Data collection
The eurIPFreg has been designed as an Internet-based, multicentre registry interlinked with the European IPF Biobank (eurIPFbank, see also
www.pulmonary-fibrosis.net) [
15]. The data protection concept was reviewed and approved by local and national networks such as the TMF (Technology
, Methods, and Infrastructure for Networked Medical Research e.V.) and authorities (e.g. Hessian Data Protection Officer, Protocol Nr. 412,101 from 25.08.2008). Both, eurIPFreg and eurIPFbank have also been reviewed and received positive votes from institutional review boards in Germany (e.g. Ethics Committee of Justus-Liebig-University of Giessen; 111/08), France, Italy, Austria, Spain, Czech Republic, Hungary and the UK. The research was conducted strictly according to the principles of the Declaration of Helsinki. Patients were included into the registry starting November 2009. The eurIPFreg and eurIPFbank are listed in
ClinicalTrials.gov (NCT02951416).
In the period between 2009 and 2016, the following sites recruited patients: Universities of Giessen and Marburg Lung Center, Germany and the nearby AGAPLESION Lung Clinic Waldhof-Elgershausen; Competence Center for Rare Pulmonary Diseases of Hopital Bichat in Paris, France; Interstitial Lung Disease Unit of Royal Brompton Hospital in London, United Kingdom; Reference Center for Rare Pulmonary Diseases, Centre Hospitalier Universitaire Dijon-Bourgogne, France; Dept. of Clinical and Molecular Biomedicine of Università degli Studi di Catania, Italy; Vienna University Hospital, Austria; Hospital Clinico San Carlos in Madrid, Spain; Department of Pulmonology Semmelweis University in Budapest, Hungary; Thomayer Hospital in Prague, Czech Republic; Ospedale San Gerardo in Monza, Italy; Università degli Studi di Napoli Federico II, Italy, and Ruhrlandklinik, University Hospital of Essen, Germany.
The software solution underlying the registry (
secuTrial®) was developed by the German Parkinson Network and is certified by the Food and Drug Administration (FDA) as well as the European Medicines Agency (EMEA). The patients’ data are transferred via a secure internet-based data collection form and all data entries are based on the unique patient’s encrypted ID number (“pseudonym”).
The patients were eligible for the enrolment if they were at least 18 years old, had IPF (prevalent or incident cases) or other ILDs (as comparator group) as diagnosed by the expert site, and had provided written informed consent prior to the inclusion. In order to facilitate research, inclusion of other lung diseases such as lung cancer, COPD as well as healthy subjects or family members as additional comparator groups was made possible in the frame of an amendment in March 2013.
On a local level, each patient’s IPF diagnosis was evaluated in a multidisciplinary discussion including at least chest physicians, pathologists and radiologists on the basis of the respective ATS/ERS/JRS/ALAT guidelines. The registry had no explicit exclusion criteria, thereby reducing selection bias. The clinical data were collected at the time of enrolment (baseline) and in intervals 3 to 12 month thereafter (dictated by clinical routine).
After entry into the registry, each case was checked by a documentation officer (BP) for data quality and by FD and AG for internal plausibility of medical data and the diagnosis of IPF (e.g. hints for collagen/vascular diseases or hypersensitivity pneumonia in patient questionnaires). Also, in 2015 and 2016, all previous IPF cases diagnosed as having IPF according to the previous guideline from 2000, were checked if they would also fulfil the guideline criteria from 2011 [
16]. No central reading of HRCT or histology samples was performed.
The clinical data acquisition took place primarily via patient and physician baseline questionnaires, which can be retrieved upon logging in to our website (
www.pulmonary-fibrosis.net). The patient questionnaire included patient’s demographics, a detailed medical history making use of the WHO classification, complaints as well as report of co-morbidities [
6]. Alongside with this questionnaire, the patient also received quality of life questionnaires, among them the EQ-5D, the SF-36 and the Mahler Index questionnaire [
17‐
19]. These documents were available in different languages and were printed out on e-paper format and with an individual pseudonym on each page, allowing scanning and automated computer entry upon manual fill-out of the form.
The physician questionnaire contained data of physical examination and laboratory tests, pulmonary function, radiology, echocardiography, 6 MWD as well as other information concerning relevant patient’s diagnosis and therapy; the form had to be filled out online in English language. Import of historical medical data was also possible. Medication was assessed making use of the official WHO list of drugs 2018 from WHO Collaborating Centre for Drug Statistics and Methodology, allowing categorial (group-wise) analysis of co-medication (
www.whocc.no/atc_ddd_index).
Next to the baseline data, follow-up data were obtained in a similar way, making use again of patient and physician questionnaires. These questionnaires consisted of a smaller number of items of the baseline questionnaires, but also included additional aspects relevant for the further course of the disease such as information on intermittent respiratory infections, working status, transplantation or any changes in the medication. In case a patient was deceased, the site investigator was asked to document this in the registry, including the underlying reasons of death (if known). In addition to the data as provided by the questionnaires, high resolution computed tomography (HRCT) and any other DICOM formatted images could be uploaded; during this procedure, the patient’s personal data in the DICOM header were replaced by the pseudonym.
Biological materials such as blood, bronchoalveolar lavage fluid (BALF) and tissue samples as well as exhaled breath condensates and electronic Nose (eNose) profiles were centrally recorded and managed through generation of patient-, time-, and specimen-specific Lab IDs and they were stored both, locally as well as in the centralized European IPF Biobank (eurIPFbank) located in Giessen.
Quality of data and statistical analysis
Quality of data was improved by introduction of internal plausibility checks, in which different items were put into a logical context, causing the generation of queries in case inconsistent entries were noted (e.g. if physician’s and patient’s report were not consistent with regard to signs of underlying collagen/vascular disease). These queries were addressed to the respective site investigator, asking for clarification of the issue. In addition, site investigators were asked to conduct on-site data verification.
All statistical procedures were performed using SPSS 24 (SPSS, IBM Corp). For baseline data, the summary descriptive statistic was generated with categorical data displayed as absolute numbers and relative frequencies. Continuous data are shown as mean (SD) for normally distributed data or as median (interquartile range) for nonparametric data. Comparisons between groups were performed using a t-test or Mann–Whitney U test, as appropriate. For assessment of overall survival Kaplan-Meier analyses were applied.