Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study)

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While low-dose computed tomography (LDCT) screening can reduce lung cancer mortality, it carries limitations such as high false-positive rates and radiation exposure. These drawbacks highlight the need for more refined screening approaches. Non-invasive biomarkers have been proposed as tools to improve risk stratification before LDCT. This umbrella review will synthesise existing systematic reviews that evaluate the use of biomarkers in guiding pre-diagnostic decision-making for lung cancer screening. A comprehensive search will be conducted across MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Database of Systematic Reviews. Eligible reviews must focus on individuals enrolled in screening before a lung cancer diagnosis and report on biomarker-based risk stratification. Outcomes of interest include lung cancer incidence and diagnostic accuracy metrics. For each included review, we will extract details on study setting, population, quality assessment methods, biomarker characteristics, and key findings, including sensitivity, specificity, and predictive values where available. The results will be summarised to assess the consistency of findings and identify research gaps. This review will provide a comprehensive overview of current evidence on biomarker use in lung cancer screening. It aims to inform future research and support more efficient, accurate, and less harmful screening strategies." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://hrbopenresearch.org/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://hrbopenresearch.org/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://hrbopenresearch.org/articles/8-87/v1", "name": "Protocol for an Umbrella Review of Non-Invasive Biomarkers used to..." } } ] } Home Browse Protocol for an Umbrella Review of Non-Invasive Biomarkers used to... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Cooper K, McGlynn S, Schuele C et al. Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.12688/hrbopenres.14139.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] Kieran Cooper https://orcid.org/0009-0000-9708-7533 1 , Sam McGlynn 1 , Carlotta Schuele 1 , [...] Ricardo Zaidan https://orcid.org/0009-0008-1474-0508 1 , Benjamin Jacob https://orcid.org/0000-0003-1119-064X 1 , Irsoon Hassan 1 , Patrick Redmond 1 Kieran Cooper https://orcid.org/0009-0000-9708-7533 1 , Sam McGlynn 1 , [...] Carlotta Schuele 1 , Ricardo Zaidan https://orcid.org/0009-0008-1474-0508 1 , Benjamin Jacob https://orcid.org/0000-0003-1119-064X 1 , Irsoon Hassan 1 , Patrick Redmond 1 PUBLISHED 06 Aug 2025 Author details Author details 1 PRiCAN, Royal College of Surgeons in Ireland Department of General Practice, Dublin, Leinster, Ireland Kieran Cooper Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing Sam McGlynn Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing Carlotta Schuele Roles: Formal Analysis, Investigation, Writing – Review & Editing Ricardo Zaidan Roles: Conceptualization, Writing – Original Draft Preparation Benjamin Jacob Roles: Conceptualization, Investigation, Methodology, Supervision, Writing – Review & Editing Irsoon Hassan Roles: Conceptualization, Writing – Original Draft Preparation Patrick Redmond Roles: Conceptualization, Project Administration, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Lung cancer remains a leading cause of mortality worldwide, largely due to diagnosis at an advanced stage. While low-dose computed tomography (LDCT) screening can reduce lung cancer mortality, it carries limitations such as high false-positive rates and radiation exposure. These drawbacks highlight the need for more refined screening approaches. Non-invasive biomarkers have been proposed as tools to improve risk stratification before LDCT. This umbrella review will synthesise existing systematic reviews that evaluate the use of biomarkers in guiding pre-diagnostic decision-making for lung cancer screening. A comprehensive search will be conducted across MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Database of Systematic Reviews. Eligible reviews must focus on individuals enrolled in screening before a lung cancer diagnosis and report on biomarker-based risk stratification. Outcomes of interest include lung cancer incidence and diagnostic accuracy metrics. For each included review, we will extract details on study setting, population, quality assessment methods, biomarker characteristics, and key findings, including sensitivity, specificity, and predictive values where available. The results will be summarised to assess the consistency of findings and identify research gaps. This review will provide a comprehensive overview of current evidence on biomarker use in lung cancer screening. It aims to inform future research and support more efficient, accurate, and less harmful screening strategies. READ ALL READ LESS Keywords Umbrella review, Early detection of cancer, Cancer screening, Lung cancer, Biomarkers, Non-invasive biomarkers, Corresponding Author(s) Kieran Cooper ( [email protected] ) Close Corresponding author: Kieran Cooper Competing interests: No competing interests were disclosed. Grant information: This work was supported by the 2025 RCSI Research Summer School for author Carlotta Schuele. No other specific funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2025 Cooper K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Cooper K, McGlynn S, Schuele C et al. Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.12688/hrbopenres.14139.1 ) First published: 06 Aug 2025, 8 :87 ( https://doi.org/10.12688/hrbopenres.14139.1 ) Latest published: 06 Aug 2025, 8 :87 ( https://doi.org/10.12688/hrbopenres.14139.1 ) Introduction Background Lung cancer represents the foremost cause of cancer-related death, prompting significant health concerns both in Ireland and on a global scale 1 . The diagnostic challenge lies in the disease's symptomatology, which often mirrors conditions like chronic obstructive pulmonary disease (COPD), asthma, and bronchitis—factors that can lead to a delayed diagnosis until advanced stages. Consequently, lung cancer is associated with a high mortality rate 1 , 2 underlining the critical need for early detection to improve patient outcomes. By detecting lung cancer when it is still asymptomatic, screening tests offer a significant means to lessen the impact of this concern. The National Lung Cancer Screening Trial (NLCST) in the US currently advocates for low-dose helical computed tomography (LDCT) over chest x-rays (CXR) as the standard 1 , 2 for LCS. It is associated with a decrease of 20% in mortality relative to screening with chest X-rays 3 . Screening facilitates early detection of tumours, lowers mortality, and improves rates of surgical tumour removal 4 . The benefits of screening are coupled with potential harms for both patients and the programmes themselves, such as radiation exposure, overdiagnosis, and false positives 3 , 5 , not to mention accessibility concerns for those who fall outside eligibility parameters 6 . To improve the ratio of benefits to harms, refining the selection criteria for LCS participants is imperative. Given that with LDCT screening the number-needed-to-screen (NNS) is 320 screenings to prevent 1 lung cancer death 3 and the number-needed-to-harm (NNH) is 59 7 , the incorporation of molecular biomarker research into screening protocols may prove crucial to improve their efficacy and reduce the rates of unnecessary invasive procedures. A biomarker allows specific pathological diseases and processes to be identified earlier than the manifestation of symptoms, which may be observed through medical signs or a quantifiable substance. Enzymes, antibodies, receptors, as well as nucleic acids are biological examples of biomarkers 8 . Epithelial cells, bronchoalveolar lavage fluid, sputum, and exhaled breath constitute valuable reservoirs of molecular biomarkers. These sources are relevant to cancer screening as they provide valuable insights into the micro-environment of the tumour cells through non-invasive means. Since biomarkers facilitate the identification of specific diseases and their underlying biological responses before the onset of clinical symptoms, their use in early detection cancer screening could complement existing methods. Their use extends through playing a role in determining eligibility in LCS programmes and in the management of indeterminate nodules 9 . Our research focus will be on non-invasive biomarkers used for LCS, exploring which biomarkers could form part of future screening programs and where future research will be best directed. Existing literature The literature on the use of biomarkers in lung cancer screening is growing, as this field strives to establish more robust and personalized screening programs. While individual biomarkers have shown promise, challenges remain in their application for routine clinical use. A recent review emphasized that while studies involving biomarkers for lung nodule triage have yielded encouraging results, no single biomarker is yet sufficient for widespread use. However, numerous new biomarker candidates have emerged, paving the way for future biomarker combinations 10 . Moreover, blood-based biomarkers, such as a 4-marker protein panel (Pro-SFTPB, CA125, CEA, and CYFRA 21-1), have demonstrated the potential to better individualize the risk of lung cancer and inform screening decisions. This panel, when combined with the PLCOm2012 risk prediction model, has shown improved identification of high-risk individuals compared to traditional screening criteria 11 . Additionally, this study suggests that repeated biomarker measurements may improve sensitivity and early detection, further enhancing lung cancer risk prediction. These findings highlight the importance of ongoing research to refine biomarker strategies and explore their potential in clinical settings. Knowledge gap, rationale and aim This umbrella review recognises the potential role of biomarkers in addressing the limitations and drawbacks of traditional lung cancer screening methods. Biomarkers offer a promising avenue for improving risk stratification, which could result in more precise identification of individuals at higher risk of developing lung cancer, allowing for earlier diagnosis and commencement of treatment. This umbrella review aims to provide a comprehensive summary of the existing literature on the use of biomarkers in pre-diagnostic decision-making for lung cancer screening. Objectives We will complete this aim through the completion of the following specific objectives: 1. to systematically search the published literature and systematic review registries for relevant reviews; 2. to perform a bibliometric analysis of the identified systematic reviews and systematic review protocols (i.e., reviews which used a systematic search), categorising according to review type, publication status, publication year, country of the affiliated institution of the first and last author, the range of years over which the search will occur, and the number of eligible papers included (in the case of completed reviews); 3. to summarise the variation, between identified reviews, in their eligibility criteria relating to the population, intervention/exposure, comparison and outcome; 4. to illustrate the overlap of included primary studies, between completed systematic reviews, by a means appropriate to the number of primary studies (e.g. a network diagram); 5. to narratively summarise the findings of all identified systematic reviews of trials of biomarkers used pre-diagnostically in LCS, and establish whether a new or updated review is needed; 6. to produce a list of non-invasive biomarker tests which have been studied in a cohort of LCS patients, as well as the study methodology and event horizons studied, while acknowledging potential gaps in the evidence where these have been identified in the prior step; 7. to rank the putative performance of the biomarkers tests identified by this umbrella review by calculating the implied positive predictive value (PPV) and implied negative predictive value (NPV) for a range of empirically observed incidence values and event horizons. Methods We will perform the proposed umbrella review in accordance with a recent published guideline 12 , reporting our results in accordance with the Preferred Reporting Items for Overview of Reviews (PRIOR) checklist 13 . The protocol will be pre-registered on the Open Science Framework. Publication type : systematic review registrations with or without meta-analysis will be included. Conference abstracts of systematic reviews will be excluded as they do not contain sufficient information to enable any assessment or analysis. Methodology : Two types of systematic reviews (SRs) will be eligible: (1) SRs of comparative observational studies (i.e., cohort and/or case control studies); (2) SRs of single-arm or multi-arm trials, regardless of randomisation or blinding. For the purposes of this review, a systematic review was defined as “a review that reports: (1) a research question; (2) the sources that were searched, with a reproducible search strategy (naming of databases, naming of search platforms/engines, search date and complete search strategy); (3) inclusion and exclusion criteria; (4) the selection (screening) methods; (5) a critical appraisal and report on the quality/risk of bias of the included studies; (6) information about data analysis and synthesis that allows the reproducibility of the results” 14 . Therefore, our review could include scoping reviews, rapid reviews and relevant narrative reviews utilising a systematic search, in addition to “traditional” systematic reviews with or without meta-analysis. Population : To be eligible for inclusion the search strategy of the systematic review must include patients enrolled in lung cancer screening programmes or patients otherwise explicitly deemed eligible for lung cancer screening. Exposure & Comparison (S/R of observational studies): In systematic reviews of observational studies, the non-invasive biomarker test must be performed before a diagnosis of lung cancer is made. Interventional & Comparison (S/R of trials): The PECO and PICO eligibility criteria, which apply to the search strategy of an SR are given in Table 1 . Table 1. PECO and PICO eligibility criteria. S/R of observational studies S/R of trials Population 1. Patients enrolled in LCS 2. Patients explicitly deemed eligible for LCS Intervention OR Exposure 1. Non-invasive biomarker test, sampled pre-diagnosis, treated as a categorical variable 2. Non-invasive biomarker test, sampled pre-diagnosis, treated as a continuous variable 1. LCS informed by a non-invasive biomarker test Comparison 1. Positive v. Negative test result (if categorical) 2. No grouping of the test result data (if continuous) 1. LCS not informed by a biomarker test 2. No comparator (if single-arm/pilot trial) Outcome Lung cancer incidence 1. Any LCS outcomes (e.g. mortality, late stage diagnosis) 2. Any diagnostic test statistics Search strategy Under three search themes, “non-invasive biomarkers”, “lung cancer”, and “screening”, a systematic search of literature will be conducted, with further manual search for other eligible articles through identified systematic reviews. The search strategy will include MeSH terms and keywords related to these themes. MEDLINE, Cochrane Database of Systematic Reviews, Embase, Scopus, and Web of Science are our databases of choice. A tailored search will be conducted to obtain the most relevant papers for our review. The following terms are included and outlined in Appendix 3: biomarker, lung cancer, screening. The approach to this search will be customized to meet the unique specifications of each database, using filters to locate primary studies as needed. The search will be limited to studies published in English from January 2010 to January 31, 2025. Full details of the search strategy will be outlined on the Open Science Framework. To ensure the integrity of our dataset, we will initiate the data collection phase by employing the (Sr-Accelerator) Deduplicator tool to identify and eliminate any duplicate papers from our initial search outcomes. Our current tailored search strategy focuses on a broad search. To convert our search terms to be applicable amongst each database, terms will be input into Systematic Review Accelerator (Sr-Accelerator) Polyglot Search tool and a result for each database will be used to retrieve search data. Study selection The systematic screening of imported literature will be streamlined using Rayyan, an AI-powered tool designed for efficient literature review management. We will apply the following exclusion criteria: no relevance to biomarker outcomes in LCS, non-human subjects, invasive biomarker/radiomic biomarker methods, and no controls. The selected literature will be directly relevant to the objectives of this umbrella review by strictly adhering to these criteria. The evaluation of titles and abstracts for inclusion in the review will be independently conducted by two reviewers (K.C.; C.S.). In instances of disagreement, a consensus will be sought through discussion. Should these discussions result in an impasse, a third reviewer (S.M.) is designated to arbitrate and make the final decision on the inclusion or exclusion of the paper. Data collection Following the deduplication process, the refined dataset will then be transferred into Rayyan for a screening and annotation phase. This phase will allow labels and notes to be made for all eligible papers post-screening, ensuring an efficient way to note data items. The steps taken to screen studies are summarised in Table 2 . Table 2. Screening algorithm. Step Concept Question Exclusion label 1 Systematic review Is this article a systematic review or meta-analysis? “NotSR” 2 Lung cancer Does this paper deal with lung cancer? “NotLungCancer” 3 Screening Are the patients in the primary studies enrolled in LCS or otherwise explicitly deemed eligible? “NotLCS” 4 Non-invasive Biomarkers Was a non-invasive biomarker test used? “NotBiomarker”, “NotNoninvasive” 5 Sampling time Was the biomarker sampled prior to diagnosis? “NotPrediagnostic” 6 Outcome Was the association between the biomarker test result and lung cancer incidence studied? “NoDiagnosisOutcome” 7 (INCLUDE) If negative to all the above, then include n/a The data extracted from review articles utilising a systematic search of the literature will be the review type, publication type, the range of years over which papers were extracted, the scope of the search in terms of the biomarker characteristics, other eligibility criteria, and the number of eligible papers included reviews. Data items to be extracted are outlined in Table 3 . Table 3. Data items to be extracted. Data Item Description Review Type Type of review (e.g., systematic, narrative, meta-analysis). Publication Type Type of publication (e.g., journal article). Range of Years The range of years over which the papers were extracted. Scope of Search (Biomarker Characteristics) Characteristics of biomarkers included in the systematic search. Other Eligibility Criteria Additional criteria for paper inclusion (e.g., language, study design). Number of Eligible Papers in Reviews Total number of eligible papers included in the reviews. Biomarker type. Biomarkers will be classified into serum tumour markers, exosomes, non-coding RNAs, micro-RNAs, long non-coding RNAs, circular RNAs, autoantibodies, metabolic biomarkers, cell-free DNA, DNA methylation, circulating tumour cells, volatile organic compounds, and combination studies. This classification is based on the recent work by Afridi et al. 10 . We will adapt this classification if biomarkers that do not fit these groups are found in the reviewed studies. Outcomes. In relation to the biomarkers, the outcomes of interest will be: 1. Diagnostic accuracy – evaluation of the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the biomarkers across all studies. This will determine how effectively biomarkers can identify the presence or absence of disease or condition. 2. Clinical Utility - Assessment of the utility of biomarkers in clinical decision-making, including their role in diagnosis, prognosis, treatment planning, and monitoring. This will also involve examining any demonstrated impact on patient outcomes such as treatment response, survival rates, or quality of life. 3. Biomarker Reproducibility and Reliability - Review of the consistency and reproducibility of biomarker results across different populations, study designs, and settings. This includes assessing whether biomarkers yield reliable and consistent results in diverse clinical environments. 4. Cost-Effectiveness - Analysis of the economic implications of utilising specific biomarkers, including cost-benefit analyses where available. This will explore the potential for biomarkers to improve efficiency in healthcare delivery and reduce overall costs, especially in relation to diagnostic and treatment procedures. 5. Integration with Other Diagnostic Tools - Examination of how biomarkers complement or enhance existing diagnostic methods, such as imaging, clinical assessment, or other laboratory tests. This will provide insights into how biomarkers might integrate into multimodal diagnostic strategies. 6. Barriers to Clinical Adoption - Identification of any challenges or barriers to the widespread adoption of biomarkers in clinical practice. This may include issues such as accessibility, cost, regulatory approval, or clinician awareness and training. Risk of bias assessment. The AMSTAR-2 tool 15 will be used to assess the overall confidence in the results of each Systematic Review and Meta Analysis. Confidence in each will be assigned a rating of: high, moderate, low or critically low. The ROB-ME Tool 16 for assessing risk of bias due to missing evidence in a meta-analysis will also be utilised. Data synthesis The data synthesis will follow a systematic approach, integrating the findings from identified systematic reviews to provide a comprehensive overview of biomarkers used in LCS. First, a bibliometric analysis will categorise the systematic reviews and protocols by review type, publication status, publication year, and country of the affiliated institution of the first and last authors. This will also include a summary of the range of years over which the search occurred and the number of eligible papers included in each review. Next, we will examine the variation in eligibility criteria across the reviews, focusing on differences in population, intervention/exposure, comparison, and outcome measures, which may impact the findings and generalisability of the results. To illustrate the overlap in primary studies included across the reviews, a network diagram will be used, highlighting the degree of redundancy in the evidence base. The narrative synthesis will summarize the findings of the systematic reviews related to biomarkers used pre-diagnostically in LCS, assessing the need for a new or updated review in this area. A comprehensive list of non-invasive biomarker tests studied in LCS patient cohorts will be compiled, detailing study methodologies and the event horizons studied, while acknowledging gaps in the evidence identified through the variation analysis. Additionally, the performance of the identified biomarkers will be ranked by calculating their implied positive predictive value (PPV) and negative predictive value (NPV) across various empirically observed incidence values and event horizons. The synthesis will focus on drawing meaningful conclusions regarding the efficacy and utility of biomarkers in clinical practice, highlighting those with the greatest potential for future research and clinical integration. Discussion Summary: This systematic review aims to provide a comprehensive evaluation of the efficacy and utility of non-invasive biomarkers in LCS through the synthesis of existing systematic reviews. By analysing the variation in study methodologies, eligibility criteria, and biomarker performance, this review will offer valuable insights into the current state of biomarker research in LCS. The findings will help identify promising biomarkers, highlight gaps in the evidence base, and assess whether a new or updated review is necessary. Ultimately, the outcomes of this review will inform future research directions and contribute to optimizing the integration of biomarkers into clinical practice for lung cancer early detection. Limitations: This review has several potential limitations. First, the scope of included reviews may be limited by publication bias, with studies reporting positive findings more likely to be published. Additionally, the variability in eligibility criteria, study designs, and biomarker types across the included reviews may introduce heterogeneity, making direct comparisons challenging. The reliance on existing systematic reviews may also overlook recent unpublished or ongoing research, leading to an incomplete representation of the current evidence base. These factors should be considered when interpreting the findings of this review and when planning future research efforts in the field. Implications: The aim of this Umbrella Review is to provide a comprehensive summary of the existing literature on biomarkers in pre-diagnostic decision-making for lung cancer screening. Through a systematic evaluation of relevant systematic reviews and meta-analyses that meet specific PECO criteria, the review will assess the types and characteristics of biomarkers, study populations, methodologies, findings, and recommendations. This review will serve as a valuable resource for clinicians, researchers, and policymakers, offering insights into the role of biomarkers in lung cancer screening. It aims to inform future efforts to enhance screening efficacy, reduce false positives and invasive procedures, minimize radiation exposure, and improve patient experience and cost-effectiveness. Ethical considerations Ethical approval and consent were not required. Data availability No data are associated with this article. Extended data Open Science Framework: Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study), https://doi.org/10.17605/OSF.IO/37EFR 17 This project contains the following underlying data: BioLux_Protocol_PRIORChecklist - PRIOR Checklist for Umbrella Review BioLux_Protocol_PRISMA-P Checklist - PRISMA-P for Systematic Review Protocol BioLux_Protocol_SearchStrategy - Search Strategy for Umbrella Review Data is available under the terms of the Creative Commons Attribution License (CC0 1.0 Universal) Faculty Opinions recommended References 1. Gasparri R, Noberini R, Cuomo A, et al. : Serum proteomics profiling identifies a preliminary signature for the diagnosis of early-stage lung cancer. Proteomics Clin Appl. 2023; 17 (2): e2200093. 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Meza R, Jeon J, Toumazis I, et al. : Evaluation of the benefits and harms of lung cancer screening with low-dose computed tomography: modeling study for the US Preventive Services Task Force. JAMA. 2021; 325 (10): 988–97. PubMed Abstract | Publisher Full Text | Free Full Text 7. Jonas DE, Reuland DS, Reddy SM, et al. : Screening for lung cancer with low-dose computed tomography: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2021; 325 (10): 971–87. PubMed Abstract | Publisher Full Text 8. Henry NL, Hayes DF: Cancer biomarkers. Mol Oncol. 2012; 6 (2): 140–6. PubMed Abstract | Publisher Full Text | Free Full Text 9. Seijo LM, Peled N, Ajona D, et al. : Biomarkers in lung cancer screening: achievements, promises, and challenges. J Thorac Oncol. 2019; 14 (3): 343–57. PubMed Abstract | Publisher Full Text | Free Full Text 10. Afridi WA, Picos SH, Bark JM, et al. : Minimally invasive biomarkers for triaging lung nodules—challenges and future perspectives. Cancer Metastasis Rev. 2025; 44 (1): 29. PubMed Abstract | Publisher Full Text | Free Full Text 11. Irajizad E, Fahrmann JF, Toumazis I, et al. : Biomarker trajectory for earlier detection of lung cancer. EBioMedicine. 2024; 108 : 105377. PubMed Abstract | Publisher Full Text | Free Full Text 12. Belbasis L, Bellou V, Ioannidis JPA: Conducting umbrella reviews. BMJ Med. 2022; 1 (1): e000071. PubMed Abstract | Publisher Full Text | Free Full Text 13. Gates M, Gates A, Pieper D, et al. : Reporting guideline for overviews of reviews of healthcare interventions: development of the PRIOR statement. BMJ. 2022; 378 : e070849. PubMed Abstract | Publisher Full Text | Free Full Text 14. Krnic Martinic M, Pieper D, Glatt A, et al. : Definition of a systematic review used in overviews of systematic reviews, meta-epidemiological studies and textbooks. BMC Med Res Methodol. 2019; 19 (1): 203. PubMed Abstract | Publisher Full Text | Free Full Text 15. Shea BJ, Reeves BC, Wells G, et al. : AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358 : j4008. PubMed Abstract | Publisher Full Text | Free Full Text 16. Page MJ, Sterne JAC, Boutron I, et al. : ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis. BMJ. 2023; 383 : e076754. PubMed Abstract | Publisher Full Text 17. Cooper KMS, Schuele C, Zaidan R, et al. : BioLux Umbrella Review Extended Data. In: Ireland RCoS, editor. Open Science Framework, 2025. Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 06 Aug 2025 ADD YOUR COMMENT Comment Author details Author details 1 PRiCAN, Royal College of Surgeons in Ireland Department of General Practice, Dublin, Leinster, Ireland Kieran Cooper Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing Sam McGlynn Roles: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing Carlotta Schuele Roles: Formal Analysis, Investigation, Writing – Review & Editing Ricardo Zaidan Roles: Conceptualization, Writing – Original Draft Preparation Benjamin Jacob Roles: Conceptualization, Investigation, Methodology, Supervision, Writing – Review & Editing Irsoon Hassan Roles: Conceptualization, Writing – Original Draft Preparation Patrick Redmond Roles: Conceptualization, Project Administration, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This work was supported by the 2025 RCSI Research Summer School for author Carlotta Schuele. No other specific funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 06 Aug 2025, 8:87 https://doi.org/10.12688/hrbopenres.14139.1 Copyright © 2025 Cooper K et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics VIEWS $counts.viewCount downloads Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Cooper K, McGlynn S, Schuele C et al. Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.12688/hrbopenres.14139.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 06 Aug 2025 Views 0 Cite How to cite this report: Van Meerbeeck J. Reviewer Report For: Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.21956/hrbopenres.15540.r49100 ) The direct URL for this report is: https://hrbopenresearch.org/articles/8-87/v1#referee-response-49100 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 20 Aug 2025 Jan Van Meerbeeck , Antwerp University Hospital, Edegem, Belgium Approved VIEWS 0 https://doi.org/10.21956/hrbopenres.15540.r49100 This manuscript is the research protocol for an umbrella 'meta-review of systematic reviews on the use of biomarkers in the selection of participants to lung cancer screening. As such no data are provided. The protocol clearly states its ... Continue reading READ ALL This manuscript is the research protocol for an umbrella 'meta-review of systematic reviews on the use of biomarkers in the selection of participants to lung cancer screening. As such no data are provided. The protocol clearly states its goals, tools and endpoints. The latter could be better defined by attributting target thresholds. The protocol will address all types of biomarkers from all sources: this is a very ambitious endeavour but risks missing those biomarkers for which no systematic review has yet been addressed. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: lung cancer (early) diagnosis and treatment I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Van Meerbeeck J. Reviewer Report For: Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.21956/hrbopenres.15540.r49100 ) The direct URL for this report is: https://hrbopenresearch.org/articles/8-87/v1#referee-response-49100 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 06 Aug 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 1 06 Aug 25 read Jan Van Meerbeeck , Antwerp University Hospital, Edegem, Belgium Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Van Meerbeeck J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 Aug 2025 | for Version 1 Jan Van Meerbeeck , Antwerp University Hospital, Edegem, Belgium 0 Views copyright © 2025 Van Meerbeeck J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript is the research protocol for an umbrella 'meta-review of systematic reviews on the use of biomarkers in the selection of participants to lung cancer screening. As such no data are provided. The protocol clearly states its goals, tools and endpoints. The latter could be better defined by attributting target thresholds. The protocol will address all types of biomarkers from all sources: this is a very ambitious endeavour but risks missing those biomarkers for which no systematic review has yet been addressed. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise lung cancer (early) diagnosis and treatment I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Van Meerbeeck J. Peer Review Report For: Protocol for an Umbrella Review of Non-Invasive Biomarkers used to Guide Pre-diagnostic Decision Making in Lung Cancer Screening (The BIOLUX-Umbrella Study) [version 1; peer review: 1 approved] . HRB Open Res 2025, 8 :87 ( https://doi.org/10.21956/hrbopenres.15540.r49100) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://hrbopenresearch.org/articles/8-87/v1#referee-response-49100 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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