NHS Digital Data Release Register - reformatted

University Hospital Southampton NHS Foundation Trust projects

• Risk Of Aneurysm Rupture Study
• Phase I Vaccine Study of pEVAC-PS
• Study Title: A randomised, phase II UK multi-centre study to determine reactogenicity and immunogenicity of booster vaccination against ancestral and novel variants of SARS-CoV-2 Short Title: Evaluating COVID-19 Vaccine Boosters (Covboost)
• MR278 - Study of Birth Cohort from Hertfordshire
• MR1175 - PROSPECTIVE STUDY OF OUTCOMES IN SPORAIC VERSUS HEREDITARY BREAST CANCER (POSH)
• MR1449 - FLuid Optimisation in Emergency LAparotomy (FLO-ELA) trial: NIHR HTA ref 15/80/54
• The Distribution of Highly Sensitive Troponin in the Critically Unwell and Associated Mortality
• Fractional Flow Reserve Derived from Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain: FORECAST TRIAL
• Mortality and HES data at 12 months for patients in the CHARIOT study (BMJ 2019;364:l729)
• Project 10

370 data files in total were disseminated unsafely (information about files used safely is missing for TRE/"system access" projects).

---

🚩 University Hospital Southampton NHS Foundation Trust was sent multiple files from the same dataset, in the same month, both with optouts respected and with optouts ignored. University Hospital Southampton NHS Foundation Trust may not have compared the two files, but the identifiers are consistent between datasets, and outside of a good TRE NHS Digital can not know what recipients actually do.

Risk Of Aneurysm Rupture Study — DARS-NIC-334745-L4J6P

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable, Yes (Section 251 NHS Act 2006)

Legal basis: Health and Social Care Act 2012 - s261(5)(d); National Health Service Act 2006 - s251 - 'Control of patient information'., National Health Service Act 2006 - s251 - 'Control of patient information'.

Purposes: No (NHS Trust)

Sensitive: Sensitive, and Non-Sensitive

When:DSA runs 2022-12-12 — 2023-12-11 2023.03 — 2024.11.

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Civil Registrations of Death
2. Hospital Episode Statistics Admitted Patient Care (HES APC)
3. Demographics
4. Maternity Services Data Set (MSDS) v1.5
5. Maternity Services Data Set (MSDS) v2

Objectives:

University Hospitals Southampton NHS Foundation Trust (UHS) requires access to NHS Digital data for the purpose of the following research project:
Risk Of Aneurysm Rupture Study

The following is a summary of the aims of the research project provided by UHS:

“Unruptured intracranial aneurysms (a bulge in a blood vessel caused by a weakness in the blood vessel wall) are a common condition (3% of the population) which have life threatening implications for the patient if they rupture. Patients who suffer a ruptured brain aneurysm are frequently left dead or severely disabled. Decision making around the prophylactic treatment (a prophylactic is a medication, or a treatment designed and used to prevent a disease from occurring) of unruptured brain aneurysms is part of routine practice in neurosurgery and the results from this study will help predict a patient's risk of rupture and thus guide the clinical management of these patients towards the lowest risk option possible.

"The aim of this study is therefore to describe the natural history of unruptured intracranial aneurysms (UIA) in Great Britain. The condition is of great clinical importance because of the high prevalence of UIA with diagnoses continually increasing due to the widespread availability of imaging and increasing age of the population. Despite this there are great uncertainties as to how to manage patients with UIA. The management is fundamentally based on the balance of risk between treatment and the natural history of the UIA. However, as described above, our understanding of UIA natural history is flawed and thus currently patients are potentially being subjected to the risk of over- or under-treatment. The possible negative outcomes from either unnecessary prophylactic aneurysm treatment or from subarachnoid haemorrhage (SAH), include stroke, long term disability and death, and thus it is crucial that patients are provided with most accurate information possible for their treatment decisions.”

The following NHS Digital data will be accessed:
• Hospital Episode Statistics (HES) Admitted Patient Care – necessary to provide information on hospital admissions for aneurysm rupture events or elective aneurysm treatment. Rupture is the primary outcome and elective treatment is a censoring event. Aneurysm rupture produces severe symptoms and thus nearly all ruptures who don't die immediately will get admitted to hospital.
• Civil Registration Mortality – necessary for two purposes. The date of death for those patients who die from causes other than aneurysm rupture will be a censoring event when a patient’s aneurysm rupture risk stops. The cause of death is important to identify patients who had an aneurysm rupture and died without attending hospital and thus will not be included in APC data.

The data are required to establish a new prediction model based on risk factors that have not previously been considered or recorded in the initial cohort data collection. There are many more risks which have not been considered which could impact UIA’s.

The level of the data will be identifiable because UHS holds the identifying details. However, the data that will be disseminated by NHS Digital will contain no identifying details.

The data will be minimised as follows:
- Limited to data for a study cohort identified by neurosurgery units and renal units in the UK and then sent to UHS – Eligibility:
- Age 18 years or older.
- Intracranial intradural unruptured aneurysm.
- Confirmed on angiogram (a type of X-ray used to check blood vessels).
- Diagnosis of UIA between January 2006 and December 2020.
- Limited to data between 2006 and latest availability (expected 2023).
- Limited to conditions relevant to the study identified by specific ICD or OPCS codes.
- Limited to pseudonymised data only when accessed for analysis purposes.

UHS 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 produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The funding comes from multiple sources. Current funders include:
• National Institute for Health and Care Research (NIHR) – Funding is in place until 31/07/2024.
• Smile4Wessex – Funding is in place until 14/06/2024.
• Polycystic Kidney Charity – Funding is in place until 30/09/2022.
Funding to continue the work described will be sought on an ongoing basis.

University of Oxford are not accessing the data but acting in an advisory capacity to the study.

A Public and Patient Information and Engagement (PPIE) group was consulted regarding the collection of the data for the purposes described above.

The PPIE group is a forum for patients and carers with SAH and UIA established in 2001 and available to over 2000 patients during that time. It runs bi-monthly meetings with typically 30 to 50 participants and has been on social media since 2016 (187 current members). Recurrently the main themes at Q&A are around anxiety, and more specifically “what is the risk I will have a haemorrhage”. These observations of patient concerns were mirrored closely in an analysis of online discussion groups of patients with UIA5.

The team therefore organised a workgroup to discuss UIA research (advertised via the support group page on social media) where it was confirmed that better decision making on aneurysm treatment is the main concern for patients, but patients do not want their management to be randomised and therefore a Random Controlled Trial (RCT) is unlikely to succeed. Consequently, a better understanding of the natural history of UIA was deemed the top priority and that long term, ideally lifetime risks, are what is relevant to patients. On the basis of this the team designed an observational natural history rather than an attempt at an RCT.

The Trial Management Group (TMG) includes a PPIE lead who is a patient representative with personal experience of both unruptured and ruptured aneurysms. They attend all TMG meetings. The team are also holding PPI meetings every 6 months which will be open to stakeholders from across the UK. These meetings will help guide secondary analysis and the methods of disseminating the results so that they are tailored to the lay audience’s needs.

Expected Benefits:

The findings of this research study are expected to contribute to evidence-based decision-making for policymakers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study.

The use of the data could:

• help the system to better understand the health and care needs of populations.
• lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.
• advance understanding of regional and national trends in health and social care needs.
• advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions.
• inform planning health services and programmes, for example to improve equity of access, experience and outcomes.
• inform decisions on how to effectively allocate and evaluate funding according to health needs.
• provide a mechanism for checking the quality of care. This could include identifying areas of good practice to learn from, or areas of poorer practice which need to be addressed.
• support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

Members of the public with an unruptured intra-cranial aneurysm are currently subject to both physical and psychological harm. The former due to over/undertreatment from using inaccurate data and the latter due to anxiety from having to make treatment decision using unreliable data. It is hoped that by disseminating the results to clinicians and the public both sources for harm will be abated.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Outputs:

The expected outputs of the processing will be:

• A report of findings to the study sponsor and the Confidentiality Advisory Group on an annual basis.
• Submissions to peer reviewed journals, these will be journals catering for neurosurgery and stroke clinicians.
• Presentations at neurosurgery and stroke conferences including the British Neurovascular Group.
• Publication of dashboards: The study has a dedicated website (www.roarstudy.co.uk) where summary data may be published at the end of the study.
• Production of a tool which will be made available. A patient specific online risk calculator will be published on the study website. This calculator will use processed data from the ROAR study in order to provide a specific rupture risk for the patient based on the clinical characteristics they enter. This is available free of charge.

The outputs will not contain NHS Digital 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.

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

1. Journals
2. Workshops involving Patient feedback groups
3. Social media
4. Industry newsletters
5. Participant newsletters

It is expected that the primary outcomes will be answered by July 2024 at which point the manuscripts for publication will be prepared, if not already published. The online patient calculator will also be ready for launch by this date. Dissemination at conferences will be an ongoing process throughout the study and beyond 2024 as further secondary analysis is conducted.

Processing:

Neurosurgery units and renal units in the UK will send the study cohort to UHS. UHS will then transfer data to NHS Digital. The data will consist of identifying details (specifically NHS Number, full name, Date of Birth, Postcode, and a unique person ID) for the cohort to be linked with NHS Digital data.

NHS Digital data will provide the relevant records from the Hospital Episode Statistics (HES) Admitted Patient Care dataset and Civil Registration Mortality dataset to UHS.

The data will contain no direct identifying data items but will contain a unique person ID which can be used to link the data with other record level data already held by the recipient.

Following processing of the NHS Digital data, the study team will contact the specific neurosurgery unit and use the person centred ID for the unit to review any radiology imaging and/or discharge summaries to confirm that the rupture event identified in HES APC matches and there are no errors in their coding. This process will only use the date of potential rupture. Only the specific neurosurgery unit will receive any contact related to their original data collection. Data will not be shared cross units.

The data will be stored on servers at University Southampton NHS Foundation Trust.

The data will be accessed either onsite at the premises of UHS or by authorised personnel via remote access. The data will always remain on the servers at UHS.

Personnel are prohibited from downloading or copying data to local devices.

The data will not leave England and Wales at any time.

Access is restricted to employees or agents of UHS who have authorisation from the Chief Investigator.

All personnel accessing the data have been appropriately trained in data protection and confidentiality.

The data will be linked at person record level with data obtained from UK neurosurgery units and renal units supplied by UHS.

Further linkage will be required to the Patient Episode Database for Wales (PEDW). Since the data from NHS Digital data covers England and Wales, individuals may appear in both. PEDW results will also be pseudonymised with a person centred ID. Any PEDW admissions and NHS Digital deaths relating to the same patient will be linked by the Study team using the person centred ID.

The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset for analysis.

Researchers from the UHS will process the data for the purposes described above.

---

Phase I Vaccine Study of pEVAC-PS — DARS-NIC-594129-R0M3W

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (NHS Trust)

Sensitive: Non-Sensitive

When:DSA runs 2021-12-09 — 2022-12-08

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Permission to Contact

Objectives:

This Data Sharing Agreement authorises the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials. The data will be processed on behalf of the Data Controller, University Hospital Southampton NHS Foundation Trust, by NHS Digital as a Data Processor for the purpose of supporting recruitment to participate in a COVID-19 vaccine trial being run by University Hospital Southampton NHS Foundation Trust.

The following provides background to the Permission to Contact (PtC) Service:

NHS Digital has agreed to work in partnership with the National Institute of Health Research (NIHR) to build and host a first of type online Permission to Contact Service on nhs.uk where members of the public can register their details and give their permission to be contacted by researchers working on NIHR approved UK coronavirus vaccine trials about participating in those trials. This PtC Service, which is called “Sign Up to be Contacted about Coronavirus Vaccine Studies” on the nhs.uk website was launched as a national service on 20th July 2020.

This Service enables participants to:
• Provide permission for NHS Digital to share an individual’s details provided through the Service with the researchers undertaking COVID-19 UK vaccine trials for the purposes of researchers contacting that individual about taking part in those trials.
• Provide their permission to be contacted by NHS Digital about progress and outcomes from COVID-19 vaccine studies and in relation to the development of the PtC Service, including to inform them of opportunities to participate in other types of health research.

The data collected from individuals who sign up includes sufficient information to achieve the following purposes:
• Matching potentially eligible participants to eligibility criteria provided by the vaccine trials for their specific studies. This data will comprise of age, sex, geographic locations, type of employment, and a number of health questions e.g. about whether they have long-term health conditions.
• Providing relevant details of potentially eligible participants which have been obtained through the Service to researchers. This will allow the researchers to contact the participants with a view to discussing their taking part in a trial and if so, to obtain their further permission to take part in the trial.
• NHS Digital will provide access to the information obtained from individuals through the Service via the existing Data Access Request Service (DARS) process available to researchers working on UK COVID-19 vaccine trials sponsored by the National Institute of Health Research. The Service will only provide researchers with the data collected directly from individuals themselves through the Service.

The contact details will be used to invite potentially eligible individuals to undertake an eligibility assessment and, if eligible, to give informed consent to participate in this trial. NHS Digital, as Data Processor acting on behalf of University Hospital Southampton NHS Foundation Trust, will be sending the communication to eligible participants.

This request relates specifically to a vaccine trial. The full title for this study is "A phase I safety, immunogenicity and dose escalation study of the candidate pan-Sarbeco Coronavirus vaccine pEVAC-PS in SARS-CoV-2 immunised UK healthy adult volunteers"

Vaccines that protect against multiple related viruses have been developed using DIOSynVax technology. This broadly protective approach is needed for Coronaviruses such as SARS-CoV-2 and SARS-CoV, two of numerous related viruses that have the potential to cause future outbreaks from zoonotic reservoirs, where pathogens (viruses in this case) in animals can cross over to humans. The pEVAC-PS vaccine was designed to induce highly focussed immune responses against key neutralising antibody targets of the Sarbeco Coronaviruses in order to protect against SARS-CoV-2, SARS-CoV and potential future outbreaks of related Coronaviruses. pEVAC-PS is well-positioned to boost existing, licenced SARS-CoV-2 vaccines and to induce SARS-CoV antibody responses.

DNA code for the virus protein components to be part of the vaccine are processed before being made as plasmid DNA for the vaccine. Plasmid DNA is different to human chromosomal DNA that carries the human genetic code. This vector is a flexible vaccine platform and any combination of antigens can be inserted to produce a different vaccine. DIOSynVax antigen inserts are engineered to be readily transferable to other scale-able vaccine delivery systems, such as Adenoviral or mRNA vectors

This study will use an established needleless vaccine delivery technology to assess the optimal dose required to trigger patients’ cells to produce the antigens, be recognised by participants immune systems and boost antibody titres that will induce durable protection against SARS-CoV-2 and SARS-CoV. Combined with needleless and powerless (no electrical source required) delivery, this platform offers a safe, widely deployable pan-Sarbeco Coronavirus vaccine for large scale immunisation programmes.

The aim is to recruit a total of 36 participants. The initial mailout will aim for around four / five times the number of potential participants to be recruited and therefore the estimate is for around 180 individuals to be contacted.

The GDPR legal basis for processing the data is GDPR Article 6 (1) (e). Processing is carried out by an NHS organisation in the public interest, in order to understand and help this patient population in the future. Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data is necessary for archiving for research purposes. Data minimisation process is being followed and only data that is required specifically for the purposes of this study has been requested, to protect the rights of the data subjects.

NHS Digital is content that the purpose of this study is the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials, thus clearly demonstrating that the study purpose is research into public health and therefore providing benefit to health and social care in the UK.

However, in the interests of full transparency, it is noted here that the data will be used in support of the development of a commercial vaccine(s) that, should the research prove successful, will generate income for the commercial companies involved, to cover the development costs of the vaccine and also generate profit for that organisation.

This study includes the involvement of the following commercial companies:
- DiosCoVax: is the grant lead and owner of Dios platform technology IP.
- Symbiosis: this is the product manufacturer for this study.
- PHARMExcel: this organisation is the Contract Research Organisation for this study.

None of the above organisations will have access to NHS Digital record-level data. As a result, none of these organisations are considered a Data Controller or Data Processor for this agreement.

Expected Benefits:

The primary benefit of using the data will be to allow researchers to identify a suitable cohort and recruit them quickly into the vaccine trial – thus reducing the overall time to recruit into the trials. This is expected to accelerate the delivery of an effective vaccine to treat individuals to manage the COVID-19 outbreak and to save lives.

It is expected that this will reduce the burden on research staff in identifying and contacting potential clinical trial participants. It is anticipated this will also support the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research and then produce a coronavirus vaccine and make sure one is made available to the public as quickly as possible.

Outputs:

The information from NHS Digital will be used to facilitate contact with individuals who are potentially eligible and who have indicated willingness to potentially participate in studies/trials of COVID-19 vaccines.

This is expected to result in individuals entering the trials screening process with a view to them participating in the trial with fully informed consent.

The main results from this trial are expected to inform development of a safe and effective multiple vaccine combination against COVID 19.

Processing:

NHS Digital will extract a list of patients meeting the following criteria, where that criteria can be ascertained using the NHS Digital COVID-19 Vaccine Research Registry:

Personal Information:

Age
Location
Sex at birth
Ethic Group


Health questions:

Flu Jab
Diabetes
Asthma
Lung conditions
Liver conditions
Heart conditions
Cancer treatment
Bleeding disorders
Immune system disorders

The inclusion and exclusion criteria noted above is based on the information provided by members on the NHS Digital COVID-19 Vaccine Research Registry (where it can be obtained from this dataset ), and is not collected from other NHS data sources. Some of the above inclusion and exclusion criteria will be used by the recruitment sites during the Screening phase. During the screening phase, the study team will use further inclusion and exclusion criteria in order to further filter the potential participants to undertake consent and discuss the trial.

NHS Digital will identify the required number of individuals within the NHS Digital COVID-19 Vaccine Research Registry meeting the relevant criteria and will extract their names, email addresses and postcodes.

It is not known in advance how many individuals meeting the above criteria will respond to the invitation. The process may be repeated, with amended numbers, depending on the level of response. This could encompass any part of the criteria, depending on how the recruitment progresses.

NHS Digital will contact individuals in the subset inviting them to participate within the trial using ethically approved text provided by University Hospital Southampton NHS Foundation Trust. The communication will remind the individuals of the background of the Permission to Contact programme and give them the opportunity to state that they do not wish to be contacted again. The communication will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information. Individuals will not be contacted multiple times under this Agreement and NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of consent. Furthermore, in order to ensure that NHS Digital are able to update the registry with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information.

Individual trial recruitment sites will supply NHS Digital with details of those who have signed up to take part in their trial so that NHS Digital can suitably capture this information within the NHS Digital COVID-19 Vaccine Research Registry. All data that flows to NHS Digital in this context falls under the controllership of the Data Controller, regardless of whether they themselves are specifically involved in the processing of that data as it flows to NHS Digital. For this agreement there may be flows from each individual recruitment site. Once the data is received at NHS Digital then NHS Digital become controller for that data in their existing role as Data Controller of the NHS Digital COVID-19 Vaccine Research Registry.

No other processing of the data will take place and the data will not be linked with information from any other sources.

University Hospital Southampton NHS Foundation Trust will not have access to any of the data being disseminated by NHS Digital under this agreement.

---

Study Title: A randomised, phase II UK multi-centre study to determine reactogenicity and immunogenicity of booster vaccination against ancestral and novel variants of SARS-CoV-2 Short Title: Evaluating COVID-19 Vaccine Boosters (Covboost) — DARS-NIC-456088-R0H0V

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c)

Purposes: No, Yes (NHS Trust)

Sensitive: Non-Sensitive

When:DSA runs 2021-05-11 — 2022-05-10

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Permission to Contact

Objectives:

This Data Sharing Agreement authorises the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials. The data will be processed on behalf of the data controller, University Hospital Southampton NHS Foundation Trust, by NHS Digital as a data processor for the purpose of supporting recruitment to participate in a COVID-19 vaccine trial being run by University Hospital Southampton NHS Foundation Trust.

The following provides background to the Permission to Contact (PtC) Service:

NHS Digital has agreed to work in partnership with the National Institute of Health Research (NIHR) to build and host a first of type online Permission to Contact (PtC) Service on nhs.uk where members of the public can register their details and give their permission to be contacted by researchers working on NIHR approved UK coronavirus vaccine trials about participating in those trials. This PtC Service, which is called “Sign Up to be Contacted about Coronavirus Vaccine Studies” on the nhs.uk website was launched as a national service on 20th July 2020.

This Service enables participants to:
• Provide permission for NHS Digital to share an individual’s details provided through the Service with the researchers undertaking COVID-19 UK vaccine trials for the purposes of researchers contacting that individual about taking part in those trials.
• Provide their permission to be contacted by NHS Digital about progress and outcomes from CV19 vaccine studies and in relation to the development of the PtC Service, including to inform them of opportunities to participate in other types of health research.

The data collected from individuals who sign up includes sufficient information to achieve the following purposes:
• Matching potentially eligible participants to eligibility criteria provided by the vaccine trials for their specific studies. This data will comprise of age, sex, geographic locations, type of employment, and a number health question e.g. about whether they have long-term health conditions.
• Providing relevant details of potentially eligible participants which have been obtained through the Service to researchers. This will allow the researchers to contact the participants with a view to discussing their taking part in a trial and if so, to obtain their further permission to take part in the trial.
• NHS Digital will provide access to the information obtained from individuals through the Service via the existing Data Access Request Service (DARS) process available to researchers working on UK COVID-19 vaccine trials sponsored by the National Institute of Health Research. The Service will only provide researchers with the data collected directly from individuals themselves through the Service.

The contact details will be used to invite potentially eligible individuals to undertake an eligibility assessment and, if eligible, to give informed consent to participate in this trial. NHS Digital, as data processor acting on behalf of University Hospital Southampton NHS Foundation Trust will be sending the email to eligible participants.

This request relates specifically to a vaccine trial. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines.

As of April 2021 the MHRA in the UK has granted Regulation 174 approval for emergency use of 3 vaccines for protection against COVID-19 in the UK, including the mRNA vaccines BNT162b2 (Pfizer) the mRNA-1273 (Moderna) vaccine, and the chimpanzee adenovirus vector vaccine ChAdOx1-nCov19 (AstraZeneca/Oxford). So far over 33 million people in the UK have received at least one dose of either BNT162b2, ChAdOx1-nCov19, or mRNA-1273. Annual or seasonal booster vaccination for high risk groups is thought likely to be required, especially in light of the emergence of new variants of the SARS-CoV-2 virus. There is concern from studies in South Africa and elsewhere that existing vaccines may be less effective against these variant strains. It is currently unclear which booster vaccine schedule will provide the best safety profile and immune responses, according to which vaccine was originally given. The Joint Committee for Vaccination and Immunisation and UK Chief Medical Officers need timely information regarding the effects of different booster vaccinations on the safety profile and immunity to previous and new variants of SARS-CoV-2 in order to inform national policy for autumn and winter 2021. This study will determine the immune responses provided from different booster vaccinations given a minimum of 3 months from the 2nd dose of an initial course of AstraZeneca/Oxford or Pfizer vaccines.

The aim for this application is to recruit a total of 2886 participants.

The initial mailout will aim for around four / five times the number of potential participants to be recruited and therefore the estimate is for around 14430 individuals to be contacted.

Expected Benefits:

The primary benefit of using the data will be to recruit participants for the clinical study/trial in a manner which:
• Enables individuals to volunteer in advance to participate in COVID-19 vaccine trials as an alternative to other potentially more intrusive mechanisms, e.g. sharing data with researchers about individuals under section 251 consents or COPI notices, which although lawful is initially less transparent.
• Allows researchers to identify a suitable cohort and recruit them quickly into the vaccine trials – thus reducing the overall time to recruit into the trials and to accelerate the delivery of an effective vaccine to treat individuals to manage the COVID-19 outbreak and to save lives.
• Reduces burden on research staff in identifying and contacting potential clinical trial participants.
• Supports the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research and then produce a coronavirus vaccine and make sure one is made available to the public as quickly as possible.

Outputs:

The information from NHS Digital will be used to facilitate contact with individuals who are potentially eligible and who have indicated willingness to potentially participate in studies/trials of COVID-19 vaccines.

This is expected to result in individuals entering the trials screening process with a view to them participating in the trial with fully informed consent.

The main results from this trial are expected to inform development of a safe and effective multiple vaccine combination against COVID 19.

---

MR278 - Study of Birth Cohort from Hertfordshire — DARS-NIC-148284-T2GPT

Type of data: information not disclosed for TRE projects

Opt outs honoured: Y, N, Yes - patient objections upheld, Identifiable, Yes (Section 251 NHS Act 2006)

Legal basis: Section 251 approval is in place for the flow of identifiable data, Health and Social Care Act 2012 – s261(7), National Health Service Act 2006 - s251 - 'Control of patient information'. , Health and Social Care Act 2012 – s261(7), Health and Social Care Act 2012 – s261(7); National Health Service Act 2006 - s251 - 'Control of patient information'.

Purposes: No (Academic)

Sensitive: Sensitive, and Non Sensitive, and Non-Sensitive

When:DSA runs 2019-03-02 — 2022-03-01 2016.04 — 2024.03.

Access method: Ongoing, One-Off

Data-controller type: UNIVERSITY OF SOUTHAMPTON

Sublicensing allowed: No

Datasets:

1. MRIS - Cause of Death Report
2. MRIS - Cohort Event Notification Report
3. MRIS - Scottish NHS / Registration
4. MRIS - Members and Postings Report
5. Civil Registration - Deaths
6. Demographics
7. Hospital Episode Statistics Admitted Patient Care
8. MRIS - Flagging Current Status Report
9. Hospital Episode Statistics Admitted Patient Care (HES APC)
10. Civil Registrations of Death

Objectives:

The University of Southampton are the Data Controller for The Hertfordshire Cohort Study (HCS), which has been active since the late 1980's during which time it has contributed to the understanding of lifecourse influences on health in later life. It was during the 1980's that the wider cohort was established by the MRC Environmental Epidemiology Unit (a forerunner of the MRC Lifecourse Epidemiology Unit (LEU)) to test the hypothesis that chronic, non-communicable diseases of ageing had their roots in fetal and infant life. 37,000 men and women born in Hertfordshire between 1911 and 1939, whose early health had been documented by health visitors, were flagged for continuous notification of death. Given the accrual of deaths over time and the increasing age of the cohort, a re-examination of early life influences on mortality is due, hence the request for further MRIS data.

A subset of 2997 cohort members born between 1931 and 1939 and still resident in Hertfordshire were genotyped and underwent a comprehensive characterisation of their health in the clinic phase of the project during 1998-2004. They have since been followed-up in repeat clinics, by postal questionnaires and through data of two types from NHS Digital.

The first of these is an extract of HES data, used to create an admission history for each participant from the date of clinic attendance to 31/03/2010. These histories, underpinned by prospectively measured data, are being used to investigate lifecourse influences on hospital admission. It is crucial to understand and prevent admissions among older people in the context of current pressures on the NHS: those aged 65+ occupy 2/3 of hospital beds though they represent only 1/6 of the population.

In addition, the civil registration data that are available for the wider cohort are also applicable to clinic participants. To date they have mainly been used to ascertain loss to follow-up (data obtained from NHS Digital). However, the rich data collected in clinic (DNA extracted from blood samples), combined with increasing numbers of deaths among clinic participants (700 approx. to date), provides the potential to examine the impact of genotype as well as health and lifestyle in early old age on subsequent longevity and cause of death. This allows the researcher to investigate whether people who survive to very old ages do so because they have 'good genes' or because they have lived 'healthy lives'.

The work is being undertaken to provide a publicly funded resource for research. By comparing observed health outcomes from the NHS Digital data with prospectively measured risk factors from the cohort data, the research aims to elucidate pathways to ill-health and mortality in old age, and the concomitant need for hospital care. Such research is an iterative process, and whilst specific outputs planned are outlined below, it is important that The Hertfordshire Cohort Study (HCS) remains reactive to changing research priorities. Any changes to the purpose would however require an amendment to this agreement.

Yielded Benefits:

Early findings from Hertfordshire provided the catalyst for a new field of research: the Developmental Origins of Adult Disease. An international learned society (https://dohadsoc.org/) has developed to support it, and the earliest paper based on Hertfordshire data (Barker DJP, Osmond C, Winter PD, Margetts BM, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;2:577-80) has nearly 2000 citations to date. Over 260 papers have been published in peer-reviewed journals. Since 2004 HCS has focused on musculoskeletal disease. Key findings are summarised below: Growth in utero and in infancy are determinants of adult bone mass, bone geometry, microarchitecture, strength and fracture risk Adult bone mass is related to circulating GH and cortisol concentration; SNPs within candidate genes; ischaemic heart disease and risk of diabetes Fracture risk is predicted by measures of bone density and architecture other than dual-energy X-ray absorptiometry Markers of bone turnover, but not volumetric bone density, are associated with knee osteoarthritis Genetic factors and vitamin D status influence the incidence and progression of knee osteoarthritis Functional limitation associated with hand OA is driven by pain rather than by comorbidity Adult bone mass and grip strength are related to quality of life Bone health is directly influenced by muscle function Early life factors are related to body composition in late adulthood Muscle size and strength are related to growth in early life Sarcopenia and frailty are prevalent conditions in older men and women, newly recognised in clinical practice Sarcopenia in later life is associated with altered muscle morphology HCS data have contributed to the development of normative guidelines on grip strength Early environment influences development of autoantibodies Inflammaging is a powerful predictor of future frailty Adult anthropometry is associated with several candidate genes Birth weight and adult fat consumption interact to determine serum cholesterol levels Unhealthy lifestyles (obesity, smoking, poor diet, physical inactivity) are strongly linked to poor physical function and increased risk of hospital admission in older men and women. The data remain as relevant today as when the work begun, and the growing percentage of deaths among the wider cohort only add to their value. In addition, notification of death is crucial for individuals with whom the study is in contact: given their age, death rates are high, but having received no mortality data for over two years sometimes unknowingly the team approach a cohort member who has died. This is distressing to the bereaved relatives and to the team and could be avoided by reinstating the flow of mortality data.

Expected Benefits:

The research described is focused on accruing evidence on risk factors for disease, thus it sits at the head of a research discovery process. In time, and with consistent evidence generated from other studies on the same theme, this body of evidence may lead to the design of an intervention. For example, if the work on risk factors for hospital admission (described above) identifies a characteristic pattern of morbidity and behaviour that is associated with increased rates of admission among older people, an intervention (perhaps a combination of treatment and behaviour change) might target individuals in whom the pattern exists with the aim of reducing the need for hospitalisation which is to the detriment of the individual and places demand on the NHS. Only after an intervention study provides evidence for the effectiveness of an intervention will implementation science be used to embed the intervention within clinical practice with the involvement of all necessary care-giving stakeholders.

Mortality: The wider study aims to inform a body of evidence about how intrauterine (occurring within the uterus) and early life conditions affect health, longevity and eventual cause of death. As such, it represents the first stage in a process which may eventually impact on health and social care. The process is long: early evidence of a link between birth weight and mortality was produced by this study in the 1990s. Investigation of the mechanisms underlying the link followed, using animal and then human models, and it is only now that Randomised Controlled Trials are being carried out with the aim of modifying intrauterine conditions. With sufficient evidence, an intervention in routine obstetric care could follow in the future.

HES: Research using HES data has thus far addressed risk factors for hospitalisation generally, although the research is not principally service based. The aim is not to identify specific procedures, interventions and policies that will have immediate benefit for the health of older people and the care that they receive from the NHS but rather, to inform a body of evidence about likely risk factors for hospitalisation. In time, this could lead to interventions as described above.

Nutrition programme: There is a very compelling case for knowing more about nutrition and health in older age. One third of older patients are categorised as being at risk of malnutrition on admission to hospital, and malnutrition is associated with poorer health outcomes and longer hospital stay. HCS is the only UK cohort that has collected dietary data in later life and offers the opportunity to define the role of nutrition as a determinant of health in later life. The MRC LEU are developing a programme that will run till 2020, using both HES and mortality data to chart the development of disease in relation to diet.

Outputs:

Over 250 publications in peer-reviewed scientific journals have resulted from the Hertfordshire Cohort Study to date; civil registration data have constituted a specific outcome in 3 of these and HES data in 4. Over the next 1-2 years the analyses proposed below will consider mortality or HES data as a specific outcome and, as explained in the processing activities, continuous notification of death will underlie many more outputs.

HES data: An exploration of the risk factors for hospital admission in later life has produced 3 papers, all of which are drafted and ready for immediate submission:
• Predictive factors for 30-day readmission among older people
• Predictive factors for emergency admission among older people
• Predictive factors for elective admission among older people

Three further papers using HES data will be written:
• The contribution of co-morbidity to risk of hospital admission
• The contribution of obesity to risk of hospital admission
• The contribution of socio-economic status to risk of hospital admission

In addition to the outputs listed, which are aimed at the scientific community, material is produced for cohort members. This includes
• An annual newsletter, the latest edition of which will be mailed in February 2019
• A website https://www.mrc.soton.ac.uk/herts/
• Occasional public meetings, most recently on 23/06/18 in Harpenden

Processing:

Tracing and flagging of the wider cohort (n=C37,000) was carried out by NHS Digital during the 1980s and 1990s on receipt, from the MRC unit, of patient identifiers from cohort members’ birth records (name, sex, DoB and address at birth). In return, current names, HA ciphers of residence and NHS numbers of flagged individuals were notified to the MRC, together with details of deaths that had already occurred. Incident mortality has subsequently been reported monthly by NHS Digital under this data sharing agreement.
Mortality data are used for two purposes:
i) To investigate the associations between conditions in early life, ageing, longevity and cause of death.
ii) To avoid unnecessary contact with bereaved relatives of those who are deceased

In 2011, the NHS numbers of 2997 clinic participants originally provided to the LEU by the NHS Central Register (NHSCR) were supplied to NHS Digital and an extract of HES data covering the period between the earliest baseline clinic and 31/03/2010 was received in return. HES data were cleaned and episode records collapsed to produce an admissions history for each HCS member from the date of their baseline assessment (which varied from person to person) to the universal end date in 2010. Admission histories (which could potentially be identified by date of birth in association with sex) were created through linkage to the HCS database and have been subjected to ongoing analyses using survival models in STATA (data analysis and statistical software). The HES data can be linked by the LEU with fact and date of death derived from civil registration data as well as with other study data, as explained in the following paragraph

Data derived from multiple sources (birth records, home interviews, clinics, postal questionnaires, health authorities, GPs, NHS Digital and ONS) are stored in a series of databases in a dedicated secure area of the MRC LEU computer server. A unique serial number acts as the primary key and is the only common field between databases. This allows the data to be linked as necessary to investigate emerging research questions. Any emerging research questions are not permitted to go beyond any significant extension of the purpose without an amendment being submitted and agreed by NHS Digital.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data).

Data will only be processed and stored at MRC LEU and will not be available to any other individual for any other purpose. All outputs will contain only aggregate level data with small numbers suppressed in line with the HES analysis guide.

Processing of NHS Digital data occurs only within the MRC LEU. The LEU is a part of the University of Southampton's Faculty of Medicine. All staff accessing the data disseminated under this agreement are substantively employed by University of Southampton but are limited to those staff based in the LEU.

The LEU is located on the campus of the University Hospitals Southampton NHS Trust but is otherwise unrelated to the NHS.

The applicant will not link the data further and the only data linkages are those permitted under this application.

---

MR1175 - PROSPECTIVE STUDY OF OUTCOMES IN SPORAIC VERSUS HEREDITARY BREAST CANCER (POSH) — DARS-NIC-148334-51PXR

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable, Yes (Section 251 NHS Act 2006)

Legal basis: Health and Social Care Act 2012 – s261(7), Health and Social Care Act 2012 – s261(7); National Health Service Act 2006 - s251 - 'Control of patient information'.

Purposes: No (NHS Trust, Academic)

Sensitive: Sensitive

When:DSA runs 2019-03-01 — 2020-11-01 2023.08 — 2023.08.

Access method: Ongoing, One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST, UNIVERSITY OF SOUTHAMPTON, UNIVERSITY OF SOUTHAMPTON

Sublicensing allowed: No

Datasets:

1. MRIS - Cause of Death Report
2. MRIS - Cohort Event Notification Report
3. MRIS - Flagging Current Status Report
4. MRIS - Members and Postings Report
5. Cancer Registration Data
6. Civil Registrations of Death
7. Demographics

Objectives:

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling The University of Southampton and The University Hospital Southampton NHS Trust to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance).

The following provides background information on the purpose of the original study:

The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) study focuses on younger patients, who have a significantly reduced chance of survival. Breast cancer is the most common type of cancer in the UK, but thanks to international research efforts, over 80 per cent of women are alive five years after diagnosis and at least two-thirds survive for 20 years or more. However, it is known that women diagnosed under the age of 40 often have more aggressive cancers, with a significantly lower chance of survival, and some carry genetic factors predisposing them to the disease.

The study is a multicentre prospective observational cohort study of 3000 young women diagnosed with breast cancer in the UK between 2000 and 2008. It completed recruitment of just over 3000 cases by 31st December 2008. The study continues to follow up annually as funding allows. Oncologists at hospitals throughout the UK recruited patients.

The primary aims of the POSH study are to determine whether:
• The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non carrier patients matched for age and other major prognostic indicators.
• Breast cancers occurring in patients with different predisposing inherited gene mutations have a consistent and distinct tumour phenotype?
• There are differences in the pattern of distant breast cancer recurrence between patients with BRCA1 or BRCA2 gene mutations and matched non carrier patients?

This study is funded by Breast Cancer Campaign and Cancer Research UK. The study began in 2001 and is a purely non-commercial study. The recruitment period ended at the end of December 2008 and since then follow up data has been collected from hospitals, and when not known by the original recruiting hospital, by requesting data from NHS Digital. NHS Digital has previously provided cohort data.

The sponsor of the study is University Hospital Southampton NHS Foundation Trust and it is being managed on their behalf by University of Southampton's Southampton Clinical Trials Unit (SCTU).
N.B. A Sponsor is an individual, company, institution, organisation or group of organisations that takes on responsibility for initiation, management and financing (or arranging the financing) of the research. A sponsor can delegate specific responsibilities to any other individual or organisation that is willing and able to accept them. All research falling under the remit of the Secretary of State for Health must have a formal sponsor. This includes all research in health and social care that involve NHS patients, their tissue or information.

More than 3,000 women diagnosed with breast cancer under the age of 40 took part in the study. Only about five per cent of all breast cancers are diagnosed in women under 40 years of age, so over the eight years that patients joined the study, this makes up around a quarter of all women with breast cancer in this age group in the UK. Participants contributed a blood sample and tumour tissue for genetic research. The progress of study participants is followed annually, including using data received from NHS Digital for women who are no longer in contact with their treating hospital centre.

Data supplied by NHS Digital is being used for long-term follow up of patients to assess their primary and secondary endpoints. SCTU Statistics Team analyse the data and alongside the chief investigator (Professor of Genetics) write a number of papers which will be published in medical journals. All outputs will be aggregated with small numbers suppressed in line with the HES Analysis Guide.
N.B. An endpoint in clinical trials, is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

The research team are examining inherited high-risk genes for breast cancer, such as BRCA1 and BRCA2, in this group, with a view to developing treatments for genetic breast cancer. They are looking at the DNA from younger breast cancer patients to find out whether clues in the BRCA genes could help predict their response to treatment and the risk of cancer coming back. There is some evidence that BRCA1 gene carriers may be more sensitive to certain types of chemotherapy.

Yielded Benefits:

To date the team have published data (Copson et al JNCI 2013) showing that two different types of breast cancer have very different patterns of relapse potentially relating to how they are treated and long term outcome data (to median of 15 years) is needed to really understand the pattern of recurrence. The study has already found that women diagnosed with breast cancer with a family history of the disease face a similar prognosis after treatment to other women with breast cancer.

Expected Benefits:

This Agreement permits the secure retention of the data only and no other processing.

The study team want to empower women who carry this faulty gene to make informed decisions about their treatment options. The research could also lead to targeted ways to treat young women with breast cancer and improve their chances of beating the disease.

This study is a unique opportunity to chart the long term outcome for patients who have a specific genetic reason for the development of breast cancer. Patient advocates have been extremely supportive of continuing follow up of the cohort study in this way.
The latest data is beginning to suggest a survival advantage across the cohort for patients with a genetic predisposition who are offered more extensive surgery after their initial cancer treatment – again the data must have longer follow up to be certain of how beneficial this might be over time.

These longer term analyses are essential to provide accurate information for patient care in the current era where early genetic testing in young onset breast cancer is becoming routine – no other study will be able to provide this detailed evidence.

The study is looking at the prognosis for breast cancer patients with BRCA1 or BRCA2 gene mutations, at differences in patterns of recurrence and whether cancers in these patients have a distinct tumour phenotype or host tissue response.
If the outlook for BRCA carrier patients is more optimistic than previously thought, preventive surgical options could be more confidently planned at the same time as breast cancer treatment. Ultimately the team want to empower women who carry this faulty gene to make informed decisions about their treatment options. The research could also lead to targeted ways to treat young women with breast cancer and improve their chances of beating the disease.

Results published January 2018 show that young onset breast cancer patients have a high mortality and those who carry a BRCA gene mutation have similar survival to non-carriers. BRCA carriers presenting with triple negative breast cancer may have a survival advantage during the first few years after diagnosis compared to non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary cancer risks should take into account prognosis associated with the first malignancy and patient preference.

A final outcome analysis is planned when the study follow up reaches a minimum duration of 15 years (2023).

Outputs:

This Agreement permits the secure retention of the data only and no other processing.

No new outputs will be produced under this Data Sharing Agreement.

Processing:

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement.

The study data, including data provided by NHS Digital under previous agreements, are currently held by University Hospital Southampton NHS Foundation Trust.

The following provides background on the processing activities undertaken prior to this Agreement:

Identifiable data was shared with ONS to carry out the linkage between the study data and civil registration data. Participants records were ‘flagged’ with the Office for National Statistics (ONS). ONS notified the study team at University Hospital Southampton NHS Foundation Trust of participants’ deaths (date and cause) and cancer events when they occurred. The ‘flagging for long-term follow up’ service transferred from ONS to the HSCIC in 2008. Data was last supplied in March 2016.

---

MR1449 - FLuid Optimisation in Emergency LAparotomy (FLO-ELA) trial: NIHR HTA ref 15/80/54 — DARS-NIC-60714-M4T1M

Type of data: information not disclosed for TRE projects

Opt outs honoured: No - consent provided by participants of research study, No - data flow is not identifiable, Identifiable, Anonymised - ICO Code Compliant, No (Reasonable Expectation, Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c), Health and Social Care Act 2012 – s261(2)(c)

Purposes: No (NHS Trust)

Sensitive: Non Sensitive, and Sensitive, and Non-Sensitive

When:DSA runs 2019-03-01 — 2022-02-28 2018.06 — 2022.02.

Access method: One-Off, Ongoing

Data-controller type: QUEEN MARY UNIVERSITY OF LONDON, UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Hospital Episode Statistics Admitted Patient Care
2. Hospital Episode Statistics Critical Care
3. MRIS - Flagging Current Status Report
4. MRIS - Cause of Death Report
5. Civil Registration - Deaths
6. Hospital Episode Statistics Admitted Patient Care (HES APC)
7. Hospital Episode Statistics Critical Care (HES Critical Care)
8. Civil Registrations of Death

Objectives:

Emergency bowel surgery (laparotomy) is a common major emergency surgical procedure, performed to treat life threatening conditions caused by cancer, infections or previous surgery. Over 30,000 people in England & Wales undergo this surgery annually at a cost of over £650m. Outcomes from emergency bowel surgery are poor; 14% of patients aged over 50 die within a month of surgery, rising to 20% within three months.

The National Emergency Laparotomy Audit (NELA) is hosted by the Royal College of Anaesthetists (RCoA) and is part of the National Clinical Audit and Patient Outcomes Programme (NCAPOP), overseen by the Healthcare Quality Improvement Partnership (HQIP). NELA was commissioned following evidence of a high incidence of death, and a wide variation in the provision of care and mortality, for patients undergoing emergency laparotomy in hospitals across England, Wales and Scotland.

NELA is an audit which looks at the improvement of the quality of care for patients undergoing emergency laparotomy (~30,000/yr within the audit) through the provision of high quality comparative data from all providers of emergency laparotomy surgery. FLO-ELA are using NELA to identify the 100 hospitals which have been invited to participate in FLO-ELA (~50% of the total NELA group). Patients who are undergoing the procedures at those hospitals will then be invited to consent to the FLO-ELA trial. Through this consent, patients agree that NELA will share pseudonymised data on aspects of their care while in hospital with the FLO-ELA trial, to allow the trial to describe the clinical characteristics and trial-related care of its participants. This is clearly described in the FLO-ELA consent materials and FLO-ELA data flow diagram and is based on an established data sharing agreement between HQIP/RCoA and FLO-ELA. The audit and the trial are two separate pieces of research which have a clear link.

FLO-ELA (FLuid Optimisation in Emergency LAparotomy) is a large randomised clinical trial proposal funded by the National Institute for Health Research Health Technology Assessment (HTA) stream. It aims to determine whether a discrete medical intervention (perioperative cardiac output-guided haemodynamic therapy) reduces deaths after emergency laparotomy when compared with usual care. Although this intervention may be beneficial for patients undergoing planned major surgery, it has not yet been tested in patients undergoing emergency laparotomy. The FLO-ELA trial is being funded by the NIHR HTA Efficient Study Design stream, for trials able to give robust research output at greater pace and scale and/or lower cost than conventional trial designs. By linking this trial to NELA - recruiting a subset of patients eligible for inclusion in NELA, utilising the existing NELA network of hospitals and the NELA webtool and dataset for trial participant data (with ONS/HES follow up) - The study have a trial proposal which will be large enough (~8000 patients) to give a definitive answer on whether this treatment is effective, in a timely and cost-effective fashion. This represents a unique opportunity to generate practice-changing research in a challenging patient group, with the potential to save hundreds of lives every year.

Trial objectives:
1. To establish whether the use of minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid (goal-directed haemodynamic therapy, GDHT), for patients aged 50 and over undergoing emergency laparotomy will reduce mortality within 90 days of randomisation, when compared with usual care.
2. To determine whether GDHT reduces mortality one year after randomisation, and is cost-effective.

Primary outcome measure
• Mortality within 90 days of randomisation

Secondary outcome and process measures
• Mortality within one year of randomisation
• Duration of hospital stay (number of days from randomisation until hospital discharge)
• Duration of stay in a level 2 or level 3 critical care bed within the primary hospital admission
• Hospital readmission as an inpatient (overnight stay) within 90 days from randomisation

Yielded Benefits:

With the data received so far, a DMEC report has been produced to evaluate patient safety. The researchers have been able to validate the pre-trial assumptions on mortality rates, giving reassurance that the planned number of participants will be enough to address the main question of the trial.

Expected Benefits:

The FLO-ELA trial will provide the highest level of evidence for this intervention, informing the decision to widely implement on a national level by confirming the extent of any clinical benefit or harm, healthcare costs and cost effectiveness. A positive outcome from this trial could change practice across the developed world. NELA would expect rapid translation of this intervention into routine clinical practice within 12-24 months of trial report. This is supported in the UK by the ongoing National Emergency Laparotomy Audit and its parent organisation the Healthcare Quality Improvement Partnership. This quality improvement vehicle will maintain long term engagement and sustained interest in this area with the large number of clinicians involved in the FLO-ELA trial and the wider clinical community after trial completion.

Further, the study will provide specific reports on the findings of the FLO-ELA trial for healthcare policy makers. Through the support of the advisory group, findings will be disseminated appropriately to NHS England and devolved nations, NHS trusts and other stakeholder groups. The research study will advise on the implications of findings and optimal implementation.

As a definitive pragmatic effectiveness trial, with an intervention delivered by clinicians in a large number of NHS sites and in a patient group highly representative of the ultimate target population, rapid and widespread uptake of the trial findings into routine practice is expected. This has the potential to rapidly change care for over 30,000 patients across the UK each year. If shown to be beneficial, this could equate to several hundred lives being saved each year. Conversely, if no benefit is found, this treatment can be discarded, allowing clinicians to focus on other areas of care for this challenging patient group.

Outputs:

Outputs from the FLO-ELA trial analysis will only include aggregated data, no individual level data received from NHS Digital will ever leave the safe haven where the analysis is taking place. The following outputs are planned:
Final Report to Funder - March 2022
Final FLO-ELA Investigators Meeting - summer 2022
Peer Reviewed Publications - summer 2022
Conferences and meetings - 2022 - ongoing

In accordance with current practice, appropriately pseudonymised record-level data may be shared with researchers in the future to support further studies in this area such as meta-analysis. This will be subject to the strict data sharing policy in place at the Pragmatic Clinical Trials Unit. Patient consent will be requested for such future data sharing at the time of recruitment into the trial. Appropriate approvals from NHS Digital will also be sought prior to any data sharing.

Details of expected outputs:
The main scientific report (aggregated / summary data only) will be sent to a high level journal such as the Lancet for their consideration first. Second choices would include the British Medical Journal, the New England Journal of Medicine, and the Journal of the American Medical Association. These are all general interest journals read by a wide range of healthcare workers worldwide.

The study plan to invite all the co-investigators (from 100 hospitals) to a final FLO-ELA meeting where they will disseminate and discuss the findings.

The study will also present the work at scientific meetings and congresses. For example the ‘Annual Congress of Enhanced Recovery and Perioperative Medicine’ and the ‘Evidence-Based Peri-Operative Medicine’ conferences. They will also disseminate the aggregated findings through the mainstream media and also through social media (e.g. Twitter) with the support of their patient representatives. The main target audience will be surgeons, anaesthetists and intensive care doctors but also patients and their carers.

A plain English summary of the trial results and any important trial information will be presented here http://www.floela.org/

More broadly, work will be carried out with patient partners and the PCPIE group at the Royal College of Anaesthetists to plan lay-orientated dissemination of the trial results to a non-medical audience.

Processing:

The Royal College of Anesthetists (RCoA) are the principal data processors for NELA and manage the extraction of the records from the NELA IT system. The FLO-ELA team at the Pragmatic Clinical Trials Unit (PCTU), Queen Mary University London will act as data processors to integrate NELA data with HES and ONS outcomes data for patients recruited into FLO-ELA. They will perform this role under contract by the study sponsor, University Hospital Southampton NHS Foundation Trust, the trust are involved in making decisions about the outputs and what the data will be used for.

The Royal College of Anaesthetists (RCoA) cannot access and is not permitted to access FLO-ELA data, including any of the data disseminated under this Agreement by NHS Digital. The Royal College of Anaesthetists role is to act as a data processor for NELA on behalf of HQIP.

The request for HES data was made following consultation with the study health economist. All selected data fields are required for an accurate appraisal of resource-use and cost during the study period. Necessary data minimisation steps were undertaken in order to exclude those fields which are not necessary to answer the research questions: this included fields related to maternal, neonatal (etc.) care.

Patient identifiers for participants in the FLO-ELA trial will be collected within the PCTU trial randomisation system. The FLO-ELA team will send the file of patient identifiers and the FLO-ELA ID to NHS Digital for linkage to HES and ONS fields. After linking, NHS Digital will remove all supplied identifiers, leaving only the FLO-ELA ID, Date and Cause of Death. The FLO-ELA team at Queen Mary University London will receive files from NHS Digital that contain the HES and ONS fields, as well as the FLO-ELA ID.

The identifiable fields received by the FLO-ELA team are ONS Date of Death and cause of death. The full Date of Death is required to be able to calculate survival at two time points (90 day, one year). The FLO-ELA team will not use ONS Date of Death to identify any individual patients.

The data received from NHS Digital will not be linked back to the identifiable NELA database. An extract of pseudonymised NELA data will be linked to the HES-ONS data via the NELA ID.

The health economic analysis in the study will combine resource-use data (to estimate the cost of care) and outcomes in terms of quality-of-life to carry out a cost-effectiveness analysis. Initial resource-use during the intervention period will be obtained from routine data recorded in the NELA database. Subsequent resource-use during the follow-up period will be estimated by observing the number of hospital admissions, critical care days, accident & emergency visits and outpatient visits recorded in HES. The quality-of-life outcomes will be estimated by mapping participant characteristics to a different but similar population in a previous study called EPOCH. No quality-of-life data will be collected from patients in the FLO-ELA study, and the EPOCH dataset represents a different group of patients from another study. Therefore this mapping does not involve onward linkage of individuals’ record-level data to other datasets containing their data.

The NELA data and the HES-ONS data will also be linked to a Health Economics (HE) dataset via the FLO-ELA ID. The HES dataset does not contain any identifiers.

The FLO-ELA team Statisticians and Health Economists who will work on the linked dataset do not have access to the identifiable data set held by the RCoA or any identifiers held locally at hospitals.

All processing of ONS data will be in line with standard ONS terms and conditions.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data).

No record level data will be shared with any organisation not noted in this application only the sharing of aggregated data with small numbers suppressed in line with the HES analysis guide is permitted.

The data from NHS Digital will not be used for any other purpose other than that outlined in this Agreement. Data will only be processed at QMUL no access will be provided at Southampton FT.

---

The Distribution of Highly Sensitive Troponin in the Critically Unwell and Associated Mortality — DARS-NIC-349889-Q7R7K

Type of data: information not disclosed for TRE projects

Opt outs honoured: Anonymised - ICO Code Compliant, Yes (Section 251 NHS Act 2006)

Legal basis: Health and Social Care Act 2012 – s261(1) and s261(2)(b)(ii), Health and Social Care Act 2012 - s261 - 'Other dissemination of information'; National Health Service Act 2006 - s251 - 'Control of patient information'., Health and Social Care Act 2012 – s261(2)(b)(ii)

Purposes: No (NHS Trust)

Sensitive: Sensitive

When:DSA runs 2020-09-01 — 2021-08-31 2021.01 — 2021.01.

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Civil Registration (Deaths) - Secondary Care Cut
2. Civil Registrations of Death - Secondary Care Cut

Objectives:

A blood test called troponin forms a key part of the diagnosis of a heart attack (myocardial infarction). Troponin refers to a group of proteins that help regulate the contractions of the heart and skeletal muscles. High troponin levels can indicate a problem with the heart. The heart releases troponin into the blood following an injury, such as a heart attack. The upper limit of normal for this test is determined by the manufacturer of the test, based on the troponin levels in healthy individuals, generally aged between 18-40. Recently assays have been developed that provide a higher degree of sensitivity and as such allow rapid exclusion of a heart attack within a few hours. This benefit does however raise another issue; elevated levels of high sensitivity troponin are now frequently seen in patients who have not suffered a heart attack, particularly in association with severe illness states, such as in patients in intensive care. In the absence of clinical features of a heart attack an elevated high-sensitivity troponin leaves clinicians uncertain as to how to interpret this result and whether it should result in changes to patient care.

The first part of the study, which is in the advanced stages of analysis, collected high-sensitivity troponin results from 1,612 consecutive patients (over the age of 18 years) who had blood samples requested by clinicians at University Hospital Southampton (UHS) during their stay in one of three intensive care units (Cardiac Intensive care, General Intensive Care and Neurosciences Intensive Care). The aim was to provide a description of the distribution of high-sensitivity troponin and to describe factors associated with it's release. Further aims were to assess whether there was an association between high-sensitivity troponin concentration and inpatient mortality. A secondary aim of the study was to apply to NHS Digital (for which this agreement is in place) for longer term mortality data (one year mortality was agreed as the most appropriate endpoint after discussion with the Confidentiality Advisory Group).

This study has highlighted that elevated concentrations of high-sensitivity troponin are frequently seen in patients in intensive care and therefore this test should not be used as a binary arbiter of whether someone has had a type 1 myocardial infarction (a traditional myocardial infarction associated with coronary artery obstruction). The
cause of the elevated high-sensitivity troponin is likely to be due to myocardial injury, rather than a type 1 myocardial infarction in most cases. The study has also demonstrated that the high-sensitivity troponin concentration is closely associated with markers of illness severity. Furthermore, outside cardiac intensive care, high-sensitivity troponin concentrations have been shown to be closely associated with inpatient mortality.

Having established these important observations in the original study, UHS now wish to move onto the pre planned secondary aim to assess whether high-sensitivity troponin taken in critical illness is a predictor of longer term mortality. Does this bio marker just act as a predictor of short term risk, as it is associated with illness severity, or does it predict future events because it acts as a marker of previously unknown cardiovascular disease?

This study will assess the one year outcomes of the cohort (mortality and cause of death). This study is of significant public interest for three reasons. Firstly, as demonstrated by the original study high-sensitivity troponin elevation is frequently seen in patients in critical care; secondly - clinicians are often unsure whether these results are of clinical significance. Finally, if this study does demonstrate an association between high-sensitivity troponin levels and outcomes then further studies will result to assess whether any medical interventions, (particularly proven cardiovascular therapies), could alter the prognosis in this group. This study therefore has significant potential implications for the healthcare of a large population of patients both in the UK and internationally.

As such the study meets the standards set out in section Article 6 (1)(E) of the General Data Protection Regulation for processing these data: "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". Furthermore for these reasons it also meets the expectations set out for processing data set out in Article 9(2)(J) of the General Data Protection Regulation: "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".

The key ethical question raised by this study is whether it is appropriate to process these data without consent. As already discussed the potential improvements that this study could offer to patient care both in the UK and internationally mean that this study is undoubtedly in the public interest. Furthermore this study will have minimal risk to the patients included in the study and their personal data will be kept pseudonymised. It is therefore clear that the study has an ethical mandate. This opinion is also held by both the Research Ethics Committee and the Confidentiality Advisory Group, as demonstrated by their support for this study.

The data requested will help the research team to assess whether there is an association between high-sensitivity troponin levels and clinical outcomes. Specifically mortality status will allow the team to assess whether there is a link between high-sensitivity troponin levels and mortality. The cause of death is important because it would seem more likely that high-sensitivity troponin levels will predict cardiovascular mortality rather than all cause mortality. Without the cause of death the research team will be unable to evaluate this.

The data returned from NHS Digital will be record level pseudonymised (just with the unique study identifier that the CRG at UHS will send) to allow the CRG at UHS to link these data with the high-sensitivity troponin levels. If data were provided on an aggregate level it would not be possible to fully assess the association between high-sensitivity troponin levels and clinical/mortality outcomes. One year outcomes should provide the research teams with a clear picture of the relationship between high-sensitivity troponin levels and outcomes. This is the minimum time frame required to answer the primary objectives of this study. It is likely that some patients will have moved or have been admitted to hospital whilst away from their permanent residence. Therefore the data will not be restricted to one particular geographical area, such as Southampton. It is not possible to achieve the aims of the study without processing these data. Furthermore the research team have specifically asked for the minimum data required to complete the objectives of this study, any less and it would not be possible to robustly evaluate the association between high-sensitivity troponin levels and clinical outcomes.

The results from these analyses will result in improvements in the way clinicians interpret high-sensitivity troponin levels but may also precipitate further studies to assess whether any medical interventions could alter the outcomes in at risk groups identified by this study.

This study is a pre specified follow up of the distribution of highly sensitive troponin in the critically unwell and associated mortality study which recruited 1,612 consecutive patients in one of the three adult intensive care units at UHS in whom a biochemistry sample was performed at UHS between the 30th January 2019 and 30th July 2019. There are no additional phases. This particular study will be referred to as the distribution of highly sensitive troponin in the critically unwell and associated mortality - one year follow up.

UHS will are the sole Data Controller. UHS and the Keele Cardiovascular Research Group (KCRG -part of the University of Keele (UoK) will are the data processors. The KCRG was set up as a specialist centre for the analysis of large cardiovascular data sets. As such the KCRG were involved in the analysis of the original the distribution of highly sensitive troponin in the critically unwell and associated mortality study and it would be remiss not to continue to use their expertise to ensure that the data supplied by NHS Digital provide robust answers to the objectives of this study. The spreadsheet that will be sent to KCRG will contain the age (not date of birth) and gender of the patients in the cohort, alongside date and cause of death from NHS Digital, but no other additional identifiable data will be shared. KCRG will act under instructions from UHS - therefore reinforcing that UHS are sole data controller for this project.

The original study was funded by an unrestricted research grant from Beckman Coulter (BC). BC had no input in the study specifics. This sub-study requires no input from industry and specifically BC have no ongoing role. There are no other organisations involved. There are no funders/commissioners involved.

Expected Benefits:

The expected measurable benefit of the data access and the study will be an important contribution to the optimal
use and interpretation of high sensitivity troponin assays in intensive care. Use of high sensitivity
troponin assays in intensive care is flawed in two ways. Firstly, there is widespread misunderstanding about the
meaning of a raised high-sensitivity troponin; such a result is often incorrectly labelled as implying type 1
myocardial infarction, due to low awareness of myocardial injury. Secondly the upper limit of normal supplied by
the manufacturer of the blood test is based upon a predominantly healthy population which is not reflective of the population of patients seen within intensive care. Thus, whilst the current application of high-sensitivity troponin is largely flawed, data are accumulating that the assay (determining the quality) may have a clinically valuable alternative role as a bio marker of cardiovascular risk.

The proposed study represents a unique opportunity to assess whether the high-sensitivity troponin levels in intensive care patients are indeed associated with longer term mortality. If so, the "never means nothing" hypothesis of high-sensitivity troponin should lead to changes in the way that intensive care clinicians interpret
the assay in practice. It would no longer be an assay mistakenly used to "rule in" type infarction, but rather a bio marker for patient risk and prognosis.

The dissemination of this data is in the public interests because it has the potential to change the way that large
groups of patients are managed. The data are likely to result in changes in the way that high-sensitivity troponins are requested and also interpreted by clinicians in intensive care. Furthermore as already discussed it is likely that these data will precipitate further study to assess whether cardiovascular interventions could change the outcomes in these patients. This study will have wide implications, because, as demonstrated by the original study elevated concentrations of high-sensitivity troponin are frequently seen in patients within the intensive care environment.

The benefit will be achieved by potential changes in clinical practice. It is expected that the dissemination of these data will occur within six months of NHS Digital releasing that data and then changes in clinical care will follow afterwards.

Outputs:

There will be a multi-faceted approach to the dissemination of the results of this study. Firstly the results will be presented at respected medical conferences. Secondly the data will be published in respected peer review journals. These two activities will ensure that the key messages are available to the scientific community. The results will also be published (in a non-scientific format) on the UHS web pages. Finally the promotion of the published article through the use of social media will also widen the audience.

The results of this study are likely to be of immediate clinical relevance to clinicians by providing them with a better
understanding of the clinical significance of the high-sensitivity troponin levels in intensive care. Furthermore, if these data demonstrate that the high-sensitivity troponin levels are associated with cardiovascular mortality then this is likely to stimulate further research to evaluate whether medical interventions can alter the outcomes seen in this group of patients.

Whilst the aggregate results will be published to allow clinicians, scientists and the public to understand the implications of raised high-sensitivity troponin levels, the data themselves will not be released and will be stored and then destroyed following the standards set out by NHS Digital.

Once the study has completed UHS plan to ensure that the results are available widely both to the medical community and the public. The outputs to the medical community will take the form of peer reviewed publications and presentations at medical conferences. The main output to the public will be through the updates and explanation of the results in the trusts patient facing research website.

All outputs will contain only aggregate level data with small numbers suppressed in line with the HES analysis guide.

Processing:

Only substantive employees of University Hospital Southampton NHS Foundation Trust and the Keele Cardiovascular Research Group (who have been trained in data protection and confidentiality) will have access to the data and only for the purposes described in this document. The data will be stored on secured computers within each of the listed data processing organisations.

University Hospital Southampton NHS Foundation Trust (UHS) will provide NHS Digital with the following identifiers of the cohort for the linkage to the data requested
- NHS number,
- date of birth,
- gender
- Study ID.

NHS digital will return mortality data (date of death and cause of death) with each unique study ID. The CRG at UHS will then use the Study ID to link the data provided by NHS digital to the high-sensitivity troponin levels. Once this is complete the data will be sent to the KCRG to allow both the CRG and KCRG to undertake further statistical analysis. Re-identification of these patients will not be possible because the database will only contain the unique study identifier and gender of the patient - no other patient identifiers will be included. The patient identifiers are kept in a separate database. KCRG have no access to these other patient identifiers.
UHS ensures that the identifying data they hold are segregated with the pseudonymised data and linkage by them is completed using the unique study ID.


No contact will be made with the patients selected. The data will only be used for this study.

The NHS Digital data is crucial to provide the most accurate information on the outcome of patients recruited to this study and will form the basis of a robust research study that will be submitted to peer reviewed journals.

The data from this study will not be used for commercial purposes, not provided in record level form to any other third party not mentioned in this agreement, and not used for direct marketing or commercial purposes.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guide.

NHS Digital reminds all organisations party to this agreement of the need to comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data).

---

Fractional Flow Reserve Derived from Computed Tomography Coronary Angiography in the Assessment and Management of Stable Chest Pain: FORECAST TRIAL — DARS-NIC-292087-M7V9Q

Type of data: information not disclosed for TRE projects

Opt outs honoured: No - data flow is not identifiable, Anonymised - ICO Code Compliant, No (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c), Health and Social Care Act 2012 – s261(2)(c)

Purposes: No (NHS Trust)

Sensitive: Non Sensitive, and Non-Sensitive

When:DSA runs 2020-01-23 — 2023-01-22 2020.06 — 2020.06.

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST, UNIVERSITY OF SOUTHAMPTON

Sublicensing allowed: No

Datasets:

1. Hospital Episode Statistics Outpatients
2. Hospital Episode Statistics Admitted Patient Care
3. Hospital Episode Statistics Admitted Patient Care (HES APC)
4. Hospital Episode Statistics Outpatients (HES OP)

Objectives:

The FORECAST Trial will assess a new non-invasive test, which looks at the flow of blood in the vessels around the heart.

Currently, there are a number of well-recognised tests to help doctors decide whether patients’ symptoms are related to their heart arteries. Some tests describe the size and shape of the arteries (anatomy) - whilst others provide information as to whether there is sufficient blood flowing to the heart muscle to enable it to work properly. The most common test is called an invasive coronary angiogram. However, the angiogram does not tell the doctor how well the blood vessels are working (i.e. how easily the blood can flow through them, the physiology). A device known as a ‘pressure wire’ is used to assess the flow of blood. This involves threading a small tube into the heart artery to measure the pressure across a narrowing. This approach allows doctors to create a more tailored treatment plan for each patient.

More recently pictures of the heart arteries have been taken using a CT (computerised tomography) heart scanner. This is much more convenient and less invasive for patients. Until recently, CT has not been able to provide the additional information about whether the heart arteries are restricting the blood flow. A company called HeartFlow Inc, have now developed new software that allows a computer to generate information called FFRCT. This test can then not only give results about the size and shape (anatomy) of the blood vessels around the heart but can also be used to calculate how well they function, by measuring the flow of blood going through the vessels (physiology), in a non-invasive way.
This trial will compare two strategies for managing patients undergoing investigation for suspected problems in the heart arteries. Patients enrolled into the trial are randomly assigned (like the toss of a coin) to either:

• Group 1: Routine investigations following the local hospital procedures
or
• Group 2: Trial investigation undergoing CT scan (with FFRct as required)

The trial approached patients aged over 18, referred to a Rapid Access Chest Pain Clinic (RACPC) for chest pain, and whose care team felt the trial would be suitable for them. They were asked to consider taking part in the trial. This trial involves 1400 participants in total.

After discussing the trial and having read the participant information sheet, a member of the research team addressed any questions or concerns from patients regarding the trial. Patients were screened for eligibility and those who were agreeable, provided written informed consent.
Patients were asked a series of questions by the researchers to describe their medical history, medications and current health status. Patients were also asked to answer questions on 3 short forms about quality of life at this time.
Patients were then randomised to group 1 or group 2.

Group 1: Routine investigations following the local hospital procedures
Patients in group 1 were referred for routine investigation as per the hospital guidelines. Based on test results, the doctor recommended a treatment plan. Patients will be followed in the trial for 9 months. This will involve 2 telephone calls at 3 and 9 months. After the 9 months telephone call participation in the trial is complete.

Group 2: Trial investigation undergoing CT scan (with FFRct as required)
Patients in group 2 were referred for a CT scan of the heart arteries as their first investigation.
A CT scan involves X-ray and this scan requires the use of iodine based dye to show the heart arteries clearly. This is a non-invasive, non-surgical procedure.

If the results from the CT scan were negative, that is no blockages or narrowings are found, then the CT results are reviewed by the doctor alone and further trial analysis is not to be performed. If any potentially significant blockages are seen, the images collected during the CT scan are sent to the researchers in California, United States of America to special computers to perform the FFRCT evaluation. The FFRCT results are sent to the doctor within one working day to assist in evaluating treatment options. The FFRCT evaluation requires no participation on the part of patients. Either way, based on test results, the doctor recommends a treatment plan. Patents are followed in the trial for 9 months. This involves 2 telephone calls at 3 and 9 months. After the 9 months telephone call participation in the trial is complete.
No NHS Digital data will flow to the USA or any third party.

Patients are followed up at 3 months and at 9 months from the date they started on the trial. They are then be discharged back to the care of the GP as appropriate.

Participation in this trial does not present any extra risks other than the risks associated with having a CT scan. This is a test routinely used by doctors to evaluate the heart arteries and may be requested by their doctor regardless of patients participation in the trial. If patients are randomised to the test arm, they have a CT scan. If randomised to the routine arm, or if they choose not to take part in the trial patients may still require a CT scan to assess their condition.

The optimal algorithm with which to assess and then manage patients who present with stable chest pain (CP) that might represent angina (i.e. ischaemia (restriction in blood supply to tissues) secondary to coronary artery disease (CAD) is not clear. In such patients, there may be both symptomatic and prognostic benefit to knowing whether they have either;

(a) significant coronary artery atheroma (build-up of plaque, i.e. the anatomy of their coronary arteries)
(b) reversible myocardial ischaemia (RMI) (i.e. assessing the physiology of the artery(ies) as a surrogate)
(c) both.

Evidence demonstrates that it is useful to know about the presence of atheroma because the medium and long-term natural history of this disease process can be altered by the administration of disease-modifying medical therapy. However, it is now accepted, based upon both observational data and randomised trials, that it is the presence and extent of RMI that most closely correlates with the near-term risk of acute myocardial infarction (MI) (heart attack) and that mechanical intervention by coronary revascularisation (restoration of blood flow) is effective both for symptoms and prognosis in the population with RMI both at patient and lesion-level. Thus, RMI is generally considered to represent the principal target for revascularisation strategies whereas optimal medical therapy (OMT) can improve prognosis regardless of the existence of RMI in some patients.

Based on this, it is clear that both coronary anatomy and physiological assessment (as a surrogate of RMI) are of value in the diagnosis and management of patients presenting with stable cardiac-sounding CP. Current tests used in patients presenting with stable CP assess either coronary anatomy or physiology: non-invasive stress tests (echo/nuclear perfusion/CMR) assess for RMI. By contrast, invasive coronary angiography (IC) and CT coronary angiography (CTCA) are tests of anatomy.

The advent of the invasive pressure wire has provided an accurate tool for the direct assessment of coronary physiology at the time of IC and until recently was therefore unique in allowing for assessment of both anatomy and RMI at the same time. However, the wide range of choice offered by this menu of noninvasive and invasive tests cannot hide the fact that there are important limitations to them all. Specifically, the noninvasive stress tests are highly specialised, expensive, not freely available to patients in all hospitals and associated with significant waiting time in the UK. Invasive angiography carries small but definite risk, is expensive and again not freely available. Furthermore, the ͞yield͟ in terms of finding significant CAD when IC is used as the front-line screening tool for patients with new onset stable CP is relatively low. For example, in 398,978 patients in one large US registry undergoing diagnostic coronary angiography, only 37.6% had obstructive CAD (defined as 50% or more of the diameter of the left main coronary artery or 70% or more of the diameter of a major epicardial coronary artery). Even in patients in whom CAD is identified, there is a well described discrepancy between the anatomical appearance and physiological evidence of RMI in a variety of clinical studies and this effectively calls into question whether an anatomy-based test is an appropriate tool with which to define the management of such patients.

The inherent limitations of both non-invasive and invasive tests for the accurate diagnosis and management of each patient presenting in this context is reflected in the diversity of management in the real world. This is well demonstrated by the 2010 NICE Guideline for Chest Pain of Recent Onset in which the recommended algorithms for assessment and management of this cohort are complex and disparate. Furthermore, one consequence of a true negative stress test is that clinicians do not establish if the patient has a coronary blockage which may represent an indication for disease-modifying therapy. By contrast, a true positive stress test inevitably then results in referral to the waiting list for IC, thus delaying the time from assessment to definitive diagnosis and management plan significantly. Conversely, a referral directly for IC in the absence of evidence of RMI subjects the patient to a stressful procedure that carries potential for serious complication merely to establish in many cases that there is no underlying cause for the CP presentation.

The ideal screening test for patients with stable CP with which to determine the coronary anatomy and physiology would be non-invasive, quick, simple, widely accessible, accurate (using a combination of IC + FFR as the gold standard reference) and as cheap as possible. However, it is possible to refine the desirable features of such a screening test even more precisely.
Firstly, the ideal test would avoid the expense, inconvenience and risk of invasive investigation in patients who turn out to have no important atheroma, whilst being able, conversely, to identify even non-flow limiting atheroma in patients who may therefore benefit from disease-modifying medical therapy.

Secondly, an ideal screening test would incorporate the value, in terms of patient outcome, of physiological assessment that has been demonstrated in the clinical trial data accumulated using the coronary pressure wire. Specifically, two basic principles of management can be applied at the diagnostic stage if it includes a physiological assessment. Firstly, that stenting an anatomical lesion deemed significant which is FFR (fractional flow reserve) negative is associated with a worse outcome than medical therapy alone. Secondly, that treating pressure wire positive lesions with OMT alone is associated with a worse clinical outcome than PCI (percutaneous coronary intervention) plus OMT is just as important. In summary, the ideal screening test for patients with stable chest pain needs to be able to deliver information about RMI (or a physiological surrogate of it), as well as anatomy. FFRCT (Fractional Flow Reserve Computerised Tomography -A non-invasive technique using CT to determine Fractional Flow Reserve) represents a plausible candidate for a screening test in this population. FFRCT is a novel method for computer-derived estimation of coronary physiology from CT angiography data, and early validation studies with regard to its diagnostic performance are promising. The original development and availability of computerised tomographic coronary angiography (CTA) has introduced this non-invasive assessment of the presence and extent of CAD as a useful additional option for the investigation of patients with suspected stable angina. Recent data from the SCOT-HEART randomised trial, for example, highlights the diagnostic value of this technique in such a population.

However, in the PROMISE trial, which randomised 10,003 patients with symptoms suggestive of CAD to stress testing or CTA, there was almost 50% more ICA performed in the CTA group without any difference in clinical outcome. Importantly, most revascularisations performed in the CTA group had no objective evidence of myocardial ischaemia. This highlights the potential limitation of anatomy-based screening in patients with symptoms thought to be due to myocardial ischaemia.

Recently, using sophisticated image assessment, computational fluid dynamics, and computer modelling, it has become possible to model FFR from the data obtained from CTA, thus known as FFRCT. A series of validation studies have assessed the diagnostic accuracy of this technique, including most recently the NXT trial, which demonstrated superior accuracy of CTA plus FFRCT versus CTA alone, using an invasive FFR of <0.80 as the reference.

RATIONALE AND RISK BENEFITS FOR CURRENT STUDY
This trial aims to test the hypothesis that FFRCT, used as the default screening tool for patients presenting with recent onset stable chest pain, would be associated with
(i) shorter rapid time period between initial consultation and definitive
management plan
(ii) better patient experience;
(iii) lower overall use of resources.

The UK is well suited to test this hypothesis because of its well-established system of Rapid Access Chest Pain Clinics (RACPC). The majority of patients presenting with stable CP that is of suspected cardiac origin are referred to such clinics, with a mandated access time within two weeks. The majority of such clinics work to the algorithm recommended in the NICE guidelines for Chest Pain of Recent Onset (March 2010). Within this guideline, patients are stratified according to their risk profile and pre-test likelihood of CAD to outcomes that include discharge, stress test, CTCA, CT coronary calcium score and IC.

Given the relative streamlining of this initial assessment of such patients throughout the country, it facilitates a comparison of strategies in FORECAST.

The 2 strategies for the FORECAST trial are:

A) TEST: all patients undergo CTCA+FFRCT as the default test, assuming they have no pre-specified contradictions to CT angiography. The result of the CTCA will determine whether the FFRCT will be performed. Results of the FFRCT will be conveyed to the supervising physician within 24 hours and will be used to determine the subsequent management plan.

B) REFERENCE: all patients will be assessed and managed exactly as they are usually treated by that centre and that RACPC using the local algorithms interpreted from the NICE Chest Pain of Recent Onset Guidance.

The study aim - To determine whether in a population of patients presenting to the rapid access chest pain clinic routine FFRct is better in terms of resource utilisation, (i.e. number and cost of investigational procedure, number of hospital visits etc.) when compared to routine clinical investigations recommended by NICE.

Primary endpoint - Resource utilisation at 9 months.

Secondary endpoints include -

- the comparison of clinical outcomes between the two groups at nine months.

(a) Major adverse cardiac events including: non-fatal MI, all coronary revascularisation, cardiac-related
hospitalisation.
(b) Requirement for non-invasive cardiac investigations
(c) Requirement for invasive coronary angiography
(d) Revascularisation
(e) Procedural complications
- the comparison of the effect on general wellbeing between the two groups at 9 months.
(a) QoL questionnaire
(b) Patient satisfaction questionnaire
(c) Angina status
(d) Time to definitive management plan
(e) Time to completion of initial management
(f) Number of hospital attendances
(g) Working days lost

Data minimisation:

The number of data items sent to NHS Digital for linkage is limited to:

i) name
ii) date of birth
iii) NHS Number

With these determinants, the research team can accurately follow consented patients tracking specified clinical events and resource utilisation as stipulated in the protocol (e.g. cardiac investigations, hospitalisations, revascularisation procedures, outpatient appointments). Using these determinants, all relevant data can be adequately linked to each patient's correct and unique study identifier, to ensure pseudonymisation of all patients.

The research team at the University of Southampton do not propose to collect any data that does not contribute to either the primary or secondary endpoints. Eleven UK sites have enrolled participants into the Forecast trial. On receiving the data from NHS Digital, the data processor (The University of Southampton) will collate and process in preparation for publication.

The study team have excluded any mortality, mental health and maternity data as this is not required.

The legal basis for processing the information requested in that it is necessary for the performance of a task carried out in the public interest (GDPR Article 6(1)(e) and under Article 9(2)(j) necessary for archiving purposes in the public interest, scientific or historical research purposes in accordance with Article 89 (1).

The data requested under this agreement is carefully selected and filtered to support the primary and secondary endpoints. Study results will be of interest to both potential patients undergoing diagnosis in the future and the wider NHS in ensuring the effective and efficient use of resource whilst diagnosing, managing and treating patients in the most cost effective, clinically effective way. Study participants have consented to the use of their data for this purpose. There are no foreseen ethical issues.

Expected Benefits:

The results of the Forecast study have the potential to change the current investigational pathway for patients presenting to RACPC according to the current NICE guidelines.

The study aims to determine whether routine use of CTCA +/- FFRct is superior in terms of resource utilisation when compared to current pathways.

Healthcare Benefits
A positive finding for this study would offer a potential fiscal benefit to individual Trusts and the NHS as a whole by reducing overall costs for the routine investigation of patients presenting to RACPC with cardiac sounding chest pain.
Clinicians will be alerted to this information through publication and presentations. Should the NICE guidelines be amended in the light of the Forecast results, this information will be disseminated to Trusts and clinicians in the standard fashion for NICE recommendations.

A competitive tariff for CTCA +/- FFRct as a standalone study providing both anatomical and physiological information in a single test would reduce the overall number of tests required to finalise a treatment plan, leading to potentially significant cost savings.

Patient benefits
From a patient perspective the opportunity to undergo a single non-invasive test to acquire both anatomical and physiological information is appealing, with significant clinical risk reduction, speedier diagnosis and for a number of patients the avoidance of an unnecessary invasive procedure.
Patients are offered the optimum test that provides clinicians with the most sensitive and accurate information from which a diagnosis and treatment plan can be generated. Clinical care teams will continue to follow the recommendations released by NICE to maximise patient safety and comfort whilst ensuring the most appropriate use of valuable NHS resource.

These potential benefits will be measured through the collection of data to support the primary and secondary endpoints of the study.

Outputs:

Patient data processed by NHS Digital will be used to clarify the role of CTCA +/- FFRct in the investigation pathway for patients presenting to rapid access chest pain clinics (RACPC) across the UK. Current guidance from NICE will be reviewed in the light of the Forecast study results.

The data from the NHS Digital download will be used for the main study analysis and it is this final report that will be available for NICE to review and consider, using aggregated results in line with NHS Digital suppression guidance.

At no point during the processing and publication of this data will individual identifiable patient information be released. Aggregate data will be used to address the principle study question of whether in a population of patients presenting to RACPC, routine FFRct as a default test is superior in terms of resource utilisation at 9 months when compared to routine clinical pathway algorithms recommended by NICE CG95.

Manuscripts will be submitted to high impact journals for consideration of publication in addition to presentations at national and international conferences.

It is planned to submit to the Lancet and will also submit a request to present at the European Society of Cardiology (ESC) Conference 2020.

Both the publication and presentation are designed to target clinical colleagues within the field of cardiovascular medicine. Southampton CTU will provide study results for research sites in a format suitable for participants. A lay study report will also drafted. This text will be supplied to all participating sites who will be able to pass this on to study participants. This may be via email or letter and will be at the discretion of the local PI and research team.

The current NICE guidelines recommend CT coronary angiography as the first line investigation for typical and atypical stable angina. NICE medical technologies guidance site HeartFlow FFRct as an additional assessment that can be performed in conjunction with the CT coronary angiogram as this may avoid the need for invasive coronary angiography and revascularization. NICE predict the use of FFRct may lead to cost savings of £214 per patient and by adopting this new technology nationally an overall saving of £9.1million as a minimum may be made to the NHS by 2020. The Forecast study will provide NICE with evidence to either support or question this assumption.

No NHS Digital data will be provided to researchers running other research studies within University Hospital Southampton NHS Foundation Trust or the University of Southampton.

All outputs will contain only data that is aggregated with small numbers suppressed in line with NHS Digital Guidance.

Processing:

Recruiting Trusts provide Southampton Clinical Trials Unit (CTU) who are based within the University of Southampton and situated at the University Hospital Southampton, with a copy of the patient consent form that is accompanied by a flagging form for those participants who agree to long term follow-up. The flagging form provides the source for identifiable information for the linkage of participants to long-term clinical and resource data in the format of - name, date of birth and NHS number. These data will be collated by the CTU and submitted as a single application to NHS Digital with a request for processing.

The University of Southampton (CTU) will send the cohorts name, date of birth and NHS number to NHS Digital for linkage to HES data.
NHS Digital will link the cohort to HES patient index and supply HES data.

- filter Admitted Patient Care data by episode start date >= consent date (start date)
further filter by OPCS codes which will be supplied.

- filter Outpatient data by appointment date >= consent date (start date)
further filter by OPCS codes which will be supplied.

No identifiable data will be returned to the University of Southampton (CTU) as the Study ID will be sufficient and no re-identification will take place.

Processing will require the collation of data to support both the primary and secondary endpoints for this study -

Primary endpoint - objective

To determine whether, in a population of patients presenting to RACPC, routine FFRct as a default test is superior, in terms of resource utilisation, when compared to routine clinical pathway algorithms recommended by NICE.

Endpoint used to evaluate resource utilisation at 9 months -

a) Requirement for non-invasive cardiac investigations
b) Invasive angiography
c) Revascularisation (including PCI & CABG)
d) Hospitalisation for cardiac event (including MI/unstable angina/revascularisation/heart failure/arrhythmia)
e) Cardiac medications

Secondary endpoint - objectives
To compare clinical outcomes between the two groups at 9 months.

Endpoint used to evaluate -
(a) Major adverse cardiac events including: non fatal MI, all coronary revascularisation, cardiac-related hospitalisation.
(b) Requirement for non-invasive cardiac investigations
(c) Requirement for invasive coronary angiography
(d) Coronary revascularisation
(e) Revascularisation procedural complications

- the comparison of the effect on general well being between the two groups at 9 months.
(a) Number of hospital attendances

Data is held securely within Southampton Clinical trials Unit which is based at the University of Southampton. The unit has controlled access to the building and to individual rooms within the building. Access is limited to individuals that have been vetted and approved through the allocation of swipe cards. All guests to the unit are required to sign in and out and are accompanied at all times. Computer access is password protected to limited individuals employed within the unit. Storage areas are securely maintained and all reasonable protection from floods, fire and physical damage are in place.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data.

Data will only be accessed and processed by substantive employees of The University of Southampton and will not be accessed or processed by any 3rd parties not named in this DSA, or for any other purpose.

---

Mortality and HES data at 12 months for patients in the CHARIOT study (BMJ 2019;364:l729) — DARS-NIC-287601-K4P2V

Type of data: information not disclosed for TRE projects

Opt outs honoured: Yes - patient objections upheld, Identifiable, Yes (Section 251 NHS Act 2006)

Legal basis: Health and Social Care Act 2012 – s261(7), Health and Social Care Act 2012 – s261(7), Health and Social Care Act 2012 - s261(5)(d); National Health Service Act 2006 - s251 - 'Control of patient information'.

Purposes: No (NHS Trust)

Sensitive: Non Sensitive, and Sensitive, and Non-Sensitive

When:DSA runs 2019-10-07 — 2022-10-06 2019.12 — 2019.12.

Access method: One-Off

Data-controller type: UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST

Sublicensing allowed: No

Datasets:

1. Hospital Episode Statistics Admitted Patient Care
2. Civil Registration - Deaths
3. HES:Civil Registration (Deaths) bridge
4. Civil Registration (Deaths) - Secondary Care Cut
5. Civil Registrations of Death - Secondary Care Cut
6. Hospital Episode Statistics Admitted Patient Care (HES APC)

Objectives:

CHARIOT stands for the following: Is the [C]urrent T[h]reshold for Diagnosis of “[A]bnormality”, including Non ST Elevation Myocardial Infarction, using [R]aised H[i]ghly Sensitive Tr[o]ponin Appropriate for a Hospi[t]al Population?

A blood test called troponin forms a key part of the diagnosis of a heart attack (myocardial infarction). Troponin refers to a group of proteins that help regulate the contractions of the heart and skeletal muscles. High troponin levels can indicate a problem with the heart. The heart releases troponin into the blood following an injury, such as a heart attack. The upper limit of normal for this test is determined by the manufacturer of the test, based on the troponin levels in healthy individuals, generally aged between 18-40. Recently assays have been developed that provide a higher degree of sensitivity and as such allow rapid exclusion of a heart attack within a few hours. This benefit does however raise another issue; elevated levels of high sensitivity troponin are now frequently seen in patients who have not suffered a heart attack. In the absence of clinical features of a heart attack an elevated high-sensitivity troponin leaves clinicians uncertain as to how to interpret this result and whether it should result in changes to patient care.

The original CHARIOT study, which has been published in the BMJ (BMJ 2019;364:l729), collected high-sensitivity troponin results from 20,000 consecutive patients who had blood samples requested by clinicians at University Hospital Southampton (UHS). The aim was to provide a description of the distribution of high-sensitivity troponin in a hospital population.
The CHARIOT study has highlighted the potential flaws in the use of the high-sensitivity troponin assay in front line clinical practice: the concern that the test is used to diagnose Type 1 myocardial infarction and yet; a) the cut off provided by the manufacturer of the test as the upper limit of normal is not appropriate, so that 1 in 20 patients at a large UK hospital have a high sensitivity troponin above this level even when there is no clinical suspicion of a myocardial infarction; b) the cause of the elevated high-sensitivity troponin is likely to be due to myocardial injury, rather than a type 1 myocardial infarction in most cases.

Having established these important observations in CHARIOT, the Coronary Research Group (CRG) at UHS now wish to pursue a secondary question from this 20,000 patient population, which the CRG is in an unique position to do: release of troponin in these patients probably indicates myocardial injury and does this act as a surrogate for worse clinical outcome?
Recent data in other patient cohorts including diabetics (Circulation 2017; 135:1911-1921) and chronic lung disease (BMC Pulm Med. 2016; 16:164) have suggested high-sensitivity troponin levels are associated with cardiovascular risk.

This study (CHARIOT - one year follow up) will aim to assess whether there is an association between high-sensitivity troponin levels and one year outcomes (mortality status, cause of death and admission diagnoses). This work is of significant public interest for three reasons. Firstly, as demonstrated by the CHARIOT study, this issue is frequently encountered in clinical practice; secondly - clinicians are often unsure whether these results are of clinical significance. Finally, if this study does demonstrate an association between high-sensitivity troponin levels and outcomes then further studies will result to assess whether any medical interventions, (particularly proven cardiovascular therapies), could alter the prognosis in this group. This study therefore has significant potential implications for the healthcare of a large population of patients both in the UK and internationally.

As such the study meets the standards set out in section Article 6 (1)(E) of the General Data Protection Regulation for processing these data: "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". Furthermore for these reasons it also meets the expectations set out for processing data set out in Article 9(2)(J) of the General Data Protection Regulation: "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".

The key ethical question raised by this study is whether it is appropriate to process these data without consent. As already discussed the potential improvements that this study could offer to patient care both in the UK and internationally mean that this study is undoubtedly in the public interest. Furthermore this study will have minimal risk to the patients included in the study and their personal data will be kept pseudonymised. It is therefore clear that the study has an ethical mandate. This opinion is also held by both the Research Ethics Committee and the Confidentiality Advisory Group, as demonstrated by their support for this study.

The data requested will help the research team to assess whether there is an association between high-sensitivity troponin levels and clinical outcomes. Specifically mortality status will allow the team to assess whether there is a link between high-sensitivity troponin levels and mortality. The cause of death is important because it would seem more likely that high-sensitivity troponin levels will predict cardiovascular mortality rather than all cause mortality. Without the cause of death the research team will be unable to evaluate this. Whilst mortality is a key aspect of health, future cardiovascular events are also of key importance . Therefore the discharge diagnoses from hospital admissions will allow the team to assess whether there is an association between high-sensitivity troponin levels and cardiovascular events.

The data returned from NHS Digital will need to be in a pseudonymised form (just with the unique study identifier that the CRG at UHS will send) to allow the CRG at UHS to link these data with the high-sensitivity troponin levels. If data were provided on an aggregate level it would not be possible to fully assess the association between high-sensitivity troponin levels and clinical/mortality outcomes. One year outcomes should provide the research teams with a clear picture of the relationship between high-sensitivity troponin levels and outcomes. This is the minimum time frame required to answer the primary objectives of this study. Is is likely that some patients will have moved or have been admitted to hospital whilst away from their permanent residence. Therefore the data will not be restricted to one particular geographical area, such as Southampton. It is not possible to achieve the aims of the study without processing these data. Furthermore the research team have specifically asked for the minimum data required to complete the objectives of this study, any less and it would not be possible to robustly evaluate the association between high-sensitivity troponin levels and clinical outcomes. The data required from the HES dataset relates to Diagnosis codes only.

The results from these analyses will result in improvements in the way clinicians interpret high-sensitivity troponin levels but may also precipitate further studies to assess whether any medical interventions could alter the outcomes in at risk groups identified by this study.

This study is a follow on from the CHARIOT study which recruited 20,000 consecutive patients (both in- and out-patients) in whom a biochemistry sample was performed at UHS between the 29th June 2017 and 24th August 2017. This request forms part of a separate study resulting from the original CHARIOT study. There are no additional phases. This particular study will be referred to as CHARIOT - one year follow up.

UHS will act as the sole Data Controller. UHS and the Keele Cardiovascular Research Group (KCRG -part of the University of Keele (UoK)) will act as the data processors. The KCRG was set up as a specialist center for the analysis of large cardiovascular data sets. As such the KCRG were involved in the analysis of the original CHARIOT study and it would be remiss not to continue to use their expertise to ensure that the data supplied by NHS Digital provide robust answers to the objectives of this study. The spreadsheet that will be sent to KCRG will contain the age (not date of birth) and gender of the patients in the cohort, alongside clinical information from NHS Digital, but no other identifiable data will be shared. KCRG will act under instructions from UHS - therefore reinforcing that UHS are sole data controller for this project.

The original CHARIOT study was funded by an unrestricted research grant from Beckman Coulter (BC). BC had no input in the study specifics. This sub-study requires no input from industry and specifically BC have no ongoing role. There are no other organisations involved. There are no funders/commissioners involved.

Expected Benefits:

The expected measurable benefit of the data access and the study will be an important contribution to the optimal use and interpretation of high sensitivity troponin assays in front line clinical practice. Use of high sensitivity troponin assays in front line practice is flawed in two ways. Firstly, there is widespread misunderstanding about the meaning of a raised high-sensitivity troponin; such a result is often incorrectly labelled as implying type 1 myocardial infarction, due to low awareness of myocardial injury. Secondly the upper limit of normal supplied by the manufacturer of the blood test is based upon a predominantly healthy population and UHS have shown in CHARIOT that this is not the 99th centile for 20,000 consecutive hospital patients.

Thus, whilst the current application of high-sensitivity troponin is largely flawed, data are accumulating that the assay (determining the quality) may have a clinically valuable alternative role as a biomarker of cardiovascular risk (Lancet 2018: 391; 10138: 2398).

The proposed study represents a unique opportunity to assess whether the high-sensitivity troponin levels in the 20,000 consecutive patients are indeed associated with mortality and future (HES derived) events. If so, the "never means nothing" hypothesis of high-sensitivity troponin should lead UHS to change the way that clinicians interpret the assay in front line hospital practice. It would no longer be an assay mistakenly used to "rule in" type 1 myocardial infarction, but rather a biomarker for patient risk prognosis.

The dissemination of this data is in the public interests because it has the potential to change the way that large groups of patients are managed.

The data are likely to result in changes in the way that high-sensitivity troponins are requested and also interpreted by clinicians. Furthermore as already discussed it is likely that these data will precipitate further study to assess whether cardiovascular interventions could change the outcomes in this group. This study will have wide implications, because, as demonstrated by the original CHARIOT study these patients are frequently seen in clinical practice. The benefit will be achieved by potential changes in clinical practice. It is expected that the dissemination of these data will occur within six months of NHS Digital releasing that data and then changes in clinical care will follow afterwards

Outputs:

There will be a multi-faceted approach to the dissemination of the results of this study. Firstly the results will be presented at respected medical conferences. Secondly the data will be published in respected peer review journals. These two activities will ensure that the key messages are available to the scientific community. The results will also be published (in a non-scientific format) on the UHS web pages. Like CHARIOT this study is also likely to generate significant press coverage which UHS will engage with to ensure that the results are widely disseminated to the general public. Finally the promotion of the published article through the use of social media will also widen the audience.

The results of this study are likely to be of immediate clinical relevance to clinicians by providing them with a better understanding of the clinical significance of the high-sensitivity troponin levels. Furthermore, if these data demonstrate that the high-sensitivity troponin levels are associated with cardiovascular outcomes then this is likely to stimulate further research to evaluate whether medical interventions can alter the outcomes seen in this group of patients. Whilst the aggregate results will be published to allow clinicians, scientists and the public to understand the implications of raised high-sensitivity troponin levels, the data themselves will not be released and will be stored and then destroyed following the standards set out by NHS Digital.

The patients included in the original CHARIOT study have not been directly informed of their participation in the study (apart from via the privacy notice) and as such UHS will not be sending any outputs directly to the patients included. The study therefore has no immediate direct benefit to the patients involved and is purely designed to guide future care of similar patients. However once the study has completed UHS plan to ensure that the results are available widely both to the medical community and the public. The outputs to the medical community will take the form of peer reviewed publications and presentations at medical conferences. The main output to the public will be through the updates and explanation of the results in the trusts patient facing research website. Furthermore, as was the case with the original CHARIOT study, it is likely that there will be some interest from the national press and so this will also provide a specific way of providing the outputs to the cohort involved and the general public.

All outputs will contain only aggregate level data with small numbers suppressed in line with the HES analysis guide.

Processing:

Only substantive employees of University Hospital Southampton NHS Foundation Trust and the Keele Cardiovascular Research Group (who have been trained in data protection and confidentiality) will have access to the data and only for the purposes described in this document. The data will be stored on secured computers within each of the listed data processing organisations.

University Hospital Southampton NHS Foundation Trust (UHS) will provide NHS Digital with the following identifiers of the cohort for the linkage to the data requested
- NHS number,
- date of birth,
- gender
- Study ID.

NHS digital will return clinical outcomes from the HES data and corresponding mortality data (date of death, cause of death and admission diagnoses) with each unique study ID. The CRG at UHS will then use the Study ID to link the data provided by NHS digital to the high-sensitivity troponin levels. Once this is complete the data will be sent to the KCRG to allow both the CRG and KCRG to undertake further statistical analysis. Re-identification of these patients will not be possible because the database will only contain the unique study identifier and gender of the patient - no other patient identifiers will be included. The patient identifiers are kept in a separate database. KCRG have no access to these other patient identifiers.

No contact will be made with the patients selected. The data will only be used for this study.
The NHS Digital data is crucial to provide the most accurate information on the outcome of patients recruited to this study and will form the basis of a robust research study that will be submitted to peer reviewed journals.

The data from this study will not be used for commercial purposes, not provided in record level form to any other third party not mentioned in this agreement, and not used for direct marketing or commercial purposes.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guide.

---

Project 10 — DARS-NIC-10497-N0K9V

Type of data: information not disclosed for TRE projects

Opt outs honoured: N

Legal basis: Health and Social Care Act 2012

Purposes: ()

Sensitive: Non Sensitive

When:2016.04 — 2016.08.

Access method: One-Off

Data-controller type:

Sublicensing allowed:

Datasets:

1. Hospital Episode Statistics Admitted Patient Care

Objectives:

The project is regarding children (<18yrs) with inflammatory bowel disease and surgery (IBD) (for IBD or an initial appendectomy) and the influence of biological agents on rates of surgery.

The data will be used to test 3 null hypotheses, i.e.
1. The introduction of biological agents has not affected the rate of Gastro Intestinal (GI) surgery in children with non-infective colitis (i.e. Inflammatory Bowel Disease)
2. Appendectomy does not change the risk of subsequently developing Inflammatory Bowel disease
3. Appendectomy performed after a diagnosis of Inflammatory Bowel disease does not change the risk of requiring a bowel resection.

The period of data (1997/98-2014/15) covers the time when use of Infliximab/Adalimumab use has increased, as well as allowing investigation of longitudinal trends to analyse the root causes of any systemic change in patient outcomes.

Expected Benefits:

At the present time there is minimal available evidence regarding the utility of appendicectomy in the management of inflammatory bowel disease in children (either as a preventative or treatment option). This study will provide an important step in the scientific basis for clinical management of these patients. This knowledge will be used by Paediatric surgeons and Gastroenterologists to guide the clinical management of children with Inflammatory Bowel Disease or a family history there-of.

There is also great potential for a randomised controlled clinical trial on this topic (such as the ACCURE trial which is the adult equivalent trial), however the baseline population data in this area is required to ensure that this is the correct path. The data under this agreement will not be used as part of a future clinical trial without an application to the HSCIC for approval.

Outputs:

Analysed aggregated results will be shared in a peer reviewed healthcare journal in 2016/17 (specifically the Journal of Pediatric Surgery, The Archives of Disease in Childhood). The Trust expect that the results of this retrospective linkage analysis will provide the best available evidence to guide management of children with inflammatory bowel disease or a strong family history of the same. Small numbers will be supressed in line with the HES analysis guide.

Processing:

It will be investigated by looking at;
Objective One
• How many children undergo appendectomy per year (1997-2015)?

Objective Two
• How many new diagnoses of Crohns’ disease or Ulcerative Colitis (UC) or Indeterminate Colitis (IC) are made per year in children?
• How many children require a surgical procedure for Crohn's, UC or IC (other than endoscopy) per year?
• What is the admission rate per year for children with a diagnosis of UC.

To answer these aims, the Trust will supply a list of operative codes of interest (including endoscopy which is to be excluded).

Objective Three
• Do children who have undergone appendectomy (for any reason) go on to have a higher or lower rate of a later diagnosis of UC. The Trust wishes to investigate whether children who undergo appendectomy, then are later diagnosed with UC are more/less likely to later require surgery (colectomy) for UC

The Trust wishes to investigate patients with multiple diagnoses or operative procedure codes:
1. UC diagnosis + subsequent colectomy
2. Appendectomy code, subsequent UC diagnosis (ever)
3. Appendectomy code, subsequent UC diagnosis, and subsequent colectomy code
4. Appendectomy diagnosis, subsequent UC diagnosis, no subsequent colectomy code.
5. Appendectomy code, subsequent UC diagnosis, and subsequent hospital admission rate
6. UC diagnosis, subsequent hospital admission rate
7. UC diagnosis, later appendectomy diagnosis, and then later colectomy code
8. UC diagnosis, later appendectomy code, subsequent hospital admission rate

Objective Four
• How many patients present each year with IBD and how many of them attend for Infliximab/Adalimumab each year - the 2 subgroups should then be analysed for further operative codes relating to IBD surgery. Specifically the Trust will be looking at the rate of colectomy operations (removal of part or whole of large bowel to treat inflammatory bowel disease). This is usually undertaken either after failure of medicines to control the disease satisfactorily, to treat narrowing of the bowel caused by disease or rarely to treat very serious inflammatory bowel disease in an emergency.

The Trust are interested in using this data to assess the rate and timing of such surgery relative to disease onset and treatment with these medicines. The Trust are able to assess the use of these medicines here as they have been allocated a high cost drug code which is recorded by HES. This data will be particularly interesting as it spans a period where it is expected that the use of these medicines has increased substantially.

---