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To cite: Benzaquen J,
Hofman P, Lopez S, et al.
Integrating artificial intelligence
into lung cancer screening:
a randomised controlled
trial protocol. BMJ Open
2024;14:e074680. doi:10.1136/
bmjopen-2023-074680
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Received 13 April 2023
Accepted 21 December 2023
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Correspondence to
Dr Jacques Boutros;
​boutros.​j@​chu-​nice.​fr
Integrating artificial intelligence into
lung cancer screening: a randomised
controlled trial protocol
Jonathan Benzaquen,1 Paul Hofman,2 Stephanie Lopez,3 Sylvie Leroy,1,4
Nesrine Rouis,1 Bernard Padovani,5 Eric Fontas,6 Charles Hugo Marquette,1
Jacques Boutros ‍ ‍,1 Da Capo Study Group
ABSTRACT
Introduction Lung cancer (LC) is the most common cause
of cancer-­related deaths worldwide. Its early detection
can be achieved with a CT scan. Two large randomised
trials proved the efficacy of low-­dose CT (LDCT)-­based
lung cancer screening (LCS) in high-­risk populations. The
decrease in specific mortality is 20%–25%.
Nonetheless, implementing LCS on a large scale faces
obstacles due to the low number of thoracic radiologists
and CT scans available for the eligible population and the
high frequency of false-­positive screening results and the
long period of indeterminacy of nodules that can reach up
to 24 months, which is a source of prolonged anxiety and
multiple costly examinations with possible side effects.
Deep learning, an artificial intelligence solution has shown
promising results in retrospective trials detecting lung
nodules and characterising them. However, until now no
prospective studies have demonstrated their importance in
a real-­life setting.
Methods and analysis This open-­label randomised
controlled study focuses on LCS for patients aged 50–80
years, who smoked more than 20 pack-­years, whether
active or quit smoking less than 15 years ago. Its objective
is to determine whether assisting a multidisciplinary team
(MDT) with a 3D convolutional network-­based analysis
of screening chest CT scans accelerates the definitive
classification of nodules into malignant or benign. 2722
patients will be included with the aim to demonstrate
a 3-­month reduction in the delay between lung nodule
detection and its definitive classification into benign or
malignant.
Ethics and dissemination The sponsor of this study is
the University Hospital of Nice. The study was approved
for France by the ethical committee CPP (Comités de
Protection des Personnes) Sud-­Ouest et outre-­mer III
(No. 2022-­A01543-­40) and the Agence Nationale du
Medicament et des produits de Santé (Ministry of Health)
in December 2023. The findings of the trial will be
disseminated through peer-­reviewed journals and national
and international conference presentations.
Trial registration number NCT05704920.
BACKGROUND AND RATIONALE
Lung cancer (LC) is the leading cause of
cancer deaths worldwide,1 with 33 000 occur-
ring in France in 2018.2 After two landmark
Benzaquen J, et al. BMJ Open 2024;14:e074680. doi:10.1136/bmjopen-2023-074680
Protocol
STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒ This is a prospective national multicentre ran-
domised trial assessing the role of a machine-­
learning analysis of chest CT for lung cancer
screening following a long series of promising ret-
rospective studies.
⇒ Insufficient power of this study to show clinical ben-
efit (ie, reduction in lung cancer mortality).
⇒ Absence of a definitive histological diagnosis in all
patients with nodules.
randomised controlled trials, LC screening
(LCS) using low-­ dose CT (LDCT) was
demonstrated to be efficacious. The Amer-
ican National Lung Screening Trial (NLST)3 4
demonstrated a significant 20% reduction in
LC mortality and the Belgo-­ Dutch Nelson
trial5 6 showed that 130 patients needed
to be screened to prevent one LC-­ related
death over 10 years of follow-­up. In addition,
they found a significant all-­ cause decrease
in mortality. In the USA, the United States
Preventive Services Task Force (USPSTF)
recommends screening for adults aged 50–80
years, who have a 20-­pack-­year smoking history
and currently smoke or have quit within the
past 15 years.6 American7 and European8 9
guidelines have paved the way to organised
screening. Nonetheless, LCS in France is still
opportunistic, with France’s national Health
Authority (Haute Authorité de Santé) currently
encouraging pilot LCS programmes using
LDCT.10 A recent Cochrane review paper
including 11 trials11 confirmed a reduction
in LC‐related mortality of LDCT screening
for high‐risk populations. However, this later
review concluded that there exists limited
data on the harm related to overdiagnosis,
false positives and the excess of screening-­
related diagnostic intervention. The Nelson
trial performed growth-­ rate assessment for
indeterminate lung nodules (ILNs), which
reduced the high 24% false positive rate
1
Open access
reported in the NLST to only 2%. Therefore, the current
challenge is to reduce the false positive rate while main-
taining a high sensitivity.
Artificial intelligence (AI) has recently been devel-
oped for medical imaging and deep learning (DL) is
the fastest-­growing approach in this regard, which has
many radiological applications that aid the field, specif-
ically thoracic CT.12 The main purpose of DL for LCS is
to help clinicians detect and classify lung nodules more
accurately and quickly. In the last 15 years, computer-­
aided detection and computer-­ aided diagnosis systems
have therefore been developed extensively.13 Various
DL techniques were retrospectively tested including the
Scale Invariant Feature Transform (SIFT)-­based classifier,
the Support Vector Machine (SVM), multiscale convolu-
tional network (CNN), and the multicrop CNN, which
are impressively accurate, exceeding 95% in some cases
.12 However, the effect on medical decision-­making of the
AI-­based estimated malignancy risk has not been studied
prospectively.14
Therefore, we have planned to prospectively test the
impact of a DL-­trained lung nodule malignancy assess-
ment software ScanRads, on the decision-­ making of
multidisciplinary teams (MDTs). Our working hypothesis
is that AI provides physicians with operational decision
support for LCS candidates who are found to have an ILN
and thus shortens the indeterminacy period.
METHODS
Objectives and study design
The primary objective of this study, namely ‘Da Capo’,
is to compare the ‘time to definitive classification’ of
lung nodules (ie, benign or malignant) detected during
LCS, using two management strategies: ‘multidisciplinary
team-­only’ versus ‘MDT+AI’.
The secondary objectives will include evaluation and
comparison of the diagnostic performance of the two
management strategies for lung nodule detection during
screening, versus the gold standard; comparison of the
rate of invasive procedures between the two management
strategies; evaluation of the medicoeconomic impact of
the two management strategies; and evaluation of the
predictive character four-­marker protein panel for LC
diagnosis at 2 years of follow-­up.15
Da Capo is a prospective national multicentre open-­
label randomised study with two experimental arms: (1)
a standard-­of-­care (SOC) and (2) an interventional arm.
Volunteers will be enrolled in a screening programme
including a consultation, where electronic medical
records will be collected, and current smokers will receive
smoking cessation advice and intervention. Volunteers
will perform a first LDCT (T0). When an ILN is found,
the patient will be randomised into the SOC or interven-
tional arm. If no ILN is found, a second round of LDCT
(T1) will be performed 1 year later and randomisation
takes place again if an ILN is found during this second
round.
2 Benzaquen J, et al. BMJ Open 2024;14:e074680. doi:10.1136/bmjopen-2023-074680
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In the SOC arm, the MDT will classify the nodule as
benign, indeterminate or malignant, and management
will be based on the French society of pulmonary diseases
guidelines for lung nodule management.9
In the interventional arm, the MDT will classify the
nodule as benign, indeterminate or malignant while
knowing the ILN analysis made with ScanRads, expressed
as a malignancy score on a scale of 1 to 10, in ascending
order of the chance of malignancy. In this interventional
arm, nodule management will be based on the same
guidelines as in the SOC arm.9
In France, as required by the ‘haute authorité de santé’,
for thoracic oncology MDTs, a minimum of a thoracic
surgeon, a radiologist, a radiotherapist, an oncologist and
a pulmonologist must attend.
As we did in our previous national study,16 17 the gold
standard to decide on the definitive nature (benign or
malignant) of an ILN will be the histological diagnosis.
In the absence of histology, it is the radiological evolu-
tion of the nodule (stable or increasing in size) at the
end of 24 months of follow-­up that will allow a decision
to be made between malignant and benign. Ground-­
glass nodules stable in size over 24 months of follow-­up
will be categorised as ‘indeterminate’. These nodules will
not be included in the diagnostic performance analysis
as the benignity of stable ground-­glass nodules over 24
months is not guaranteed and therefore does not meet
the defined gold standard. It should be noted that the
classification of a nodule by the MDT may be different
from the real nature of the nodule. In patients without
histology at 24 months of follow-­up, a chest CT will be
systematically done.
A blood sample (two tubes of 10 mL Cell-­Free DNA
BCT, Streck, Omaha, USA) will be taken on a voluntary
basis during the screening and will be sent within 72 hours
to the Nice Hospital Biobank (BB-­0033–00025) (http://
www.biobank-cotedazur.fr/). The non-­exclusive purpose
of this sample will be to evaluate the predictive character
of the appearance of LC at 2 years of follow-­up of a four-­
marker protein panel15
Endpoints
Primary
This includes comparison of time to definitive classifica-
tion of ILN (ie, benign or malignant) between the SOC
arm (MDT-­only) and the interventional arm (MDT+AI)
with the log-­rank test.
If the nodule remains indeterminate at the end of the
study period (24 months), the patient’s data are censored
for analysis. This may occur in particular with ground-­
glass nodules that are not diagnosed as malignant at the
end of follow-­up.
Secondary
Sensitivity, specificity, positive predictive value and nega-
tive predictive value of the two management strategies
will be compared with the gold standard; it also includes
comparison of invasiveness and the complication rate
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BMJ Open: first published as 10.1136/bmjopen-2023-074680 on 13 February 2024. Downloaded from http://bmjopen.bmj.com/ on February 15, 2024 by guest. Protected by copyright.
Figure 1 ScanRad training principle. FP, false positive; TP, true positive.

of diagnostic procedures between the two management Inclusion and procedures

strategies as well as comparative cost-­consequence anal-
ysis of the two management strategies.
ScanRad
ScanRad is a software developed by the Université Côte
d’Azur (Nice, France) that generates, for each nodule,
a malignancy score based on a DL algorithm: 3D CNN
applied to images. The algorithm was trained on CT
scans of 1103 patients from the NLST study, and the
results were presented at the European Congress of
Radiology 2020.18
Its operating principle is based on machine learning.
During a training phase, the algorithm relies on super-
vised learning techniques to estimate a risk of malig-
nancy of pulmonary nodules. For this, a training dataset
consisting of annotated scanners is used. The annotations
consist in particular of the location of the nodule(s) on
the scanner as well as their associated label (ie, ‘malig-
nant’ or ‘benign’). From these data, the training consists
in inferring the particularities, making it possible to detect
a nodule and to characterise its state, in other words, to
estimate whether it is malignant or benign. The medical
device trained in this way can then be used to analyse new
datasets corresponding, for example, to patients moni-
tored for LCS. (figure 1)
Participants who meet all the inclusion criteria and none
of the exclusion criteria will be enrolled by a designated
investigator from each centre, after signing the written
informed consent. Inclusion will be performed online
using the dedicated Da Capo-­secured web-­based platform,
which has been developed to centralise all patient data,
images, LDCT reports, ScanRads analyses of the images
and MDT reports. Only participants with a 6–30 mm lung
nodule found on the first (T0) or second (T1) LDCT
will be randomised. Inclusion and exclusion criteria are
shown in table 1. The study flow diagram is displayed in
figure 2.
Recruitment
Information to the general public about the trial will
be delivered via a public information campaign in the
investigating centres participating in the study, via social
networks and a dedicated web-­based application named
Depiscann (http://depiscann.dacapo-preprod.ascan.​
io/) that allows citizens to test their eligibility for LCS
and via a local advertising campaign among family practi-
tioners and the regional daily press.
Statistical analysis and sample size
We considered that with the SOC strategy, the estimated
median time between the discovery of a solid ILN and the

Table 1 Inclusion and exclusion criteria

Inclusion criteria
► Age between 50 and 80 years
► Active smoker or ex-­smoker who
quit less than 15 years ago
► Smoking history of at least 20
pack-­years
► Capacity to give informed consent ►
► Affiliated to the French social
security
Exclusion criteria
► Clinical signs suggestive of cancer.
► Chest CT within 12 months before enrolment.
► Radiological abnormality requiring follow-­up or additional investigations.
► Health problems considerably limiting life expectancy.
► Health problems limiting the possibility of obtaining a histological diagnosis.
History of neoplasia treated less than 5 years ago, except basal cell carcinoma of
the skin or localised prostate cancer with radical treatment.
► Vulnerable people: adults under guardianship or curatorship.
► Medical and/or psychiatric problems possibly limiting adherence to the study.

Benzaquen J, et al. BMJ Open 2024;14:e074680. doi:10.1136/bmjopen-2023-074680 3

Open access
Figure 2 Flow diagram of the trial. ILN, indeterminate lung nodule; Interv, interventional arm; LDCT, low-­dose chest CT scan;
SOC, standard of care.
definitive classification by MDT into benign or malignant
is 12 months and that the addition of ScanRads analysis
could reduce this median time to 9 months. This 3-­month
improvement interval is not based on trials. First, it is
based on clinical pertinence as evaluated by thoracic
oncologists in France. Also, the 3 months delay is the
usual minimal interval between follow-­up chest CT scans
in patients with a suspicious nodule.
Considering that a two-­sided test has a power of 90%
and a level of significance of 5%, the estimated number
of subjects with a solid ILN is 324 (log-­rank test, nQuery
Advisor, V.9.1). The proportion of subjects with a solid
ILN is estimated at 25% at baseline or on the first year of
follow-­up. Considering that there will be 5% of possible
loss to follow-­ up, it will be necessary to include 2722
volunteers in the study.
In the absence of a decision by the end of 24 months
of follow-­up, patients will be censored on this date. Data
from patients lost to follow-­up or who died during the 24
months of follow-­up after the discovery of a ILN will be
censored at the last date of follow-­up. The time to defin-
itive classification will be described for each group using
Kaplan-­Meier survival curves and compared using the log-­
rank test.
Collection of data and monitoring
The usual demographic data will be recorded and an
electronic case report form will be created. All LDCTs
4 Benzaquen J, et al. BMJ Open 2024;14:e074680. doi:10.1136/bmjopen-2023-074680
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will be anonymised and stored in electronic format for
further centralised analysis. The MDT decision will be
stored along with all follow-­up visits. Access to nomina-
tive data will be strictly reserved to the referring physi-
cian, radiologist and doctors constituting the MDT of the
corresponding centre.
Quality control will be done by clinical research moni-
tors appointed by the sponsor. The nature and frequency
of monitoring will be based on the rate of inclusion.
They will check for the accuracy and completeness
of the case report form entries, source documents and
other trial-­related records. They will verify that written
informed consent was obtained and that the trial follows
the currently approved protocol/amendment(s) in each
centre, with good clinical practice and with the applicable
regulatory requirement(s).
Adverse events
An adverse event (AE) is defined as any untoward medical
occurrence happening during the participation of a
subject in the trial, independently of the relationship with
the study-­related interventions and procedures. A serious
adverse event (SAE) is defined as any AE that results in
death, is life-­threatening, requiring participants’ hospi-
talisation or prolongation of an existing hospitalisation
and that results in persistent or significant disability/inca-
pacity. Each AE must be judged by the investigator and
the sponsor, for assessment of the severity of the causal

link between AE and the procedure and the character
expected or unexpected.
A suspected unexpected severe adverse reaction is an
adverse reaction that is both unexpected (not consistent
with the study-­ related interventions and procedures)
and also meets the definition of an SAE. According to
the law of 9 August 2004 of the Code of Public Health,
any occurrence of an SAE will immediately be reported
to the sponsor. The sponsor will declare SAE likely to be
related to biomedical research to the Ethics Committees
(EC) and to the French ‘Agence Nationale du Medica-
ment et des produits de Santé’ (ANSM) without delay
and no later than 7 calendar days in case of death or life-­
threatening situations and at the latest within 15 days for
the other SAEs.
AEs and SAEs might occur in patients in whom further
investigations will be programmed in case of abnormali-
ties on chest CTs.
Ethics, regulatory clearances and dissemination
The study sponsor is the University Hospital of Nice. The
study was approved for France on 14 December 2022 by
the ethical committee CPP Sud-­Ouest et outre-­mer III
(No. 2022-­A01543-­40) and on 21 December 2022 by the
ANSM (Ministry of Health) in December 2023 (N° IDRCB
2022-­A01543-­40-­A). ​ClinicalTrial.​gov no: NCT05704920.
The findings of the trial will be disseminated through
reviewed journals and national and international
peer-­
conference presentations.
Patient involvement
The patient and members of the public are not involved
so far at any stage of the trial.
Data sharing statement
The individual participant data collected during the trial
will be shared after deidentification. Data will be available
since publication and until 5 years following publication,
for researchers who provide a methodologically sound
proposal.
Milestones
The first study participant will be enrolled on April 2024.
The estimated study completion date is in 2029.
DISCUSSION
AI is a game changer for various medical fields. None-
theless, some of its impressive retrospective results need
to be demonstrated prospectively, which is due to many
methodological issues including trials comparing the
diagnostic performance of DL models and that of health-
care professionals often lacking external validation.19
In addition, the performance and utility of a machine-­
learning algorithm is unpredictable because it depends
on the quality and relevance of the data on which it is
trained.20 One main driver of AI system malfunction,
known as ‘dataset shift’ occurs when a machine-­learning
system underperforms because of a mismatch between
Benzaquen J, et al. BMJ Open 2024;14:e074680. doi:10.1136/bmjopen-2023-074680
Open access
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the training dataset and the data on which it is applied.21
Therefore, until the beginning of the trial, ScanRads will
be enriched by real-­life chest CTs with annotated nodules.
Another interesting observation is that this prospec-
tive trial will explore the clinicians’ behaviour in case of
mismatch between the predictions of the model and their
own clinical judgement, a facet that is seldom explored
in the literature. Will the clinicians be influenced and
dragged into inaccuracies when counting on AI? If that
is the case, we might find a shorter time to definitive clas-
sification of nodules in the interventional arm but with a
lower specificity.
As with all the studies into LCS, this trial will have one
main limitation, that is the absence of a definitive histo-
logical diagnosis in patients.
We hope that by the end of our recruitment, we will be
able to tell if incorporating DL models into MDT discus-
sions can improve their performance and accelerate the
time to nodule classification and therefore to appropriate
decisions.
Author affiliations
1
Department of Pulmonary Medicine and Thoracic Oncology, FHU OncoAge, IHU
RespirERA, Centre Hospitalier Universitaire de Nice, Nice, France
2
Laboratory of Clinical and Experimental Pathology, FHU OncoAge, IHU RespirERA,
Universite Cote d'Azur, Centre hospitalier Universitaire de Nice, Nice, France
3
Université de Nice Sophia Antipolis, Nice, France
4
Institut de Pharmacologie Moléculaire et Cellulaire, Nice, France
5
Department of Radiology, Centre Hospitalier Universitaire de Nice, Nice, France
6
Délégation à la Recherche Clinique et à l’Innovation, Centre Hospitalier
Universitaire de Nice, Nice, France
Contributors JoB, PH, NR, EF, SyL, BP, CHM and JaB designed the study, JaB and
CHM wrote the paper with input from all authors, and StL developed the artificial
intelligence software.
Funding Institut National du Cancer, Conseil Départemental 06, Maskini
Foundation, Fondation du Souffle, AstraZeneca, Award/Grant number is not
applicable.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
Jacques Boutros http://orcid.org/0000-0002-6468-1648
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