenció Primaria Jordi Gol (IDIAP Jordi Gol). Mataró, Spain.
Del Río-Navarro, Catalina. Barrio La Salud Health Centre, Santa Cruz de Tenerife, Spain.
Erazo, Susana. La Garriga Health Centre, La Garriga, Spain.
Góngora Andrades, Miguel A. Son Pisa Health Centre, Palma de Mallorca, Islas Baleares, Spain.
Gorreto López, Lucia. Coll d’en Rebassa Health Centre, Palma de Mallorca, Islas Baleares, Spain.
Hamulka, Daniela. Zagreb-East Health Centre, Zagreb, Croatia.
Hernández-Rodríguez, Alicia. El Chorrillo Health Centre, Santa Cruz de Tenerife, Spain.
Hristeva Foreva, Gergana. Medical University of Plovdiv, Dept. General Practice, Plovdiv, Bulgaria.
Jovanovska, Suzana. JZU Zdravstven dom, Skopje, Macedonia
Lazic, Anera. School of Medicine, University of Zagreb, Zagreb, Croatia.
Martín-Campos, Candelaria. Casco Botánico Health Centre, Puerto de la Cruz, Spain.
Mayrata, Adriano. Escuela Graduada, Palma de Mallorca, Islas Baleares, Spain.
Miteva, Gordana. P.Z.U., Sveti Nikole, Macedonia
Montero Alia, Pilar. Mataró 1 (La Riera) Health Centre. Institut Universitari d’Investigació en Atenció Primaria Jordi Gol (IDIAP Jordi Gol). Mataró, Spain.
Negrete Palma, Antonio. Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d’Investigació en Atenció Primaria Jordi Gol (IDIAP Jordi Gol). Mataró (Barcelona), Spain.
Núñez-Chicharro, Leonor. Barrio La Salud Health Centre, Santa Cruz de Tenerife, Spain.
Padure, Ioana. Cabinet Medical Individual, Timisoara, Romania.
Palmer Simó, José F. Son Rutllan Health Centre, Palma de Mallorca, Islas Baleares, Spain.
Pérez-Villar, MV. Matamá Health Centre, Vigo, Spain.
Rego-Sieiro, Esther. Matamá Health Centre, Vigo, Spain.
Robles Sánchez, Cristina. Ponteareas Health Centre, Vigo, Spain.
Rodríguez-Reneda, Lucinda. Public Health Officer, Vigo, Spain.
Schmiemann, Guido. Gesundheitspraxis Georgstraße, University of Bremen, Bremen, Germany.
Sorribes Lopez, Josep. Unitat de Suport a la Recerca Metropolitana Nord, Institut Universitari d’Investigació en Atenció Primaria Jordi Gol (IDIAP Jordi Gol). Mataró, Spain.
Spasovska, Aleksandra. Promedika Medical Centre, Skopje, Macedonia
Stanic, Jelena. Zagreb-Centre Health Centre, Zagreb, Croatia.
Stefanescu, Srl. Centrul Medical, Timisoara, Romania.
Tiljak, Anja. Private GP practice, Zagreb, Croatia.
Valero Suau, Alejandra. Port de Pollensa Health Centre, Islas Baleares, Spain.
Vila Rigat, Rosa. La Garriga Health Centre. La Garriga, Spain.
Volkenand, Katrin. Hannover Medical School, Hannover, Germany.
Wöbkenberg, Josef. Gesundheitscentrum Damme, Damme, Germany.