The Roy Castle Lung Cancer Research Programme, Liverpool Lung Project - University of Liverpool

The University of Liverpool requires access to NHS England data for the purpose of the following research project:

The Roy Castle Lung Cancer Research Programme’s Liverpool Lung Project (LLP)

The following is a summary of the aims of the research programme provided by the University of Liverpool:

The Liverpool Lung Project (LLP) has been active since 1997 with participants providing informed consent to their involvement. This observational study investigates differences between those diagnosed with lung cancer and control subjects without lung cancer, or between different lung cancers, to identify opportunities for improving diagnosis or treatment.

The LLP is one of the largest prospective lung cancer case-control and population cohort studies in Europe.

The primary objective of the LLP is to create risk models for lung cancer and identify risk models or “biomarkers” that inform the risk of lung cancer, provide opportunities for early diagnosis, or give information on disease prognosis. The LLP achieves those objectives through a rolling portfolio of projects which are devised in response to publications and developments in science. It is an evolving process as knowledge and research practices develop (e.g. the integration of new analytical methodologies). The research agenda is ultimately determined by the Chief Investigator in conjunction with collaborative researchers at the University of Liverpool. All projects (under the LLP) are interrelated and within the overarching scope of the LLP. Projects require funding and funding applications typically take between 3 and 6 months. Funding for a project is typically for between 1 and 5 years. New ideas for projects within the LLP arise on a constant basis but the process to lead an idea to a funding grant application typically takes 6 months. As part of that process, proposals are referred to a review group including the Principal Investigator, statistical advisor and peer reviewers, and ethical opinion is obtained.

A newer aim is to facilitate the development of Multi-Cancer Early Detection (MCED) tests, including lung cancer, and additionally to provide valuable pre-diagnostic samples collected as part of LLP to researchers studying other diseases.

The following NHS England data will be accessed:

• Hospital Episode Statistics Admitted Patient Care and Outpatients – necessary to provide more detail of cancer diagnostic pathways and treatment, which have a bearing on outcome measures and inform research on potential changes to care pathways influenced by the risk models being researched, and to provide information on co-morbidities (illness arising alongside lung cancer) and predisposing illness (e.g. respiratory diseases that has shown contribute to lung cancer risk) which informs both risk model and allows the LLP to correct outcome measures for confounding factors

• Hospital Episode Statistics for Accident & Emergency were initially obtained, as it is known many lung cancers are diagnosed in this setting, and linked to the epidemiology data already gathered from participants through detailed questionnaires obtained upon recruitment into the study and from their medical notes.;

• Civil Registration Mortality – necessary to identify both lung cancer incidence (within causes of death) and the time from recruitment or treatment until death (all-cause mortality and lung cancer-specific mortality, important measures of health status and outcome);

• Cancer Registration – necessary to identify lung cancer incidence and provide additional information on timing and specific diagnosis of lung cancers (a primary outcome measure of the study) and other cancers (which may be significant confounding factors that must be taken into account during analysis);

• Demographics – necessary to inform the current status of participants (alive, dead or lost to follow-up)

• NDRS Cancer Registration and NDRS Cancer Registration (pre-1995) (added 2024 as unavailable previously through DARS) – providing greater depth of data for cancer diagnosis (e.g. stage and basis of diagnosis), which are highly relevant to studies of early diagnosis, and treatment, which is especially important of analysis of disease outcome.

• NDRS Somatic Molecular Testing (added 2024 as unavailable previously through DARS) – provides definition to the subtype of cancer and how it's related to treatment and therefore outcome analysis.

The LLP are no longer requesting HES data relating to emergency care, as all subsequent diagnosis and treatment data will be within the inpatient and outpatient care, and/or included in Cancer Registration and Civil Registration Mortality data.

Following a substantial ethics amendment (Number 56 approved June 2023), use of cancer data for LLP participants now includes research for multi-cancer early detection; consent was already in place for use of data for other diseases and basic cancer registration and mortality data is already provided. However, this amendment explicitly states the objective of using the data with the aim of identifying biomarkers for multiple different types of cancer (rather than just for lung cancer).

Furthermore, the amendment also clarifies that "gold standard" extended, collated cancer registration data, provided by the National Disease Registration Service (NDRS) and including cancer stage, is also covered, for all cancers. Data on stage at diagnosis is fundamental to early detection and improved diagnosis research.

The level of the data will be:

• Identifiable – necessary to enable linkage of the data with data collected from other sources, including the participants themselves.

Data returned is subsequently linked only via the Member Number (LLP Master Patient Index), as a pseudonymisation key.

The data will be minimised as follows:

• Limited to data for a study cohort of 14,683 participants recruited by the LLP.

Participants were recruited in one of two ways, as a population cohort, or as a hospital cohort. Between 1996 and 2009, the LLP approached over 100,000 people in certain age groups living in certain postcode areas where it was known people were at the highest risk of developing lung cancer and those people were invited to consent to participate. Similar high-risk groups were recruited in the primary care setting from 2005 until 2015. Additionally, the LLP recruited individuals in hospital settings who had been referred with suspected lung cancer or were being treated for lung cancer. Recruitment to the first subset ended in 2015 but recruitment of cancer patients and suspected cancer patients to the ‘case-control’ subset continued.

All 14,683 participants consented to allow access to their medical records. For 11,028, consent also allowed the sharing of their identifying details with NHS England to facilitate data linkage and access. For 3,655, support under Section 251 NHS Act 2006 provides the legal gateway for sharing their identifiers with NHS England.

The University of Liverpool is the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research and aims to improve understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

The funding is provided by multiple organisations (research charities and government agencies, including international bodies). Their role is to provide funding for the research to the University of Liverpool (and collaborating research centres); they also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour. Research staff at the University take part in collaborations with research partners, some of which are from commercial organisations (e.g. Biotech or Pharmaceutical companies: https://liverpoollungproject.org.uk/commercial-collaborations/) and those organisations may provide grants to fund University staff or cover costs associated with provision of samples for joint analysis and publication.

Individuals from the Liverpool Heart & Chest Hospital, Clatterbridge Cancer Centre and Aintree University Hospitals NHS Foundation Trust are core collaborators in the LLP. Their roles are limited to providing additional data and information to the LLP during recruitment or from case note review. If the data collected provide under this Agreement indicates something of note, the University of Liverpool may request the appropriate clinical partner to undertake additional case review. A collaborator from the Wolfson Institute of Preventive Medicine acts in an advisory role on statistical modelling, but does not require access to the primary confidential patient information under this Agreement to do this. None of those individuals have access to the data under this Agreement.

Public and Patient Engagement for the LLP included representation during study design (contributing to the ethically approved protocol) including consideration of patient confidentiality. Ongoing engagement includes representation on local research groups and funding bodies.

Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

The expected outputs of the processing will be:

• Reports for grant awarding bodies will be produced. This will include reports in support of additional funding applications for further analysis, ensuring maximum utility and benefit from the data provided.

• Submissions to peer reviewed internationally renowned oncology, epidemiology and public health journals

• Presentations at major cancer conferences including the World Conference on Lung Cancer, the American Association for Cancer Research Annual Meeting and the National Cancer Research Institute Annual Meeting

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

1. How will the outputs be disseminated or otherwise communicated to relevant recipients?

• The outputs will be communicated to relevant recipients through the following dissemination channels: Journals

• Workshops involving the wider scientific community (as part of conferences)

• Webinars open to members of the University of Liverpool

• Social media (through University and funding body press offices)

• Public reports (e.g. of funding bodies)

• Direct bilateral engagement with research sponsors (e.g. the Roy Castle Lung Cancer Foundation), charitable donors to supporting charities (including participants and family members), interested members of the public, during the course of open days or laboratory visits.

• Co-hosted events, including laboratory tours and charity functions

• Public events, e.g. University public engagement events, open days or laboratory tours

• Posters displayed at scientific conferences and subsequently within the University department

• Patient Information leaflets available at recruitment sites.

• Press/media engagement

• Public promotion of the research, via our own web-pages and those of supporting charities.

• Reports aimed at funding bodies

Outputs are produced and disseminated on an ongoing basis. Current plans include:

• Papers on genetic risk of lung cancer are currently submitted or in the process of being submitted as part of a multinational collaboration (5 papers published 2023).

• LLP risk score linked to a consumer classification for marketing, in order to investigate the best way to contact different risk groups; a publication is currently being prepared (2024).

• Plasma Tumour Markers with diagnostic potential have been tested in lung cancer cases and controls in order to determine their potential utility in early detection. A report to the funding body was prepared (mid 2023) and a paper is being submitted early 2024.

• An investigation of plasma protein markers of lung cancer risk has been performed, with a patent application submitted summer 2022. A paper was published July 2023, with accompanying press release. The results were presented as an invited speaker at an Olink user group meeting September 2023 and as a peer-reviewed poster at a CRUK meeting October 2023. Additional data for two other types of biomarker is available from the same samples, with a similar ranger of publications expected over the next 2 years.

• Press-releases will be used to inform the wider public of the journal articles when they are published and an update on our web-page made.

The Liverpool Lung Project has utilised data from NHS England to develop and validate the LLP risk model. This has been used in the UKLS lung cancer screening trial to identify a cohort of high risk individuals and half of these underwent low dose CT screening, identifying a number of lung cancer (notably the majority of which were early stage an underwent potentially curative surgery).

Similarly the risk model is being used in the Liverpool Healthy Lung Project to identify potential cancer patients in a community setting and has been adopted by similar regional trials and implementation projects. For example, the Liverpool Healthy Lung Check programme, utilised the LLP risk model to identify individuals for LDCT cancer detection. Having scanned 6826 high-risk patients (who would not otherwise have been referred for lung cancer diagnosis), 126 lung cancers were identified; notably most (67%) were early stage disease and suitable for surgery.

Of note, the NHS is funding a NHS Targeted Lung Health Check programme that will use the LLP risk score as part of identification of individuals for a low-dose CT lung cancer screen.

Other yielded benefits include a wide range of publications that have contributed to improved understanding of lung cancer and identified potential biomarkers. These outputs and benefits clearly address the primary aim and support the legitimate interest in utility of NHS England data.

The Liverpool Lung Project has contributed to over 160 research publication, including 30 since 2020.

As mentioned above, the area that has made the largest impact thus far is the LLP lung cancer risk score, used to identify those most likely to benefit from early detection (e.g. lung cancer screening): first published in 2008.

The LLP have now identified a lung cancer mortality reduction by low-dose CT screening in the UKLS lung cancer screening study that is of a similar magnitude as that seen for larger US and European studies and utilised the UKLS data in a meta-analysis of CT screening trials, demonstrating significant long-term gains in lung cancer mortality reduction. Furthermore, the lung cancer-related mortality was significantly better in the low-dose CT arm of UKLS than in the control arm. This was achieved in part by LLP's ability to identify those at greatest risk of lung cancer, using the LLP lung cancer risk score, with UKLS being the first randomised control trial to take this risk-based approach to recruitment.

Additional publications have provided insight into other aspects of lung cancer, e.g.:

Genetic risk - LLP contributed to major Genome Wide Association Studies (GWAS) that identified novel genetic variants contributing to an increased risk of lung cancer and more recently, the OncoArray project looking at genetic risk in the largest cross-cancer genetic analysis to date.

These genetic risk biomarkers provide insights into why cancer occurs more frequently in some individuals, potential targets for preventative medicine and may contribute to lung cancer risk prediction to identify individuals for screening.

DNA mutation - As part of the CURELUNG project and the Clinical Lung Cancer Genome Project, Next Generation Sequencing has revealed the mutational profiles of cancers collected as part of LLP and these have been used to help generate new histo-molecular classifications for different types of lung cancer. Mutations identified in these studies not only provide biological insight, but targets for novel personalised medicines.

Epigenetic Biomarkers - A panel of DNA methylation biomarkers has been shown to improve the accuracy lung cancer diagnosis based on bronchial lavage cytology.

A microRNA signature, detectable in small quantities of biopsy material can differentiate between tumour and normal tissue to help identify NSCLC.

A prognostic DNA methylation signature was identified for stage I Non-Small Cell Lung Cancer.

A study of lncRNA in lung cancer indicated frequent dysregulation in Non-small Cell Lung Cancer.

As well as providing specific insights into potential biomarkers for diagnosis, prognosis and targeted therapy, these publications contribute to the wider understanding of the lung cancer process and by comparison, the biology of cancer in general.

The University of Liverpool requires access to NHS England data for the purpose of the following research project:

The Roy Castle Lung Cancer Research Programme’s Liverpool Lung Project (LLP)

The following is a summary of the aims of the research programme provided by the University of Liverpool:

"The Liverpool Lung Project (LLP) has been active since 1997 with participants providing informed consent to their involvement. This observational study investigates differences between those diagnosed with lung cancer and control subjects without lung cancer, or between different lung cancers, to identify opportunities for improving diagnosis or treatment.

"The LLP is one of the largest prospective lung cancer case-control and population cohort studies in Europe.

"The primary objective of the LLP is to create risk models for lung cancer and identify risk models or “biomarkers” that inform the risk of lung cancer, provide opportunities for early diagnosis, or give information on disease prognosis. The LLP achieves those objectives through a rolling portfolio of projects which are devised in response to publications and developments in science. It is an evolving process as knowledge and research practices develop (e.g. the integration of new analytical methodologies). The research agenda is ultimately determined by the Chief Investigator in conjunction with collaborative researchers at the University of Liverpool. All projects (under the LLP) are interrelated and within the overarching scope of the LLP. Projects require funding and funding applications typically take between 3 and 6 months. Funding for a project is typically for between 1 and 5 years. New ideas for projects within the LLP arise on a constant basis but the process to lead an idea to a funding grant application typically takes 6 months. As part of that process, proposals are referred to a review group including the Principal Investigator, statistical advisor and peer reviewers, and ethical opinion is obtained."

The following NHS England data will be accessed:

• Hospital Episode Statistics Admitted Patient Care and Outpatients – necessary to provide more detail of cancer diagnostic pathways and treatment, which have a bearing on outcome measures and inform research on potential changes to care pathways influenced by the risk models being researched, and to provide information on co-morbidities (illness arising alongside lung cancer) and predisposing illness (e.g. respiratory diseases that has shown contribute to lung cancer risk) which informs both risk model and allows the LLP to correct outcome measures for confounding factors

• Hospital Episode Statistics for Accident & Emergency were initially obtained, as it is known many lung cancers are diagnosed in this setting, and linked to the epidemiology data already gathered from participants through detailed questionnaires obtained upon recruitment into the study and from their medical notes.;

• Civil Registration Mortality – necessary to identify both lung cancer incidence (within causes of death) and the time from recruitment or treatment until death (all-cause mortality and lung cancer-specific mortality, important measures of health status and outcome);

• Cancer Registration – necessary to identify lung cancer incidence and provide additional information on timing and specific diagnosis of lung cancers (a primary outcome measure of the study) and other cancers (which may be significant confounding factors that must be taken into account during analysis);

• Demographics – necessary to inform the current status of participants (alive, dead or lost to follow-up)

The LLP are no longer requesting HES data relating to emergency care, as all subsequent diagnosis and treatment data will be within the inpatient and outpatient care, and/or included in Cancer Registration and Civil Registration Mortality data.

Following a substantial ethics amendment (Number 56 approved June 2023), use of cancer data for LLP participants now includes research for multi-cancer early detection; consent was already in place for use of data for other diseases and basic cancer registration and mortality data is already provided. However, this amendment explicitly states the objective of using the data with the aim of identifying biomarkers for multiple different types of cancer (rather than just for lung cancer).

The level of the data will be:

• Identifiable – necessary to enable linkage of the data with data collected from other sources, including the participants themselves.

Data returned is subsequently linked only via the Member Number (LLP Master Patient Index), as a pseudonymisation key.

The data will be minimised as follows:

• Limited to data for a study cohort of 14,683 participants recruited by the LLP.

Participants were recruited in one of two ways, as a population cohort, or as a hospital cohort. Between 1996 and 2009, the LLP approached over 100,000 people in certain age groups living in certain postcode areas where it was known people were at the highest risk of developing lung cancer and those people were invited to consent to participate. Similar high-risk groups were recruited in the primary care setting from 2005 until 2015. Additionally, the LLP recruited individuals in hospital settings who had been referred with suspected lung cancer or were being treated for lung cancer. Recruitment to the first subset ended in 2015 but recruitment of cancer patients and suspected cancer patients to the ‘case-control’ subset continued.

All 14,683 participants consented to allow access to their medical records. For 11,028, consent also allowed the sharing of their identifying details with NHS England to facilitate data linkage and access. For 3,655, support under Section 251 NHS Act 2006 provides the legal gateway for sharing their identifiers with NHS England.

The University of Liverpool is the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official

authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research and aims to improve understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

The funding is provided by multiple organisations (research charities and government agencies, including international bodies). Their role is to provide funding for the research to the University of Liverpool (and collaborating research centres); they also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour. Research staff at the University take part in collaborations with research partners, some of which are from commercial organisations (e.g. Biotech of Pharmaceutical companies) and those organisations may provide grants to fund University staff or cover costs associated with provision of samples for joint analysis and publication.

Individuals from the Liverpool Heart & Chest Hospital, Clatterbridge Cancer Centre and Aintree University Hospitals NHS Foundation Trust are core collaborators in the LLP. Their roles are limited to providing additional data and information to the LLP during recruitment or from case note review. If the data collected provide under this Agreement indicates something of note, the University of Liverpool may request the appropriate clinical partner to undertake additional case review. A collaborator from the Wolfson Institute of Preventive Medicine acts in an advisory role on statistical modelling, but does not require access to the primary confidential patient information under this Agreement to do this. None of those individuals have access to the data under this Agreement.

Public and Patient Engagement for the LLP included representation during study design (contributing to the ethically approved protocol) including consideration of patient confidentiality. Ongoing engagement includes representation on local research groups and funding bodies.

The expected outputs of the processing will be:

• Reports for grant awarding bodies will be produced. This will include reports in support of additional funding applications for further analysis, ensuring maximum utility and benefit from the data provided.

• Submissions to peer reviewed internationally renowned oncology, epidemiology and public health journals

• Presentations at major cancer conferences including the World Conference on Lung Cancer, the American Association for Cancer Research Annual Meeting and the National Cancer Research Institute Annual Meeting

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

1. How will the outputs be disseminated or otherwise communicated to relevant recipients?

• The outputs will be communicated to relevant recipients through the following dissemination channels: Journals

• Workshops involving the wider scientific community (as part of conferences)

• Webinars open to members of the University of Liverpool

• Social media (through University and funding body press offices)

• Public reports (e.g. of funding bodies)

• Direct bilateral engagement with research sponsors (e.g. the Roy Castle Lung Cancer Foundation), charitable donors to supporting charities (including participants and family members), interested members of the public, during the course of open days or laboratory visits.

• Co-hosted events, including laboratory tours and charity functions

• Public events, e.g. University public engagement events, open days or laboratory tours

• Posters displayed at scientific conferences and subsequently within the University department

• Patient Information leaflets available at recruitment sites.

• Press/media engagement

• Public promotion of the research, via our own web-pages and those of supporting charities.

• Reports aimed at funding bodies

Outputs are produced and disseminated on an ongoing basis. Current plans include:

• Papers on genetic risk of lung cancer are currently submitted or in the process of being submitted as part of a multinational collaboration (5 papers published 2023).

• LLP risk score linked to a consumer classification for marketing, in order to investigate the best way to contact different risk groups; a publication is currently being prepared (2024).

• Plasma Tumour Markers with diagnostic potential have been tested in lung cancer cases and controls in order to determine their potential utility in early detection. A report to the funding body was prepared (mid 2023) and a paper is being submitted early 2024.

• An investigation of plasma protein markers of lung cancer risk has been performed, with a patent application submitted summer 2022. A paper was published July 2023, with accompanying press release. The results were presented as an invited speaker at an Olink user group meeting September 2023 and as a peer-reviewed poster at a CRUK meeting October 2023. Additional data for two other types of biomarker is available from the same samples, with a similar ranger of publications expected over the next 2 years.

• Press-releases will be used to inform the wider public of the journal articles when they are published and an update on our web-page made.

The Liverpool Lung Project has utilised data from NHS England to develop and validate the LLP risk model. This has been used in the UKLS lung cancer screening trial to identify a cohort of high risk individuals and half of these underwent low dose CT screening, identifying a number of lung cancer (notably the majority of which were early stage an underwent potentially curative surgery).

Similarly the risk model is being used in the Liverpool Healthy Lung Project to identify potential cancer patients in a community setting and has been adopted by similar regional trials and implementation projects. For example, the Liverpool Healthy Lung Check programme, utilised the LLP risk model to identify individuals for LDCT cancer detection. Having scanned 6826 high-risk patients (who would not otherwise have been referred for lung cancer diagnosis), 126 lung cancers were identified; notably most (67%) were early stage disease and suitable for surgery.

Of note, the NHS is funding a NHS Targeted Lung Health Check programme that will use the LLP risk score as part of identification of individuals for a low-dose CT lung cancer screen.

Other yielded benefits include a wide range of publications that have contributed to improved understanding of lung cancer and identified potential biomarkers. These outputs and benefits clearly address the primary aim and support the legitimate interest in utility of NHS England data.

The Liverpool Lung Project has contributed to over 160 research publication, including 30 since 2020.

As mentioned above, the area that has made the largest impact thus far is the LLP lung cancer risk score, used to identify those most likely to benefit from early detection (e.g. lung cancer screening): first published in 2008.

The LLP have now identified a lung cancer mortality reduction by low-dose CT screening in the UKLS lung cancer screening study that is of a similar magnitude as that seen for larger US and European studies and utilised the UKLS data in a meta-analysis of CT screening trials, demonstrating significant long-term gains in lung cancer mortality reduction. Furthermore, the lung cancer-related mortality was significantly better in the low-dose CT arm of UKLS than in the control arm. This was achieved in part by LLP's ability to identify those at greatest risk of lung cancer, using the LLP lung cancer risk score, with UKLS being the first randomised control trial to take this risk-based approach to recruitment.

Additional publications have provided insight into other aspects of lung cancer, e.g.:

Genetic risk - LLP contributed to major Genome Wide Association Studies (GWAS) that identified novel genetic variants contributing to an increased risk of lung cancer and more recently, the OncoArray project looking at genetic risk in the largest cross-cancer genetic analysis to date.

These genetic risk biomarkers provide insights into why cancer occurs more frequently in some individuals, potential targets for preventative medicine and may contribute to lung cancer risk prediction to identify individuals for screening.

DNA mutation - As part of the CURELUNG project and the Clinical Lung Cancer Genome Project, Next Generation Sequencing has revealed the mutational profiles of cancers collected as part of LLP and these have been used to help generate new histo-molecular classifications for different types of lung cancer. Mutations identified in these studies not only provide biological insight, but targets for novel personalised medicines.

Epigenetic Biomarkers - A panel of DNA methylation biomarkers has been shown to improve the accuracy lung cancer diagnosis based on bronchial lavage cytology.

A microRNA signature, detectable in small quantities of biopsy material can differentiate between tumour and normal tissue to help identify NSCLC.

A prognostic DNA methylation signature was identified for stage I Non-Small Cell Lung Cancer.

A study of lncRNA in lung cancer indicated frequent dysregulation in Non-small Cell Lung Cancer.

As well as providing specific insights into potential biomarkers for diagnosis, prognosis and targeted therapy, these publications contribute to the wider understanding of the lung cancer process and by comparison, the biology of cancer in general.

The University of Liverpool requires access to NHS England data for the purpose of the following research project:

The Roy Castle Lung Cancer Research Programme’s Liverpool Lung Project (LLP)

The following is a summary of the aims of the research programme provided by the University of Liverpool:

"The Liverpool Lung Project (LLP) has been active since 1997 with participants providing informed consent to their involvement. This observational study investigates differences between those diagnosed with lung cancer and control subjects without lung cancer, or between different lung cancers, to identify opportunities for improving diagnosis or treatment.

"The LLP is one of the largest prospective lung cancer case-control and population cohort studies in Europe.

"The primary objective of the LLP is to create risk models for lung cancer and identify risk models or “biomarkers” that inform the risk of lung cancer, provide opportunities for early diagnosis, or give information on disease prognosis. The LLP achieves those objectives through a rolling portfolio of projects which are devised in response to publications and developments in science. It is an evolving process as knowledge and research practices develop (e.g. the integration of new analytical methodologies). The research agenda is ultimately determined by the Chief Investigator in conjunction with collaborative researchers at the University of Liverpool. All projects (under the LLP) are interrelated and within the overarching scope of the LLP. Projects require funding and funding applications typically take between 3 and 6 months. Funding for a project is typically for between 1 and 5 years. New ideas for projects within the LLP arise on a constant basis but the process to lead an idea to a funding grant application typically takes 6 months. As part of that process, proposals are referred to a review group including the Principal Investigator, statistical advisor and peer reviewers, and ethical opinion is obtained."

The following NHS England data will be accessed:

• Hospital Episode Statistics Admitted Patient Care and Outpatients – necessary to provide more detail of cancer diagnostic pathways and treatment, which have a bearing on outcome measures and inform research on potential changes to care pathways influenced by the risk models being researched, and to provide information on co-morbidities (illness arising alongside lung cancer) and predisposing illness (e.g. respiratory diseases that has shown contribute to lung cancer risk) which informs both risk model and allows the LLP to correct outcome measures for confounding factors

• Hospital Episode Statistics for Accident & Emergency were initially obtained, as it is known many lung cancers are diagnosed in this setting, and linked to the epidemiology data already gathered from participants through detailed questionnaires obtained upon recruitment into the study and from their medical notes.;

• Civil Registration Mortality – necessary to identify both lung cancer incidence (within causes of death) and the time from recruitment or treatment until death (all-cause mortality and lung cancer-specific mortality, important measures of health status and outcome);

• Cancer Registration – necessary to identify lung cancer incidence and provide additional information on timing and specific diagnosis of lung cancers (a primary outcome measure of the study) and other cancers (which may be significant confounding factors that must be taken into account during analysis);

• Demographics – necessary to inform the current status of participants (alive, dead or lost to follow-up)

The LLP are no longer requesting HES data relating to emergency care, as all subsequent diagnosis and treatment data will be within the inpatient and outpatient care, and/or included in Cancer Registration and Civil Registration Mortality data.

The level of the data will be:

• Identifiable – necessary to enable linkage of the data with data collected from other sources, including the participants themselves.

Data returned is subsequently linked only via the Member Number (LLP Master Patient Index), as a pseudonymisation key.

The data will be minimised as follows:

• Limited to data for a study cohort of 14,683 participants recruited by the LLP.

Participants were recruited in one of two ways, as a population cohort, or as a hospital cohort. Between 1996 and 2009, the LLP approached over 100,000 people in certain age groups living in certain postcode areas where it was known people were at the highest risk of developing lung cancer and those people were invited to consent to participate. Similar high-risk groups were recruited in the primary care setting from 2005 until 2015. Additionally, the LLP recruited individuals in hospital settings who had been referred with suspected lung cancer or were being treated for lung cancer. Recruitment to the first subset ended in 2015 but recruitment of cancer patients and suspected cancer patients to the ‘case-control’ subset continued.

All 14,683 participants consented to allow access to their medical records. For 11,028, consent also allowed the sharing of their identifying details with NHS England to facilitate data linkage and access. For 3,655, support under Section 251 NHS Act 2006 provides the legal gateway for sharing their identifiers with NHS England.

The University of Liverpool is the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official

authority vested in the controller;

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research and aims to improve understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

The funding is provided by multiple organisations (research charities and government agencies, including international bodies). Their role is to provide funding for the research to the University of Liverpool (and collaborating research centres); they also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour. Research staff at the University take part in collaborations with research partners, some of which are from commercial organisations (e.g. Biotech of Pharmaceutical companies) and those organisations may provide grants to fund University staff or cover costs associated with provision of samples for joint analysis and publication.

Individuals from the Liverpool Heart & Chest Hospital, Clatterbridge Cancer Centre and Aintree University Hospitals NHS Foundation Trust are core collaborators in the LLP. Their roles are limited to providing additional data and information to the LLP during recruitment or from case note review. If the data collected provide under this Agreement indicates something of note, the University of Liverpool may request the appropriate clinical partner to undertake additional case review. A collaborator from the Wolfson Institute of Preventive Medicine acts in an advisory role on statistical modelling, but does not require access to the primary confidential patient information under this Agreement to do this. None of those individuals have access to the data under this Agreement.

Public and Patient Engagement for the LLP included representation during study design (contributing to the ethically approved protocol) including consideration of patient confidentiality. Ongoing engagement includes representation on local research groups and funding bodies.

The expected outputs of the processing will be:

• Reports for grant awarding bodies will be produced. This will include reports in support of additional funding applications for further analysis, ensuring maximum utility and benefit from the data provided.

• Submissions to peer reviewed internationally renowned oncology, epidemiology and public health journals

• Presentations at major cancer conferences including the World Conference on Lung Cancer, the American Association for Cancer Research Annual Meeting and the National Cancer Research Institute Annual Meeting

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

1. How will the outputs be disseminated or otherwise communicated to relevant recipients?

• The outputs will be communicated to relevant recipients through the following dissemination channels: Journals

• Workshops involving the wider scientific community (as part of conferences)

• Webinars open to members of the University of Liverpool

• Social media (through University and funding body press offices)

• Public reports (e.g. of funding bodies)

• Direct bilateral engagement with research sponsors (e.g. the Roy Castle Lung Cancer Foundation), charitable donors to supporting charities (including participants and family members), interested members of the public, during the course of open days or laboratory visits.

• Co-hosted events, including laboratory tours and charity functions

• Public events, e.g. University public engagement events, open days or laboratory tours

• Posters displayed at scientific conferences and subsequently within the University department

• Patient Information leaflets available at recruitment sites.

• Press/media engagement

• Public promotion of the research, via our own web-pages and those of supporting charities.

• Reports aimed at funding bodies

Outputs are produced and disseminated on an ongoing basis. Current plans include:

• Papers on genetic risk of lung cancer are currently submitted or in the process of being submitted as part of a multinational collaboration (multiple, ongoing throughout 2023).

• A paper on the relationship between lung cancer risk and radon exposure and will be submitted early 2023.

• LLP risk score linked to a consumer classification for marketing, in order to investigate the best way to contact different risk groups; a publication is currently being prepared (2023).

• Plasma Tumour Markers with diagnostic potential have been tested in lung cancer cases and controls in order to determine their potential utility in early detection. A report to the funding body will be prepared (spring 2023) prior to potential presentation at suitable research conference (mid 2023) and submission for peer-reviewed publication (mid 2023).

• An investigation of plasma protein markers of lung cancer risk has been performed, with a patent application submitted summer 2022. A paper for a peer reviewed journal is in preparation (for submission early 2023). Conference presentation and press-release are likely to follow the journal publication (2023).

• Further, similar outputs are planned for other aspects of the same risk biomarker project (2023 onwards).

A press-release will be used to inform the wider public of the journal articles when they are published and an update on our web-page made at the same time.

The Liverpool Lung Project has utilised data from NHS England to develop and validate the LLP risk model. This has been used in the UKLS lung cancer screening trial to identify a cohort of high risk individuals and half of these underwent low dose CT screening, identifying a number of lung cancer (notably the majority of which were early stage an underwent potentially curative surgery).

Similarly the risk model is being used in the Liverpool Healthy Lung Project to identify potential cancer patients in a community setting and has been adopted by similar regional trials and implementation projects. For example, the Liverpool Healthy Lung Check programme, utilised the LLP risk model to identify individuals for LDCT cancer detection. Having scanned 6826 high-risk patients (who would not otherwise have been referred for lung cancer diagnosis), 126 lung cancers were identified; notably most (67%) were early stage disease and suitable for surgery.

Of note, the NHS is funding a NHS Targeted Lung Health Check programme that will use the LLP risk score as part of identification of individuals for a low-dose CT lung cancer screen.

Other yielded benefits include a wide range of publications that have contributed to improved understanding of lung cancer and identified potential biomarkers. These outputs and benefits clearly address the primary aim and support the legitimate interest in utility of NHS England data.

The Liverpool Lung Project has contributed to over 160 research publication, including 40 since 2019.

As mentioned above, the area that has made the largest impact thus far is the LLP lung cancer risk score, used to identify those most likely to benefit from early detection (e.g. lung cancer screening): first published in 2008.

The LLP have now identified a lung cancer mortality reduction by low-dose CT screening in the UKLS lung cancer screening study that is of a similar magnitude as that seen for larger US and European studies and utilised the UKLS data in a meta-analysis of CT screening trials, demonstrating significant long-term gains in lung cancer mortality reduction. Furthermore, the lung cancer-related mortality was significantly better in the low-dose CT arm of UKLS than in the control arm. This was achieved in part by LLP's ability to identify those at greatest risk of lung cancer, using the LLP lung cancer risk score, with UKLS being the first randomised control trial to take this risk-based approach to recruitment.

Additional publications have provided insight into other aspects of lung cancer, e.g.:

Genetic risk - LLP contributed to major Genome Wide Association Studies (GWAS) that identified novel genetic variants contributing to an increased risk of lung cancer and more recently, the OncoArray project looking at genetic risk in the largest cross-cancer genetic analysis to date.

These genetic risk biomarkers provide insights into why cancer occurs more frequently in some individuals, potential targets for preventative medicine and may contribute to lung cancer risk prediction to identify individuals for screening.

DNA mutation - As part of the CURELUNG project and the Clinical Lung Cancer Genome Project, Next Generation Sequencing has revealed the mutational profiles of cancers collected as part of LLP and these have been used to help generate new histo-molecular classifications for different types of lung cancer. Mutations identified in these studies not only provide biological insight, but targets for novel personalised medicines.

Epigenetic Biomarkers - A panel of DNA methylation biomarkers has been shown to improve the accuracy lung cancer diagnosis based on bronchial lavage cytology.

A microRNA signature, detectable in small quantities of biopsy material can differentiate between tumour and normal tissue to help identify NSCLC.

A prognostic DNA methylation signature was identified for stage I Non-Small Cell Lung Cancer.

A study of lncRNA in lung cancer indicated frequent dysregulation in Non-small Cell Lung Cancer.

As well as providing specific insights into potential biomarkers for diagnosis, prognosis and targeted therapy, these publications contribute to the wider understanding of the lung cancer process and by comparison, the biology of cancer in general.

Over the years, the Roy Castle Lung Cancer Research Programme (RCLCRP) has been at the forefront of research in early detection of lung cancer.

The RCLCRP’s Liverpool Lung Project (LLP) is a large, prospective, population-based study of lung cancer, together with a case-control cohort collecting data and samples from diagnostic and surgical patients.

The University of Liverpool requires follow-up data for the Liverpool Lung Project, a longitudinal observational study aimed at identification of risk factors and biomarkers that will allow improved early detection and treatment of lung cancer and respiratory disease. Hence it is a task in the public interest, leading to improved understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

The University of Liverpool is the sole Data Controller and also processes the data for this study. No other organisations process the data for this purpose. The study protocol names core collaborators from the Wolfson Institute of Preventive Medicine, Liverpool Heart & Chest Hospital, Clatterbridge Cancer Centre and Aintree University Hospitals NHS Foundation Trust. These individuals do not have any bearing on the data under this Agreement. Their roles are limited to providing data and information to the LLP. If the data collected by the University of Liverpool indicates something of note, the University of Liverpool will request the appropriate clinical partner to undertake a case review. A collaborator from the Wolfson Institute of Preventive Medicine has additionally acting in an advisory role on statistical modelling but has not required access to the data under this Agreement to do this.

The LLP, which is based at the University of Liverpool, includes one of the largest collections of data and samples in the UK and Europe from a population cohort at high risk of lung cancer (approximately 9000 individuals from the Liverpool area, recruited whilst healthy 1996 - 2014). By determining which of these individuals get lung cancer, the LLP can perform scientific studies to integrate risk factors into its ongoing risk prediction modelling research, building on the LLP Lung Cancer Risk Model.

The LLP also includes patients referred for “query lung cancer” investigations and continues to recruit these patients at different times in their diagnostic pathway. In addition, the LLP recruits patients undergoing treatment for lung cancer, predominantly surgical patients. To date the LLP has recruited over 4000 of these diagnostic and surgical patients into its “hospital cohort”, the majority at the Liverpool Heart & Chest Hospital (LHCH).

Samples and data from these patients, together with controls from the population cohort, are primarily used in scientific studies to discover new genetic risk factors and potential biomarkers – i.e. substances that can be measured in samples of blood, sputum or tissue that can tell something useful about the disease.

This may be, for example, differences or changes in a patient’s DNA (mutation or methylation) when detected in biopsy samples or blood, which can potentially indicate the person’s risk of lung cancer, can confirm the presence of lung cancer or indicate what type of lung cancer a person has (which may lead to personalised treatment).

The aims of the LLP are to:

i. determine factors associated with the risk of lung cancer (to help identify ways to select people for screening);

ii. identify better ways to detect lung cancer earlier (to improve diagnosis, which will save lives);

iii. to better understand the biology of lung cancer (leading to potential new therapies);

iv. identify ways of selecting patients for the best current and future treatment;

v. contribute to improving patients' outcome and ultimately save lives.

To this end, a documentation of previous history of diseases is essential for exploring the impact of comorbidity on lung cancer. A rich source of data for exploring the potential role of comorbidity in lung cancer pathogenesis is the Hospital Episode Statistics (HES).

The University of Liverpool requires NHS Digital data to inform the current status (alive/dead) and dates and causes of death; this data specifically informs the prime question of the study, helping to identify both lung cancer incidence (within causes of death) and the time from recruitment or treatment until death (all-cause mortality, an important measure of health status and outcome). This data needs to be provided for specific individuals (by linkage through NHS number with verification by month/year of birth) to allow appropriate data for personal level risk model development and evaluation. As a longitudinal study, it is important to follow as many subjects as possible until death, so the LLP plan to ask for data on all available years (including retention of data already provided and incremental updates). Although the study was based in Liverpool, recruited individuals at local hospitals included those who had travelled from out of area for specialist care and individuals may have moved subsequent to recruitment, therefore all UK data is requested. Alternative methods of assessing mortality status (e.g. re-contacting individuals) would be either more intrusive (likely to cause harm/distress), less informative or incomplete.

NHS Digital will also provide cancer registry data, identifying all cancer diagnosis, with dates (where available). The justification for this is broadly the same as for cause of death, but this data provides additional information on timing and specific diagnosis of lung cancers (a primary outcome measure of the study) and other cancers (which may be significant confounding factors that must be taken into account during analysis). Again, this must be at the individual level, for all dates available and all geographical areas to provide the best dataset of personalised prognostic prediction. Alternative methods (e.g. case-note review) are likely more intrusive, less efficient and incomplete.

Health Episode Statistics (HES) for inpatient and outpatient care data is required to provide more detail of cancer diagnostic pathways and treatment, which have a bearing on outcome measures and informs research on potential changes to care pathways influenced by the risk models being researched. However, the main reason for accessing this data is that information is provided on co-morbidities (illness arising alongside lung cancer) and predisposing illness (e.g. respiratory diseases that has shown contribute to lung cancer risk); this data will help inform both risk model and allow the LLP to correct outcome measures for confounding factors. The same considerations on individualised data, data timing, geographical spread and alternative methods apply.

Data requirements have been limited to those health-related events that directly impact the aims of the study and address the public interest justification. The LLP has collected patient identifying information used for linkage directly from subjects; for quality assurance purposes, they ask that NHS number, name, DoB, gender and postcode are returned by NHS Digital (to ensure unequivocal matching). Data returned is subsequently linked only via the Member Number (LLP Master Patient Index), as a pseudonymisation key.

The LLP previously obtained the HES data (inpatient, outpatient and emergency care) of consented participants from NHS Digital and linked this to the epidemiology data already gathered from the participant through detailed questionnaires obtained upon recruitment into the study and from their medical notes.

The LLP are no longer requesting HES data relating to emergency care, as all subsequent diagnosis and treatment data will be within the inpatient and outpatient care.

In addition, all information gathered is linked to the mortality data obtained from NHS Digital to study the mortality patterns of participants in the LLP.

Data obtained from Cancer Registries via NHS Digital is also linked to such participants in order to record date of cancer incidence and type of cancer.

The study investigators are not aware of any moral or ethical issues raised by the proposed dissemination of NHS Digital data to the University of Liverpool, nor the dissemination of the aggregated study results to the wider public. The study investigators are unaware of any risk of potential harm to the public by the dissemination. The potential for harm has been assessed by University of Liverpool (Data Protection and Study Sponsor), by NRES ethical approval and by the Confidentiality Advisory Group (CAG).

Safeguards are in place that protect the interests of the data subject, these have been judged as proportional to the substantial public interest, including approval by CAG under section 251 of the NHS Act 2006 (which together with informed consent also safeguards the common law duty of confidentiality). Safeguards include physical and operational barriers protecting privacy and allowing processing of personal identifying and sensitive data only by staff contractually obliged to fulfil the requirements set out by the University of Liverpool Data Protection Policy, compliant with all laws and approvals.

Processing activity and storage of personal and sensitive (special category) data is limited according to best practice (both in terms of scope and timing), but recognising that longitudinal studies require long-term data linkage and that research studies require anonymised and pseudonymised data to be available for a significant amount of time. These issues have been explained to participants during informed consent and are covered in a publicly accessible Privacy Notice.

The research project is part of a wider international effort to address the critical issue of earlier detection of lung cancer, required to address the single largest cause of cancer-related mortality. As such, the University of Liverpool share processed data with other research groups, but do so in a controlled way, bound by Data Sharing Agreements that confer the same level of adherence to protecting the rights of individuals involved in research and specifically covered by informed consent of subjects. All such data shared is either aggregate (as in publication), anonymous, or pseudonymised (such that additional data provided by the collaboration can be added to the sum of knowledge about subjects within the LLP, but not allowing others to link data and risk re-identification – this includes measures to suppress rare events).

The work undertaken by the LLP is funded by multiple organisations (research charities and government agencies, including international bodies). Their role is to provide funding for the research to the University of Liverpool (and collaborating research centres); they also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour.

As a University using health data for research purposes, “task in the public interest” is the legal basis for processing personal and sensitive information under the General Data Protection Regulations [Article 6 (1) (e)]. As the study is for scientific research purposes, the University also rely on Article 9 (2) (j) of the General Data Protection Regulation.

All outputs are aggregate with small number suppressed in line with the HES analysis guide.

Outputs will include;

1. Reports:

Reports for grant awarding bodies will be produced. This will include reports in support of additional funding applications for further analysis, ensuring maximum utility and benefit from the data provided.

2. Publications:

It is anticipated that the analysis from this study will be included in internationally renowned oncology, epidemiology and public health journals. Publications will be prepared for 2020 and subsequent years. Journals for consideration will include:

Thorax

Journal of Thoracic Oncology

Lung Cancer

British Journal of Cancer

Cancer epidemiology, biomarkers & prevention

Scientific Reports

Oncology Letters

Nature Genetics

Nature Communications

Lancet

Lancet Oncology

More information on publications can be found on the on the web-pages of the Principal Investigator, Prof. John Field:

https://www.liverpool.ac.uk/translational-medicine/staff/john-field/publications/

3. Presentations:

In accordance with previous years it is expected that presentations will be given at major cancer conferences. These presentations will provide dissemination of results from studies primarily to scientific audiences.

Conferences are expected to include:

World Conference on Lung Cancer

American Association for Cancer Research Annual Meeting

National Cancer Research Institute Annual Meeting

Results will also be presented to lay audiences at outreach events and during laboratory tours or via web-pages (including University of Liverpool and funding bodies, e.g. Roy Castle Lung Cancer Foundation).

The Liverpool Lung Project has utilised data from NHS Digital to develop and validate the LLP risk model. This has been used in the UKLS lung cancer screening trial to identify a cohort of high risk individuals and half of these underwent low dose CT screening, identifying a number of lung cancer (notably the majority of which were early stage an underwent potentially curative surgery).

Similarly the risk model is being used in the Liverpool Healthy Lung Project to identify potential cancer patients in a community setting and has been adopted by similar regional trials and implementation projects.

Of note, the NHS is funding a NHS Lung Health Check programme that will use the LLP risk score as part of identification of individuals for a low-dose CT lung cancer screen.

Other yielded benefits include a wide range of publications that have contributed to improved understanding of lung cancer and identified potential biomarkers. These outputs and benefits clearly address the primary aim and support the legitimate interest in utility of NHS Digital data.

The Liverpool Lung Project has contributed to over 150 research publication, including 11 during 2019 (Further details in Outputs section).

As mentioned above, the area that has made the largest impact thus far is the LLP lung cancer risk score, used to identify those most likely to benefit from early detection (e.g. lung cancer screening): first published in 2008 (Cassidy et al., British Journal of Cancer 2008, 98(2):270-6); subject to validation 2012 (Raji et al., Annals of Internal Medicine 2012, 157(4):242-50); used in UKLS (Field et al., Health Technol Assess 2016, 20(40):1-146; Field et al., Thorax 2016, 71(2):161-70), used in local implementation LHLP (Ghimire et al., Lung Cancer 2019, 134:66-71) and has recently been updated to provide more accurate assessment (publication due this year) to be used in NHS Targeted Lung Health Checks.

Additional publications have provided insight into other aspects of lung cancer, e.g.:

Genetic risk - LLP contributed to major Genome Wide Association Studies (GWAS) that identified novel genetic variants contributing to an increased risk of lung cancer (McKay et al., Nature Genetics 2008, 40(12), 1404-1406) and more recently, the OncoArray project looking at genetic risk in the largest cross-cancer genetic analysis to date (McKay et al., Nature Genetics 2017, 49(7):1126-1132 ). These genetic risk biomarkers provide insights into why cancer occurs more frequently in some individuals, potential targets for preventative medicine and may contribute to lung cancer risk prediction to identify individuals for screening.

DNA mutation - As part of the CURELUNG project and the Clinical Lung Cancer Genome Project, Next Generation Sequencing has revealed the mutational profiles of cancers collected as part of LLP and these have been used to help generate new histo-molecular classifications for different types of lung cancer (Fernandez-Cuesta et al., Nature Communications 2014, 5:3518 , Clinical Lung Cancer Genome Project & Network Genomic Medicine, Science Translational Medicine 2013, 5(209):209ra153). Mutations identified in these studies not only provide biological insight, but targets for novel personalised medicines.

Epigenetic Biomarkers - A panel of DNA methylation biomarkers has been shown to improve the accuracy lung cancer diagnosis based on bronchial lavage cytology (Nikolaidis et al., Cancer Research 2012, 72(22):5692-5701).

A microRNA signature, detectable in small quantities of biopsy material can differentiate between tumour and normal tissue to help identify NSCLC (Bediaga et al., British Journal of Cancer 2013, 109(9):2404-2411).

A prognostic DNA methylation signature was identified for stage I Non-Small Cell Lung Cancer (Sandoval et al., Journal of Clinical Oncology 2013, 31(32):4140-4147)

A study of lncRNA in lung cancer indicated frequent dysregulationin Non-small Cell Lung Cancer (Acha-Sagredo et al., British Journal of Cancer 2020, 122(7):1050-1058)

As well as providing specific insights into potential biomarkers for diagnosis, prognosis and targeted therapy, these publications contribute to the wider understanding of the lung cancer process and by comparison, the biology of cancer in general.

Over the years, the Roy Castle Lung Cancer Research Programme (RCLCRP) has been at the forefront of ground breaking research in early detection of lung cancer.

The RCLCRP’s Liverpool Lung Project (LLP) is a large, prospective, population-based study of lung cancer, together with a case-control cohort collecting data and samples from diagnostic and surgical patients.

The University of Liverpool requires follow-up data for the Liverpool Lung Project, a longitudinal observational study aimed at identification of risk factors and biomarkers that will allow improved early detection and treatment of lung cancer and respiratory disease. Hence it is a task in the public interest, leading to improved understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

The University of Liverpool is the sole Data Controller and also processes the data for this study. No other organisations process the data for this purpose. The study protocol names core collaborators from the Wolfson Institute of Preventive Medicine, Liverpool Heart & Chest Hospital, Clatterbridge Cancer Centre and Aintree University Hospitals NHS Foundation Trust. These individuals do not have any bearing on the data under this Agreement. Their roles are limited to providing data and information to the LLP. If the data collected by the University of Liverpool indicates something of note, the University of Liverpool will request the appropriate clinical partner to undertake a case review. A collaborator from the Wolfson Institute of Preventive Medicine has additionally acting in an advisory role on statistical modelling but has not required access to the data under this Agreement to do this.

The LLP, which is based at the University of Liverpool, includes one of the largest collections of data and samples in the UK and Europe from a population cohort at high risk of lung cancer (approximately 9000 individuals from the Liverpool area, recruited whilst healthy 1996 - 2014). By determining which of these individuals get lung cancer, the LLP can perform scientific studies to integrate risk factors into its ongoing risk prediction modelling research, building on the LLP Lung Cancer Risk Model.

The LLP also includes patients referred for “query lung cancer” investigations and continues to recruit these patients at different times in their diagnostic pathway. In addition, the LLP recruits patients undergoing treatment for lung cancer, predominantly surgical patients. To date the LLP has recruited over 4000 of these diagnostic and surgical patients into its “hospital cohort”, the majority at the Liverpool Heart & Chest Hospital (LHCH).

Samples and data from these patients, together with controls from the population cohort, are primarily used in scientific studies to discover new genetic risk factors and potential biomarkers – i.e. substances that can be measured in samples of blood, sputum or tissue that can tell something useful about the disease.

This may be, for example, differences or changes in a patient’s DNA (mutation or methylation) when detected in biopsy samples or blood, which can potentially indicate the person’s risk of lung cancer, can confirm the presence of lung cancer or indicate what type of lung cancer a person has (which may lead to personalised treatment).

The aims of the LLP are to:

i. determine factors associated with the risk of lung cancer (to help identify ways to select people for screening);

ii. identify better ways to detect lung cancer earlier (to improve diagnosis, which will save lives);

iii. to better understand the biology of lung cancer (leading to potential new therapies);

iv. identify ways of selecting patients for the best current and future treatment;

v. contribute to improving patients' outcome and ultimately save lives.

To this end, a documentation of previous history of diseases is essential for exploring the impact of comorbidity on lung cancer. A rich source of data for exploring the potential role of comorbidity in lung cancer pathogenesis is the Hospital Episode Statistics (HES).

The University of Liverpool requires NHS Digital data to inform the current status (alive/dead) and dates and causes of death; this data specifically informs the prime question of the study, helping to identify both lung cancer incidence (within causes of death) and the time from recruitment or treatment until death (all-cause mortality, an important measure of health status and outcome). This data needs to be provided for specific individuals (by linkage through NHS number with verification by month/year of birth) to allow appropriate data for personal level risk model development and evaluation. As a longitudinal study, it is important to follow as many subjects as possible until death, so the LLP plan to ask for data on all available years (including retention of data already provided and incremental updates). Although the study was based in Liverpool, recruited individuals at local hospitals included those who had travelled from out of area for specialist care and individuals may have moved subsequent to recruitment, therefore all UK data is requested. Alternative methods of assessing mortality status (e.g. re-contacting individuals) would be either more intrusive (likely to cause harm/distress), less informative or incomplete.

NHS Digital will also provide cancer registry data, identifying all cancer diagnosis, with dates (where available). The justification for this is broadly the same as for cause of death, but this data provides additional information on timing and specific diagnosis of lung cancers (a primary outcome measure of the study) and other cancers (which may be significant confounding factors that must be taken into account during analysis). Again, this must be at the individual level, for all dates available and all geographical areas to provide the best dataset of personalised prognostic prediction. Alternative methods (e.g. case-note review) are likely more intrusive, less efficient and incomplete.

Health Episode Statistics (HES) for inpatient and outpatient care data is required to provide more detail of cancer diagnostic pathways and treatment, which have a bearing on outcome measures and informs research on potential changes to care pathways influenced by the risk models being researched. However, the main reason for accessing this data is that information is provided on co-morbidities (illness arising alongside lung cancer) and predisposing illness (e.g. respiratory diseases that has shown contribute to lung cancer risk); this data will help inform both risk model and allow the LLP to correct outcome measures for confounding factors. The same considerations on individualised data, data timing, geographical spread and alternative methods apply.

Data requirements have been limited to those health-related events that directly impact the aims of the study and address the public interest justification. The LLP has collected patient identifying information used for linkage directly from subjects; for quality assurance purposes, they ask that NHS number, name, DoB, gender and postcode are returned by NHS Digital (to ensure unequivocal matching). Data returned is subsequently linked only via the Member Number (LLP Master Patient Index), as a pseudonymisation key.

The LLP previously obtained the HES data (inpatient, outpatient and emergency care) of consented participants from NHS Digital and linked this to the epidemiology data already gathered from the participant through detailed questionnaires obtained upon recruitment into the study and from their medical notes.

The LLP are no longer requesting HES data relating to emergency care, as all subsequent diagnosis and treatment data will be within the inpatient and outpatient care.

In addition, all information gathered is linked to the mortality data obtained from NHS Digital to study the mortality patterns of participants in the LLP.

Data obtained from Cancer Registries via NHS Digital is also linked to such participants in order to record date of cancer incidence and type of cancer.

The study investigators are not aware of any moral or ethical issues raised by the proposed dissemination of NHS Digital data to the University of Liverpool, nor the dissemination of the aggregated study results to the wider public. The study investigators are unaware of any risk of potential harm to the public by the dissemination. The potential for harm has been assessed by University of Liverpool (Data Protection and Study Sponsor), by NRES ethical approval and by the Confidentiality Advisory Group (CAG).

Safeguards are in place that protect the interests of the data subject, these have been judged as proportional to the substantial public interest, including approval by CAG under section 251 of the NHS Act 2006 (which together with informed consent also safeguards the common law duty of confidentiality). Safeguards include physical and operational barriers protecting privacy and allowing processing of personal identifying and sensitive data only by staff contractually obliged to fulfil the requirements set out by the University of Liverpool Data Protection Policy, compliant with all laws and approvals.

Processing activity and storage of personal and sensitive (special category) data is limited according to best practice (both in terms of scope and timing), but recognising that longitudinal studies require long-term data linkage and that research studies require anonymised and pseudonymised data to be available for a significant amount of time. These issues have been explained to participants during informed consent and are covered in a publicly accessible Privacy Notice.

The research project is part of a wider international effort to address the critical issue of earlier detection of lung cancer, required to address the single largest cause of cancer-related mortality. As such, the University of Liverpool share processed data with other research groups, but do so in a controlled way, bound by Data Sharing Agreements that confer the same level of adherence to protecting the rights of individuals involved in research and specifically covered by informed consent of subjects. All such data shared is either aggregate (as in publication), anonymous, or pseudonymised (such that additional data provided by the collaboration can be added to the sum of knowledge about subjects within the LLP, but not allowing others to link data and risk re-identification – this includes measures to suppress rare events).

The work undertaken by the LLP is funded by multiple organisations (research charities and government agencies, including international bodies). Their role is to provide funding for the research to the University of Liverpool (and collaborating research centres); they also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour.

All outputs are aggregate with small number suppressed in line with the HES analysis guide.

Outputs will include;

1. Reports:

Reports for grant awarding bodies will be produced. This will include reports in support of additional funding applications for further analysis, ensuring maximum utility and benefit from the data provided.

Annual Report(s) for funding body, e.g. The Roy Castle Lung Cancer Foundation (RCLCF) to identify type of research undertaken, recruitment statistics and specific research developments within the funding period. This report is seen by the Roy Castle Lung Cancer Foundation Executive and Scientific Committee and its Trustees to inform policy and quantify the benefit of future funding of the research programme.

2. Publications:

It is anticipated that the analysis from this study will be included in internationally renowned oncology, epidemiology and public health journals. Publications will be prepared for 2017, 2018, 2019 and 2020. Journals for consideration will include;

Thorax

Journal of Thoracic Oncology

Lung Cancer

British Journal of Cancer

Cancer epidemiology, biomarkers & prevention

Scientific Reports

Oncology Letters

Nature Genetics

Nature Communications

Lancet

Lancet Oncology

More information on past publications can be found on the study website - http://www.liverpoollungproject.co.uk/publications

3. Presentations:

In accordance with previous years it is expected that presentations will be given at major cancer conferences. These presentations will provide dissemination of results from ongoing studies of LLP Risk Modelling, Methylation, MicroRNA, Sequencing, etc.

Conferences are expected to include:

World Conference on Lung Cancer

American Association for Cancer Research Annual Meeting

National Cancer Research Institute Annual Meeting

The Liverpool Lung Project has utilised data from NHS Digital to develop and validate the LLP risk model. This has been used un the UKLS lung cancer screening trial to identify a cohort of high risk individuals and half of these underwent low dose CT screening, identifying a number of lung cancer (notably the majority of which were early stage an underwent potentially curative surgery). Similarly the risk model is being used in the Liverpool Healthy Lung Project to identify potential cancer patients in a community setting and has been adopted by similar trials and implementation projects. Other yielded benefits include a wide range of publications that have contributed to improved understanding of lung cancer and identified potential biomarkers. These outputs and benefits clearly address the primary aim and support the legitimate interest in utility of NHS Digital data.