Early imaging biomarkers of lung cancer, COPD and coronary artery disease in the general population: rationale and design of the ImaLife (Imaging in Lifelines) Study

The National Lung Screening Trial (NLST) showed the benefit of low-dose CT to reduce lung cancer mortality in at-risk individuals [8]. However, there was a high false-positive rate due to the single measurement of a nodule diameter for determining screen result. The key to reduce false-positive rates may be found in using semi-automated volumetric nodule quantification and calculating volume doubling time (VDT) of indeterminate lung nodules [2]. The Dutch-Belgian lung cancer screening trial (NELSON) provided evidence that volume-based CT screening is an effective method of lung cancer screening, with much lower false positives [9, 10]. Reference values of nodule volume and VDT are important, especially when aiming to prevent unnecessary follow-up CT scans and unnecessary fear of cancer. While lung cancer screening studies focused on high-risk long-term smokers, little is known about the prevalence and size and growth of lung nodules in a general population.

The coronary artery calcium score (CACS) is the strongest non-invasive predictor for coronary events [11‐16], and its impact as screening tool is currently under investigation [17]. Previously, the Heinz Nixdorf Recall (HNR) study [15] and the Multi-Ethnic Study of Atherosclerosis (MESA) [16] provided the distribution of CACS in unselected adult populations without clinical CVD in Germany, and USA respectively. The Rotterdam study evaluated the CACS in the older population [18]. Apart from MESA, these studies only focused on CAD, without relating CACS to other B3 diseases.

Early stages of COPD can be quantified by measuring emphysema, bronchial wall thickness and air trapping on chest CT scans [19]. Structural lung abnormalities on CT were found to increase the risk of lung cancer and mortality [20‐22]. Presence and severity of COPD imaging biomarkers in the general population are largely unknown. In a subset of MESA, the cardiac CT scan was used to determine some estimate of COPD measures, however, the higher lung fields, where emphysema typically starts, were not imaged.

The Lifelines study is a longitudinal cohort study and biobank in a large three-generation population in the northern part of the Netherlands, comprising over 167,000 participants [7, 23]. The Lifelines cohort study has been established in 2006. Baseline assessments were completed in 2013, after which second-round assessments have been started and completed in 2017. The third-round assessments will start in 2019. Participants are invited to complete a physical examination with lab testing once every assessment round, and questionnaires once (on average) every 1.5 years. Not only medical information but also environmental data are collected to investigate the complex interaction between possible risk factors, chronic diseases, and healthy aging. More details about specific variables that collected in the Lifelines biobank can be found at [www.​lifelines.​nl]. Lifelines has regular examination rounds, in which participants, amongst other exams, fill in questionnaires. The questionnaire includes questions about health status, and the occurrence and prevalence of disease such as lung cancer or CAD. This is the primary way in which information regarding incidence of B3 diseases is obtained within Lifelines [7]. Also, Lifelines is working to create a link with GP data, in order to obtain clinical diagnoses of the participants. From the Lifelines cohort, 12,000 participants aged 45 years and above are invited for the ImaLife substudy (expected age range 45–94 years, and at least 50% women).

The ImaLife substudy is an imaging study with state-of-the-art CT scanning procedures embedded in Lifelines. For an overview of the study, see Fig. 1. The ImaLife study includes Lifelines participants who completed the second round assessment of the Lifelines study, and as part of the second round assessment, completed a lung function test. The cohort invited for lung function testing was unselected (primarily based on scheduling of lung function test slots). However, there was a number of exclusion criteria for lung function testing, related to conditions in which intrathoracic pressure increase need to be prevented, namely: (1) known abdominal hernia (including inguinal, umbilical, incisional), rib fracture, aneurysm, or tuberculosis, (2) recent cardiac catheterization (within 2 weeks prior), (3) recent respiratory infection (within 3 weeks prior), (4) recent (within 6 weeks) surgery for abdominal hernia, ocular surgery, thoracic or abdominal surgery, (5) recent (within 6 weeks) pneumothorax or more than 2 times spontaneous pneumothorax, (6) recent (within 2–6 weeks) pulmonary embolism, (7) recent (within 2–6 weeks) myocardial infarction, (8) indication by general practitioner or medical specialist that no (heavy) exercise was to be performed. Also, participants who were unable to complete the lung function test due to dizziness or hyperventilation were excluded. In total, 32,113 Lifelines participants completed the lung function test (age range 18–94 years, 58.8% female). Of these, all Lifelines individuals aged 45 years and above are invited for the ImaLife study (n = 22,000).

A cut-off of age 45 years is chosen because early B3 stages, as well as positive imaging biomarkers for lung nodules, COPD and CAD are rare below 45 years [24‐26]. This lower cut-off is similar to other large-scale imaging studies (see Table 1). Even though f.e. coronary calcium is less prevalent in women than in men, it is important to have the same lower age cut-off to be able to compare early B3 imaging biomarkers in terms of presence and extent for men and women at the same age.

Participants who are invited to participate in the ImaLife study receive an invitation letter, an information brochure about the ImaLife study including discussion of possible risks and benefits, an informed consent form and an availability form. Participants who return the signed informed consent will be included in the ImaLife study. We exclude pregnant women and individuals who underwent chest CT in the past year. The latter because of the probability of existing clinically potential life-limiting B3 disease. Subsequently, participants receive an appointment to undergo the CT scan from the Lifelines organization. With an expected positive response rate for the invitation 50–60%, the total number of participants for the ImaLife study will be around 12,000. For the primary objective, outcomes will be obtained for all participants, namely quantitative imaging biomarkers on lung nodules, lung density, bronchial wall thickness, and CACS. This allows determination of reference values of the imaging biomarkers of early stages the B3 in this general population by gender and 5 or 10-year age groups.

Study participants undergo a low dose chest CT examination with third-generation dual-source CT (SOMATOM Force, Siemens, Germany). First a CACS acquisition with electrocardiography (ECG) triggering is performed, followed by a low dose chest CT acquisition. The protocol of cardiac CT is based on the acquired experience of the ROBINSCA study [17], while the protocol of low-dose thoracic CT is modified from the low-dose CT protocol in the NELSON study [27]. Both are adapted to the latest generation dual-source CT system. In addition, a subset of 100 participants for each 5-year age/gender category (in total, about 1000 participants) will undergo an additional acquisition with end-expiratory breath hold, in order to determine normal values for expiratory lung density and air trapping. Details of the acquisition and reconstruction parameters are presented in Tables 2 and 3. Radiologic technologists who are trained in the low-dose CT scan protocol are responsible for CT scanning.

Syngo.via software (version VB30) with MM Oncology application (Siemens Healthineers, Germany) will be used for lung analysis and volumetric quantification of lung nodules. If a non-calcified lung nodule is found (100–300 mm³), the participant is invited for a repeat low-dose CT scan of the lungs in inspiration after 3 to 4 months to study the persistence of nodules, and reference values of VDT in the general population. The VDT will be determined basing on the formula as previously reported [28].

Evaluation of COPD will be performed on low dose chest CT scans with inspiratory and expiratory breath hold Bronchial wall thickness and pulmonary volume and density will be analyzed using semi-automated software (Pulmo3D, Siemens Healthineers, and others).

Coronary calcification will be evaluated using semi-automated CACS software (CaSc, Siemens Healthineers, Germany). Agatston score, volume score and mass score will be archived, overall and per artery. Although coronary calcification is a predictor for cardiovascular disease [11, 13, 14], there is no clinical evidence that early intervention in case of higher burden of coronary calcification can reduce cardiovascular risk or improve clinical outcomes so far. Therefore, in view of ethical considerations in the context of ImaLife being an observational population study, the result of CACS will not be reported to study participants and GPs.

Reading of the scans is performed by and/or under the supervision of radiologists (6–12 years of experience in cardiothoracic imaging). Researchers with a background in (technical) medicine perform the measurements of lung nodule volumes, COPD imaging biomarkers, and calcium scoring, after adequate training (educational dataset of at least 50 cases for lung nodules and 50 cases for calcium scoring, with feedback on trainee evaluations).

ImaLife is in principle an observational study. In accordance with the observational nature of the study, information on early imaging biomarkers of COPD or coronary calcium, and lung nodules with small volume, is not reported to the participants. B3 imaging biomarkers are considered early imaging biomarkers of subclinical disease that may or may not lead to clinical expression in the future. Only an incidentally detected, potentially life-shortening and thus clinically relevant finding will be reported to the participant and his/her GP. This finding may require further management if it was not previously known. In case the radiologist notices a potentially clinically relevant finding while reviewing the lung scan, he/she will report this in the digital notification system to Lifelines. The findings that are reported if incidentally detected, are listed in Table 4. In such cases, the GP will be the first to receive the information regarding the potentially clinically relevant finding. Results regarding incidental findings are in principle available within 10 working days after the CT scan and sent to the GP. Participants will receive a letter within 10 working days after the GP receives the result. The participant is advised to contact the GP for more information and referral to a medical specialist, if the incidental finding was not previously known. Taking the medical history into account, the GP will make the final decision to refer the participant to a medical specialist to further investigate the finding. The medical specialist can request a DVD with the (anonymized) CT scan. One of the incidental findings that is reported to participant and GP, is a lung nodule of at least 300 mm³, according to published recommendations [2], as it cannot be ruled out that a nodule with this volume is an early stage of pulmonary malignancy that is assumed to inevitably result in clinical expression. Incidental findings without evident potential clinical relevance will not be reported in view of ethical considerations in this non-screening, observational study in the general population.

With the use of third-generation dual-source CT and modified scan protocols, the effective radiation dose for participants undergoing a baseline ImaLife CT scan will be between 0.6 and 1.8 mSv, depending on weight and length. Additionally, the subset of participants who undergo an expiratory breath hold scan, will receive an extra 0.1 to 1.3 mSv. In case of a follow-up scan (nodule 100–300 mm³, expected in 5–10% of participants), the repeat thorax CT scan in three to four months will result in an additional 0.8 mSv on average. To put these estimates into perspective, the natural background radiation dose in the Netherland is about 2.5 mSv per year [29]. These dose ranges fit within the radiation dose limits for population imaging as described by the Dutch Health Council [30]. The CT system will provide a dose warning when the projected radiation dose for the CT scan will exceed the upper dose limit based on dose-length product. The overall radiation dose will be checked at regular intervals in order to check the actual radiation dose in the scanned population.

Participants are invited by Lifelines and are linked to a new ImaLife participant identification number (ID) that is unrelated to their Lifelines participant ID. The CT scanning and scan evaluation is performed using this specific ImaLife participant ID. Only Lifelines has the key to link pseudonymous imaging biomarkers to the Lifelines database. By this method, the researchers involved in ImaLife who are performing the data evaluation have no link whatsoever to the real identity of the participant. This identity can only be retrieved by Lifelines, which is why communication to the participants or their GP is done by Lifelines. In this setup, Lifelines is acting as a Trusted Third Party thus achieving optimal protection of the privacy of the participants. Pseudonymous scans will be uploaded to a secure virtual research workspace which allows access to imaging software for analyses, connection with research Picture Archiving and Communication System (PACS), and linkage to data storage. Image analyses will be conducted by the trained researchers and radiologists via the ENACT workspace. Registration of all measurement results is made in a dedicated ImaLife data management system. Only validated imaging markers derived from the quantitative image analyses will be added to the Lifelines database.

The percentage of women in Lifelines is relatively high (58.5% versus 50.7% in the entire population of the Northern Netherlands) [23]. In the Lifelines cohort, there is a sufficient prevalence of ever smoking and (other) cardiovascular risk factors, with more than 70% of participants having at least one traditional cardiovascular risk factor [31].

Within the B3, COPD and CAD are most common with 10% prevalence including early stages in the adult population. The expected number of individuals with early stages of COPD and CAD is at least 1000 each, allowing detailed analyses of the research questions. The study is calculated to have more than 95% power to identify the relationship between risk factors with a prevalence of at least 10% in the ImaLife cohort and presence of coronary calcium with an odds ratio of 1.3 or greater, and presence of COPD with an odds ratio of 1.5 or greater, given an alpha error of 5%. It is expected that there will be approximately 900 CVD events and 300 COPD events occurring in a 5 year period, given the incidence rate of CVD and COPD of nearly 15 and 5 per 1000 per year, respectively [32, 33], allowing the analyses of the relationship between imaging biomarkers and outcomes. The prevalence of (early) lung cancer in the general population above 45 years is low, although lung nodules are common (about 50% in (ex-) smokers, based on the NELSON study, and 2.6% with a positive screen test [27]). The prevalence of current smoking in Lifelines is about 25%, which is lower compared to the NELSON study. We hereby estimate that there will be about 120–240 individuals (1–2%) with a positive test that need referral to a pulmonologist and further work-up. This is adequate to answer the research questions for the whole population, but insufficient to perform analyses in subgroups of gender, age, and environmental exposure.

The ImaLife study was approved by the medical ethics committee of the University Medical Center Groningen, the Netherlands. All participants sign an informed consent form prior to the investigational procedures; informed consent forms are stored at the Lifelines organization. The ImaLife study was registered with the Dutch Central Committee on Research Involving Human Subjects (https://​www.​toetsingonline.​nl, Identifier:NL58592.042.16). By implementing a twofold de-identification process decoupling the identity of the participant completely from the ImaLife ID, we are complying with the rules and regulations concerning the protection of privacy (General Data Protection Regulation—GDPR).