Understanding the long-term effects of whole blood and platelet donation

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

BACKGROUND NHS Blood and Transplant (NHSBT) and the University of Cambridge require access to NHS England data for the purpose of the following research project: NHS Blood and Transplant (NHSBT) and other blood services have a duty of care for their donors, not only ensuring that they are fit to donate, but also that possible harmful effects of single or repeat donations are avoided. However, while much attention has been given to transfusion safety through improvement of disease screening and donor selection, very little is known about the possible long-term health effects of either repeated whole blood donation or platelet donation by apheresis (e.g. plasma and platelet components of the blood) on outcomes such as cardiovascular disease, diabetes, cancer etc. Moreover, studies investigating these effects have typically focused on only one disease outcome and have included only a few hundred disease cases. Thus, the question of the impact of blood donation on long term health, though essential to donors, remains largely unanswered. Understanding the long-term effects of whole blood and platelet donation AIM AND PURPOSE NHSBT and other blood services have a duty of care for their donors, not only ensuring that they are fit to donate, but also that possible harmful effects of single or repeat donations are avoided. However, while much attention has been given to transfusion safety through improvement of disease screening and donor selection, very little is known about the possible long-term health effects of either repeated whole blood donation or platelet donation by apheresis (e.g., plasma and platelet components of the blood) on outcomes such as cardiovascular disease, diabetes, cancer etc. Moreover, studies investigating these effects have typically focused on only one disease outcome and have included only a few hundred disease cases. Thus, the question of the impact of blood donation on long term health, though essential to donors, remains largely unanswered. Primary objective: The long-term objective of this research study is to establish a powerful, cost-effective and pragmatic surveillance platform, embedded within the NHSBT service, that may provide evidence-based assessment of the long-term effect of whole blood and platelet donation on several chronic disease outcomes. The University of Cambridge is establishing this resource by linking existing donor’s records with multiple electronic health record sources. This e-health resource hopes to provide unprecedented power to evaluate claims about the putative risk and benefits of frequent whole blood donation and platelet donation by apheresis, both in relation to existing longstanding claims (e.g., cardiovascular disease and type 2 diabetes), more recent claims (e.g., neurodegenerative disease) and un-anticipated claims which may arise in the future. The immediate objective of the current demonstration study is to determine whether establishing a surveillance platform by linkage of donor’s records with e-health records is feasible and informative. Specific aims of this pilot study include: The long-term objective of this research study (see here for the study website - http://www.donorhealth-btru.nihr.ac.uk/nhsbt-linkage-study/) is to establish a powerful, cost-effective and pragmatic surveillance platform, embedded within the NHSBT service, that may provide evidence based assessment of the long-term effect of whole blood and platelet donation on several chronic disease outcomes. The University of Cambridge is establishing this resource by linking existing donor’s records with multiple electronic health record sources. This e-health resource hopes to provide unprecedented power to evaluate claims about the putative risk and benefits of frequent whole blood donation and platelet donation by apheresis, both in relation to existing longstanding claims (e.g. cardiovascular disease and type 2 diabetes), more recent claims (e.g. neurodegenerative disease) and un-anticipated claims which may arise in the future. The immediate objective of the current demonstration study is to determine whether establishing a surveillance platform by linkage of donor’s records with e-health records is feasible and informative. Specific aims of this pilot study include: [8 paragraphs unchanged] COHORT The project is now complete. NHSBT and the University of Cambridge would like to retain this Data to ensure reconstruction of the study analysis is possible if required. All donors registered in the NHSBT PULSE database aged 18 years or older with a history of at least one whole blood or apheresis donation may be included in the study. Participants are selected from the full donor pool held in the PULSE database to obtain a representative sample of the NHSBT blood donor population. NHSBT PULSE records contain donation records on all donors within NHSBT for donations at all 25 fixed donation centres and the numerous mobile centres. A random sample of 200,000 donor records including active and inactive donors has been obtained from the NHSBT PULSE database for linkage in the pilot study to which this Agreement relates. No additional data is required under this iteration of the Agreement. All data disseminated is within the scope of what DAAG/CAG originally provided approval for. The record level data supplied by NHS England has not been/will not be shared with third parties. The demonstration study sample size of 200,000 participants has been determined on the basis of several factors including: (1) Need to assess linkage feasibility in a sufficiently large sample to capture the full complexity of a large-scale study including >2 million donors (2) Obtaining a representative sample of the blood donor population (a sample size of 200,000 donors represents approximately 10% of the active donor population) DATA SUMMARY [1 paragraph unchanged] Hospital Episodes Statistics (HES) Admitted Patient Care for the period 2003/2004 – 2012/2013 > Hospital Episode Statistics (HES) HES Outpatients for the period 2003/2004 – 2012/2013 - Admitted Patient Care (APC) Civil Registration (Deaths) – Secondary Care Cut (linked to HES data) – filtered to deaths which occurred between 01/04/2003 and 31/03/2013. - Outpatients (OP) No additional data is required under this iteration of the Agreement. All data disseminated is within the scope of what DAAG/CAG originally provided approval for. The record level data supplied by NHS England has not been/will not be shared with third parties. > Civil Registration Mortality The University of Cambridge and NHSBT are conducting a retrospective data linkage study using blood donor records from the NHSBT PULSE database. Donor records are linked to electronic health data to determine the long-term effects of blood donation on chronic disease outcomes and bone fracture. Retrospective linkage is being sought between Civil Registration (Deaths) – secondary care cut records and previously linked Hospital Episode Statistics (HES)-NHSBT blood donor records. In this pilot study, only retrospective linkage was sought in accordance with the ethical approvals obtained from the Research Ethics Committee East of England - Cambridge East (Ref: 14/EE/0182). Any future studies will be based on a consent framework and will be subject to separate data requests and ethical approvals. The level of the Data being retained will be: The University of Cambridge, in collaboration with NHSBT, expect to be able to provide strong evidence for the medium and long-term health effects of blood donation through analysis of the linked NHS England data. Results from this research may help to guide future NHSBT practice and strategies to ensure the long-term health of their donor population. Data is required for a 10-year period as the aim is to investigate the long term effect of blood donation on donor health. As part of the pilot study, it is essential that the data mimics the time frame the University of Cambridge expect to perform analyses for the full phase of the study (pending further approvals). Only product fields required for the purposes of the research study have been disseminated by NHS England in line with the GDPR principle of data minimisation. > Pseudonymised DATA CONTROLLERSHIP/FUNDING The data was minimised as follows: NHSBT and the University of Cambridge are joint data controllers for the purposes of this Data Sharing Agreement. The NHS England data disseminated under this Agreement will be accessed by the University of Cambridge alone. NHSBT have no means to access or process NHS England data. > Limited to data for a study cohort (approximately 200,000 individuals) identified by NHSBT – cohort consists of all donors registered in the NHSBT PULSE database aged 18 years or older with a history of at least one whole blood or apheresis donation. Participants are selected from the full donor pool held in the PULSE database to obtain a representative sample of the NHSBT blood donor population. NHSBT PULSE records contain donation records on all donors within NHSBT for donations at all 25 fixed donation centres and the numerous mobile centres. A random sample of 200,000 donor records including active and inactive donors has been obtained from the NHSBT PULSE database for linkage in the pilot study to which this Agreement relates; The study is funded by National Institute for Health and Care Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Behaviour (formally Donor Health and Genomics). The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge has received core support from the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and the NIHR Cambridge Biomedical Research Centre. The funding organisation will not have access to the record-level data disseminated under this Agreement; only aggregate outputs with small numbers suppressed in line with the HES analysis guide. Furthermore, none of the listed organisations have any decision-making responsibility regarding the use of NHS England data, nor can they access or process the NHS England disseminated. > Limited to data between 2003/2004 – 2012/2013 LEGAL BASIS FOR PROCESSING NHSBT and the University of Cambridge are joint Controllers as the organisations jointly responsible for ensuring that the Data will only be processed for the purpose described above. The University of Cambridge have a legal basis to process the data requested under article 6(1)(e) and article 9(2)(j) of the General Data Protection Regulation (GDPR): 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 University of Cambridge is considered a public authority under Schedule 1 Section 53(1)(b) of the Freedom of Information Act - 'a university receiving financial support under section 65 of the Further and Higher Education Act 1992' is considered a public authority. The Higher Education Funding Council (now the Office for Students) names the University of Cambridge as one of the institutions to which they provide funding. The University of Cambridge also has a basis in law for lawfulness of processing, per Part 2 Chapter Section 8(e) of the Data Protection Act 2018, as they hold a Royal Charter. > 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; - Article 9(2)(j) – ‘Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes’. The data are required for research purposes in the public interest – meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) – which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public, thereby demonstrating that the processing is in the public interest, are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’. The lawful basis for processing special category data under the UK GDPR is: PATIENT AND PUBLIC INVOLVEMENT > 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. The NIHR BTRU in Donor Health and Behaviour has a management group that advises on the study. Two lay public members sit on the management group panel. The University of Cambridge work closely with the Patient and Public Involvement and Engagement panel of blood donors, managed by the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, who provide advice on planning strategies and the dissemination of results. The NIHR BTRU in Donor Health and Behaviour also has an active public engagement programme (see http://www.donorhealthbtru.nihr.ac.uk/btru_events/). The study team will continue to work with the public members when disseminating the results. The funding comes from multiple sources. Current funders include: > National Institute for Health and Care Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Behaviour (formally Donor Health and Genomics) > UK Medical Research Council > British Heart Foundation > NIHR Cambridge Biomedical Research Centre Funding to continue the work described will be sought on an ongoing basis. The funder(s) will have no ability to suppress or otherwise limit the publication of findings. The NIHR BTRU in Donor Health and Behaviour has a management group that advises on the study. Two lay public members sit on the management group panel. The University of Cambridge work closely with the Patient and Public Involvement and Engagement panel of blood donors, managed by the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, who provide advice on planning strategies and the dissemination of results. The NIHR BTRU in Donor Health and Behaviour also has an active public engagement programme. The study team will continue to work with the public members when disseminating the results.

Processing activities

The data linkage process was as follows: No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). 1. NHSBT sent the encrypted HESIDs for each of the 200,000 individuals comprising the blood donor cohort to NHS England. The University of Cambridge holds the relevant records from the HES and deaths datasets. 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. 2. NHS England de-encrypted the HES IDs for the cohort and linked to HES and Civil Registration (Deaths) – secondary care cut data. No additional data will be disseminated by NHS England for the purposes of this DSA. 3. NHS England sent the linked dataset containing the pseudonymised HES, Civil Registration (Deaths) – secondary care cut data and the Study ID to the University of Cambridge’s Department of Public Health and Primary Care. There the health data was linked to blood donation history using the Study ID. The Data will be stored on the Secure Data Hosting Service (SDHS) at the University of Cambridge. University of Cambridge have a legal basis under the common law duty of confidentiality to allow NHSBT to flow identifiers (NHS number, surname, date of birth, postcode and a unique pseudo ID) to NHS England for linkage to HES and Civil Registrations (Deaths) - secondary care cut data under s.251 of the NHS Act 2006. The data may not be transferred to any other location and may only be accessed by substantive employees of the University of Cambridge for the purposes described above. NHS Blood and Transplant (NHSBT) do not access any record level data. The record level data is not shared with any third parties. This DSA does not permit any further processing that involves analysis or linkage other than for the purpose in line with the original objectives of the study described. The data is held on the Secure Data Hosting Service (SDHS) at the University of Cambridge. The SDHS provides a dedicated network, separated from the production network by a firewall, for storing sensitive personal data and hosting computers involved in its management and analysis. Access to the SDHS is restricted to designated members of staff and requires two factor authentication. Only substantive employees of the University of Cambridge, under the direction of the Principal Investigator, will access NHS England data. All processing will be carried out by the University of Cambridge on the SDHS. The Data will not be transferred to any other location. Analyses To answer the central research question of the study (what are the risks and benefits of repeated whole blood and platelet donation on major chronic disease outcomes?) the University of Cambridge will perform extensive analyses on the number of whole blood donations and a list of major diseases (e.g., cardiovascular, cancer-related, others). The University of Cambridge will also perform similar analyses to compare donors who performed apheresis donation (e.g. platelet donation) with donors who did not. As the natural history of chronic diseases requires months or years between the initial biological damage and the disease’s clinical onset, the University of Cambridge will perform analyses across three different time periods: zero, two or five years from the date of last donation. For each disease, the University of Cambridge will count only events that occurred after each latency threshold. The proposed analyses above are within the scope of the original pilot study approved by CAG/NHS England. If further analysis/data sets are required, additional approval from CAG will need to be sought along with NHS England approval.

Expected output

To date, preliminary results have been presented at the 3rd European Conference on Donor Health and Management (5-7 September 2018 in Copenhagen, Denmark). Outputs have however, in the main, been delayed due to the COVID-19 pandemic and to the delayed reception of the first extension request. In the previous version of the agreement, the initial aim was to submit outputs for publication in peer reviewed journals (for example Transfusion or Vox Sanguinis) and feedback study findings to NHSBT by June 2023. As the team received the data on 25/07/2023, this target is not achievable anymore. Now, the team will target submitting outputs for publication in February 2024. The expected outputs of the processing will be: In October 2023, analysis of mortality data in the context of the previous analysis (that focused on disease outcomes from Hospital Episode Statistics) was complete. Now this has been completed, the University of Cambridge have the following targets: > A manuscript • October 2023-February 2024: publication write-up and submission. > Presentations at appropriate conferences; preliminary results have been presented at the 3rd European Conference on Donor Health and Management • March 2024-February 2025: peer-review process and completion of any additional analyses that peer-reviewers may request. The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. The pilot study will be completed by February 2025, providing there are no further major setbacks. The outputs will be communicated to relevant recipients through the following dissemination channels: Results will also be communicated through the study website (http://www.donorhealth-btru.nihr.ac.uk/), newsletters, press releases and media interviews. > Conferences When sharing research findings, results will be displayed as aggregate data only with small numbers suppressed, in line with the HES analysis guide. > Study website updates > Press/media engagement

Expected measurable benefits

Once analyses are completed by February 2024, results will be fed back to NHSBT. NHSBT will be kept informed of any preliminary findings as the analyses take place. The following information describes the expected measurable benefits as specified in the previous version of this Data Sharing Agreement (DSA): [5 paragraphs unchanged]

Benefits reported

Initial, preliminary findings from the analysis (using HES data) have been presented at the 3rd European Conference on Donor Health and Management (5-7 September 2018) in Copenhagen, Denmark. The main findings of the study are that there was no evidence of associations between apheresis donation (e.g., platelet donation) and health outcomes. There was evidence of an increased risk of coronary and thromboembolic outcomes in certain blood groups, but this warrants further analysis and investigation. The preliminary results of this study are generally in line with the broader existing literature and show evidence of healthy donor bias - a distortion arising from donors being usually healthier than the general population, and more frequent donors being usually healthier than less frequent donors. The University of Cambridge’s preliminary analysis has shown that there was no evidence of associations between apheresis donation (e.g. platelet donation) and health outcomes. There was evidence of an increased risk of coronary and thromboembolic outcomes in certain blood groups, but this warrants further analysis and investigation. The preliminary results of this study are generally in line with the broader existing literature - there is still uncertainty on their interpretation and further analysis is required.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

[26 paragraphs unchanged] The University of Cambridge has a legal basis under the common law duty of confidentiality to supply identifiers to NHS England for linkage to HES and Civil Registrations (Deaths) - secondary care cut data as they have s.251 support under the NHS Act 2006 from the Health Research Authority Confidential Advisory Group (reference - CAG 1-07(c)/2014). [9 paragraphs unchanged]

Processing activities

[4 paragraphs unchanged] University of Cambridge have a legal basis under the common law duty of confidentiality to allow NHSBT to flow identifiers (NHS number, surname, date of birth, postcode and a unique pseudo ID) to NHS England for linkage to HES and Civil Registrations (Deaths) - secondary care cut data under s.251 of the NHS Act 2006. [3 paragraphs unchanged] To answer the central research question of the study study (what are the risks and benefits of repeated whole blood and [44 words unchanged] who performed apheresis donation (e.g. platelet donation) with donors who did not. [2 paragraphs unchanged]

Expected output

To date, preliminary results have been presented at the 3rd European Conference [11 words unchanged] Outputs have however, in the main, been delayed due to the COVID-19 pandemic. The pandemic and to the delayed reception of the first extension request. In the previous version of the agreement, the initial aim is was to submit outputs for publication in peer reviewed journals (for example Transfusion or Vox Sanguinis) and feedback study findings to NHSBT by June 2023. As the team received the data on 25/07/2023, this target is not achievable anymore. Now, the team will target submitting outputs for publication in February 2024. Once this version In October 2023, analysis of mortality data in the context of the agreement previous analysis (that focused on disease outcomes from Hospital Episode Statistics) was complete. Now this has been signed off and processing of the data can be resumed, completed, the University of Cambridge have the following targets: • December 2022-January 2023: analysis of ONS mortality data in the context of the previous analysis (that focused on disease outcomes from Hospital Episode Statistics). • October 2023-February 2024: publication write-up and submission. • February 2023-June 2023 : publication write-up and submission. • March 2024-February 2025: peer-review process and completion of any additional analyses that peer-reviewers may request. • July 2023-December 2023: peer-review process and completion of any additional analyses that peer-reviewers may request. The pilot study will be completed by February 2025, providing there are no further major setbacks. The pilot study will be complete by December 2023, providing there are no further major setbacks. [2 paragraphs unchanged]

Expected measurable benefits

Once analyses are completed at the end of 2022, by February 2024, results will be fed back to NHSBT. NHSBT will be kept informed of any preliminary findings as the analyses take place. The short and long-term benefits below remain the same for the purposes of this application to extend and amend the Data Sharing Agreement: The expected short and long-term benefits are detailed below: [2 paragraphs unchanged] In the long term, this study hopes to provide the basis for [77 words unchanged] donation in the UK and worldwide. Further, the information provided to donors will should allow them to make a more informed decision about frequent blood donation with regards to their long-term health. [1 paragraph unchanged]

Changed only in punctuation, spacing or capitalisation: Benefits reported.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. BACKGROUND Data held by the University of Cambridge must be securely stored and not otherwise processed. NHS Blood and Transplant (NHSBT) and other blood services have a duty of care for their donors, not only ensuring that they are fit to donate, but also that possible harmful effects of single or repeat donations are avoided. However, while much attention has been given to transfusion safety through improvement of disease screening and donor selection, very little is known about the possible long-term health effects of either repeated whole blood donation or platelet donation by apheresis (e.g. plasma and platelet components of the blood) on outcomes such as cardiovascular disease, diabetes, cancer etc. Moreover, studies investigating these effects have typically focused on only one disease outcome and have included only a few hundred disease cases. Thus, the question of the impact of blood donation on long term health, though essential to donors, remains largely unanswered. The following provides background information on the purpose of the original study: AIM AND PURPOSE NHS Blood and Transplant (NHSBT) and other blood services have a duty of care for their donors, not only ensuring that they are fit to donate, but also that possible harmful effects of single or repeat donations are avoided. However, while much attention has been given to transfusion safety through improvement of disease screening and donor selection, very little is known about the possible long-term health effects of either repeated whole blood donation or platelet donation by apheresis on outcomes such as cardiovascular disease, diabetes, cancer etc. Moreover, studies investigating these effects have typically focused on only one disease outcome, and have included only a few hundred disease cases. Thus the question of the impact of blood donation on long term health, though essential to donors, remains largely unanswered. Primary objective: As such, the long-term objective of this project is to address a question of considerable national and international public health importance: What is the balance of any risks and benefits of repeated whole blood and platelet donation by apheresis on major chronic disease outcomes? In order to answer this question, the long-term aim of this research will be to establish an unprecedentedly large and detailed population research platform involving donors enrolled within NHSBT, who will be linked to a variety of electronic health (e-health) records such as Hospital Episode Statistics (HES), Civil Registration mortality and cancer data, Myocardial Ischaemia National Audit Project (MINAP) data. The record level data will not be shared with third parties. With the broad range of health outcomes available from these health records, this platform will allow University of Cambridge in collaboration with NHSBT, to provide strong evidence in large numbers of donors on the question of the medium and long-term health effects of blood donation. Results from this research will help to guide future NHSBT practice and strategies to ensure the long term health of their donor population. This future study will be subject to a separate data application and will undergo a separate ethics approval. The long-term objective of this research study (see here for the study website - http://www.donorhealth-btru.nihr.ac.uk/nhsbt-linkage-study/) is to establish a powerful, cost-effective and pragmatic surveillance platform, embedded within the NHSBT service, that may provide evidence based assessment of the long-term effect of whole blood and platelet donation on several chronic disease outcomes. The University of Cambridge is establishing this resource by linking existing donor’s records with multiple electronic health record sources. This e-health resource hopes to provide unprecedented power to evaluate claims about the putative risk and benefits of frequent whole blood donation and platelet donation by apheresis, both in relation to existing longstanding claims (e.g. cardiovascular disease and type 2 diabetes), more recent claims (e.g. neurodegenerative disease) and un-anticipated claims which may arise in the future. The immediate objective of the current demonstration study is to determine whether establishing a surveillance platform by linkage of donor’s records with e-health records is feasible and informative. Specific aims of this pilot study include: The aim of the current pilot study to which this Agreement relates, is to determine whether it is operationally feasible to establish a non-identifiable electronic haemovigilance platform which will allow NHSBT to address immediate questions relating to donor health. As part of this pilot study, retrospective linkage is being sought between Civil Registration records and previously linked HES-NHSBT blood donor records. In this pilot study, only retrospective linkage is being requested in accordance with the ethical approvals obtained. Any future studies will be based on a consent framework and will be subject to separate data requests and ethical approvals. (1) developing formal processes for obtaining permission for data usage from different organisations; Under previous iterations of this Agreement, the University of Cambridge received Civil Registration Mortality and HES Admitted Patient Care and Outpatient data. (2) establishing protocols for data extraction, linkage, transportation, and storage; University of Cambridge Department of Public Health and Primary Care (DPHPC) will only have access to pseudonymised record-level data. (3) obtaining reliable records linkage with mortality and hospital data using a trusted third party; All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide. (4) exploring linkage with disease-specific registries and primary care data; (5) developing and refining methods for data cleaning and harmonisation; (6) establishing protocols for data analysis and performing initial key analyses to assess the validity of the data. Secondary objective: The added value provided by this study hopes to be the creation of a national epidemiological bioresource that is anticipated to enable further research relevant to blood donors. COHORT All donors registered in the NHSBT PULSE database aged 18 years or older with a history of at least one whole blood or apheresis donation may be included in the study. Participants are selected from the full donor pool held in the PULSE database to obtain a representative sample of the NHSBT blood donor population. NHSBT PULSE records contain donation records on all donors within NHSBT for donations at all 25 fixed donation centres and the numerous mobile centres. A random sample of 200,000 donor records including active and inactive donors has been obtained from the NHSBT PULSE database for linkage in the pilot study to which this Agreement relates. The demonstration study sample size of 200,000 participants has been determined on the basis of several factors including: (1) Need to assess linkage feasibility in a sufficiently large sample to capture the full complexity of a large-scale study including >2 million donors (2) Obtaining a representative sample of the blood donor population (a sample size of 200,000 donors represents approximately 10% of the active donor population) DATA SUMMARY The University of Cambridge hold the following NHS England data (pseudonymised, record-level): Hospital Episodes Statistics (HES) Admitted Patient Care for the period 2003/2004 – 2012/2013 HES Outpatients for the period 2003/2004 – 2012/2013 Civil Registration (Deaths) – Secondary Care Cut (linked to HES data) – filtered to deaths which occurred between 01/04/2003 and 31/03/2013. No additional data is required under this iteration of the Agreement. All data disseminated is within the scope of what DAAG/CAG originally provided approval for. The record level data supplied by NHS England has not been/will not be shared with third parties. The University of Cambridge and NHSBT are conducting a retrospective data linkage study using blood donor records from the NHSBT PULSE database. Donor records are linked to electronic health data to determine the long-term effects of blood donation on chronic disease outcomes and bone fracture. Retrospective linkage is being sought between Civil Registration (Deaths) – secondary care cut records and previously linked Hospital Episode Statistics (HES)-NHSBT blood donor records. In this pilot study, only retrospective linkage was sought in accordance with the ethical approvals obtained from the Research Ethics Committee East of England - Cambridge East (Ref: 14/EE/0182). Any future studies will be based on a consent framework and will be subject to separate data requests and ethical approvals. The University of Cambridge, in collaboration with NHSBT, expect to be able to provide strong evidence for the medium and long-term health effects of blood donation through analysis of the linked NHS England data. Results from this research may help to guide future NHSBT practice and strategies to ensure the long-term health of their donor population. Data is required for a 10-year period as the aim is to investigate the long term effect of blood donation on donor health. As part of the pilot study, it is essential that the data mimics the time frame the University of Cambridge expect to perform analyses for the full phase of the study (pending further approvals). Only product fields required for the purposes of the research study have been disseminated by NHS England in line with the GDPR principle of data minimisation. The University of Cambridge has a legal basis under the common law duty of confidentiality to supply identifiers to NHS England for linkage to HES and Civil Registrations (Deaths) - secondary care cut data as they have s.251 support under the NHS Act 2006 from the Health Research Authority Confidential Advisory Group (reference - CAG 1-07(c)/2014). DATA CONTROLLERSHIP/FUNDING NHSBT and the University of Cambridge are joint data controllers for the purposes of this Data Sharing Agreement. The NHS England data disseminated under this Agreement will be accessed by the University of Cambridge alone. NHSBT have no means to access or process NHS England data. The study is funded by National Institute for Health and Care Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Behaviour (formally Donor Health and Genomics). The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge has received core support from the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and the NIHR Cambridge Biomedical Research Centre. The funding organisation will not have access to the record-level data disseminated under this Agreement; only aggregate outputs with small numbers suppressed in line with the HES analysis guide. Furthermore, none of the listed organisations have any decision-making responsibility regarding the use of NHS England data, nor can they access or process the NHS England disseminated. LEGAL BASIS FOR PROCESSING The University of Cambridge have a legal basis to process the data requested under article 6(1)(e) and article 9(2)(j) of the General Data Protection Regulation (GDPR): 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 University of Cambridge is considered a public authority under Schedule 1 Section 53(1)(b) of the Freedom of Information Act - 'a university receiving financial support under section 65 of the Further and Higher Education Act 1992' is considered a public authority. The Higher Education Funding Council (now the Office for Students) names the University of Cambridge as one of the institutions to which they provide funding. The University of Cambridge also has a basis in law for lawfulness of processing, per Part 2 Chapter Section 8(e) of the Data Protection Act 2018, as they hold a Royal Charter. - Article 9(2)(j) – ‘Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes’. The data are required for research purposes in the public interest – meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) – which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public, thereby demonstrating that the processing is in the public interest, are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’. PATIENT AND PUBLIC INVOLVEMENT The NIHR BTRU in Donor Health and Behaviour has a management group that advises on the study. Two lay public members sit on the management group panel. The University of Cambridge work closely with the Patient and Public Involvement and Engagement panel of blood donors, managed by the NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, who provide advice on planning strategies and the dissemination of results. The NIHR BTRU in Donor Health and Behaviour also has an active public engagement programme (see http://www.donorhealthbtru.nihr.ac.uk/btru_events/). The study team will continue to work with the public members when disseminating the results.

Processing activities

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 data linkage process was as follows: The following describes the processing activities permitted under previous iterations of this Agreement: 1. NHSBT sent the encrypted HESIDs for each of the 200,000 individuals comprising the blood donor cohort to NHS England. 1. University of Cambridge sent the encrypted HESIDs for each individual to NHS Digital for linkage of a demographic blood donor dataset on 200 000 donors, for linkage to: 2. NHS England de-encrypted the HES IDs for the cohort and linked to HES and Civil Registration (Deaths) – secondary care cut data. - Civil Registration Mortality Data including date of death 3. NHS England sent the linked dataset containing the pseudonymised HES, Civil Registration (Deaths) – secondary care cut data and the Study ID to the University of Cambridge’s Department of Public Health and Primary Care. There the health data was linked to blood donation history using the Study ID. 2. NHS Digital provided a linked dataset containing mortality data together with the internal (non-identifiable) study id to University of Cambridge Department of Public Health and Primary Care. There the health data will be linked to blood donation history using the internal study id. The research dataset will be stored on secure servers at the University of Cambridge Clinical School and will be accessible only to authorised staff members nominated in the ethics approvals. Only substantive employees of University of Cambridge will have access to the NHS Digital data. University of Cambridge have a legal basis under the common law duty of confidentiality to allow NHSBT to flow identifiers to NHS England for linkage to HES and Civil Registrations (Deaths) - secondary care cut data under s.251 of the NHS Act 2006. The HES data had already been provided to University of Cambridge Department of Public Health and Primary Care. NHS Blood and Transplant (NHSBT) do not access any record level data. The record level data is not shared with any third parties. NHS Blood and Transplant (NHSBT) will not access any record level data. The record level data will not be shared with any third parties. The data is held on the Secure Data Hosting Service (SDHS) at the University of Cambridge. The SDHS provides a dedicated network, separated from the production network by a firewall, for storing sensitive personal data and hosting computers involved in its management and analysis. Access to the SDHS is restricted to designated members of staff and requires two factor authentication. Only substantive employees of the University of Cambridge, under the direction of the Principal Investigator, will access NHS England data. All processing will be carried out by the University of Cambridge on the SDHS. All outputs and publications will contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide. Analyses All processing of mortality data will be in line with ONS standard conditions “Individuals, working under appropriate supervision on behalf of data controller(s) / processor(s) within this agreement, who are subject to the same policies, procedures and equivalent controls as substantive employees”. To answer the central research question of the study study (what are the risks and benefits of repeated whole blood and platelet donation on major chronic disease outcomes?) the University of Cambridge will perform extensive analyses on the number of whole blood donations and a list of major diseases (e.g., cardiovascular, cancer-related, others). The University of Cambridge will also perform similar analyses to compare donors who performed apheresis donation (e.g. platelet donation) with donors who did not. 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 i.e. employees, agents and contractors of the Data Recipient who may have access to that data As the natural history of chronic diseases requires months or years between the initial biological damage and the disease’s clinical onset, the University of Cambridge will perform analyses across three different time periods: zero, two or five years from the date of last donation. For each disease, the University of Cambridge will count only events that occurred after each latency threshold. The data approved under this Data Sharing Agreement will not be linked further. The proposed analyses above are within the scope of the original pilot study approved by CAG/NHS England. If further analysis/data sets are required, additional approval from CAG will need to be sought along with NHS England approval.

Expected output

This Agreement permits the secure retention of the data only and no other processing. To date, preliminary results have been presented at the 3rd European Conference on Donor Health and Management (5-7 September 2018 in Copenhagen, Denmark). Outputs have however, in the main, been delayed due to the COVID-19 pandemic. The aim is to submit outputs for publication in peer reviewed journals (for example Transfusion or Vox Sanguinis) and feedback study findings to NHSBT by June 2023. No new outputs will be produced under this Data Sharing Agreement. Once this version of the agreement has been signed off and processing of the data can be resumed, the University of Cambridge have the following targets: Data was supplied for the purpose of a demonstration study aiming to assess the feasibility of large scale record linkage of blood donor records to health records. When applying for the data, the applicant stated that the findings of this pilot study will be reported in peer-reviewed medical journals and that it was anticipated that the outputs of this research will be presented at blood donor research conferences to inform the wider blood donors research community and will also be communicated to donors via NHSBT newsletters and a publicly accessible website: https://www.nhsbt.nhs.uk/research-and-development/current-research/clinical-research/donor-health/. • December 2022-January 2023: analysis of ONS mortality data in the context of the previous analysis (that focused on disease outcomes from Hospital Episode Statistics). The applicant stated that initial study outputs were expected by 2019-2020. • February 2023-June 2023 : publication write-up and submission. The applicant has reported that the design and initial results of this study were communicated at the European Conference on Donor Health and Management in 2016, the largest international conference on blood donor health. Preliminary findings of the effects of whole blood donation on hospital episode statistics have also been presented to blood donors and NHSBT researchers at the National Institute for Health Research (NIHR) Blood and Transplant Research Unit Training Day in Cambridge in 2017. • July 2023-December 2023: peer-review process and completion of any additional analyses that peer-reviewers may request. There is no evidence of any outputs being produced between 2018 and 2021. Any further extension of this Data Sharing Agreement will be conditional on the applicant demonstrating the necessity for further retention and reuse of the data and providing realistic time frames for delivery of specific outputs. The pilot study will be complete by December 2023, providing there are no further major setbacks. Results will also be communicated through the study website (http://www.donorhealth-btru.nihr.ac.uk/), newsletters, press releases and media interviews. When sharing research findings, results will be displayed as aggregate data only with small numbers suppressed, in line with the HES analysis guide.

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. Once analyses are completed at the end of 2022, results will be fed back to NHSBT. NHSBT will be kept informed of any preliminary findings as the analyses take place. In the short term, this study will expand scientific knowledge of the possible approaches to investigate the health effects of blood donation, and will provide initial insight into the health effects of blood donation. Given the lack of previous studies investigating blood donor health with comparable size in the UK and worldwide, this study will provide crucial evidence regarding the feasibility of large scale linkage studies in blood donor populations. Results from this study will also help to improve the design and analysis of future large scale studies on blood donor health, which will be essential for future studies seeking to understand the long term effects of frequent blood donation. These short term benefits will be realised by means of publications in peer-reviewed medical journals and direct interaction with the international blood donation community at conferences and collaboration meetings. In the short term it is expected that this study will provide critical information to clinicians, decision-makers and academic scientists working in the field of blood donor health. In the short term this study will not benefit patients directly but will be essential for the progression to further studies that will produce substantial benefits for patients. The short and long-term benefits below remain the same for the purposes of this application to extend and amend the Data Sharing Agreement: In the long term, this study will provide the basis for the creation of an electronic-haemovigilance platform which will provide NHSBT with the means to answer crucial questions regarding donor health and well-being, in particular regarding the consequences of blood donation on chronic disease outcomes. The answers obtained from this surveillance platform are expected to help to inform future NHSBT policies and strategies benefiting the 5 million donors registered with NHSBT. These benefits will be realised by means of publications in peer-reviewed medical journal, interaction with the international blood donation community, and direct cooperation with relevant policymakers within the UK. In the long term it is expected that this study will provide vital information on how best to monitor and preserve blood donor health, improving efficiency and safety of blood donation in the UK and worldwide. Further, the information provided to donors will allow them to make a more informed decision about frequent blood donation with regards to their long term health. In the short term, this study hopes to expand scientific knowledge on the possible approaches to investigating the health effects of blood donation, and to provide initial insight into the health effects of blood donation. Given the lack of previous studies of comparable size in the UK and worldwide investigating blood donor health, this study plans to provide crucial evidence regarding the feasibility of large-scale linkage studies in blood donor populations. These short-term benefits hope to be realised by means of publications in peer-reviewed medical journals and direct interaction with the international blood donation community at conferences and collaboration meetings. The study is expected to provide critical information to clinicians, decisionmakers and academic scientists working in the field of blood donor health. The expected short-term benefits of the study may not benefit patients directly but could be essential for the progression of further studies that will produce substantial patient-related benefits. In the long term, this study hopes to provide the basis for the creation of an electronic-haemovigilance (haemovigilance is a set of surveillance procedures comprising the entire blood transfusion chain) platform which may provide NHSBT with the means to answer crucial questions regarding donor health and well-being, in particular regarding the consequences of blood donation on chronic disease outcomes. In the long term it is expected that this study will provide vital information on how best to monitor and preserve blood donor health, improving efficiency and safety of blood donation in the UK and worldwide. Further, the information provided to donors will allow them to make a more informed decision about frequent blood donation with regards to their long-term health. The answers obtained from this surveillance platform are expected to help inform future NHSBT policies and strategies benefiting the 5 million donors registered with NHSBT.

Benefits reported

Not stated in the previous version; added here.

Initial, preliminary findings from the analysis (using HES data) have been presented at the 3rd European Conference on Donor Health and Management (5-7 September 2018) in Copenhagen, Denmark.

The University of Cambridge’s preliminary analysis has shown that there was no evidence of associations between apheresis donation (e.g. platelet donation) and health outcomes. There was evidence of an increased risk of coronary and thromboembolic outcomes in certain blood groups, but this warrants further analysis and investigation. The preliminary results of this study are generally in line with the broader existing literature - there is still uncertainty on their interpretation and further analysis is required.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. Data held by the University of Cambridge must be securely stored and not otherwise processed. The following provides background information on the purpose of the original study: [2 paragraphs unchanged] The aim of the current pilot study to which this application relates to, Agreement relates, is to determine whether it is operationally feasible to establish a non-identifiable [63 words unchanged] framework and will be subject to separate data requests and ethical approvals. The applicant has previously received HES admitted patient care and outpatient data. No further HES data is being requested as part of this agreement. Under previous iterations of this Agreement, the University of Cambridge received Civil Registration Mortality and HES Admitted Patient Care and Outpatient data. Data transfers will be between University of Cambridge Department of Public Health and Primary Care and NHS Digital. All outputs (DPHPC) will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide. have access to pseudonymised record-level data. University of Cambridge DPHPC will only have access to pseudonymised record-level data. All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

Processing activities

1. University of Cambridge will resend to NHS Digital the encrypted HESIDs for each individual (provided under the previously approved Agreement) to allow linkage of a demographic blood donor dataset on 200 000 donors, for linkage to: 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 following describes the processing activities permitted under previous iterations of this Agreement: 1. University of Cambridge sent the encrypted HESIDs for each individual to NHS Digital for linkage of a demographic blood donor dataset on 200 000 donors, for linkage to: [1 paragraph unchanged] 2. Once linkage to mortality data is complete, NHS Digital will provide provided a linked dataset containing mortality data together with the internal (non-identifiable) study id to [59 words unchanged] of University of Cambridge will have access to the NHS Digital data. The HES data has had already been provided to University of Cambridge Department of Public Health and Primary Care. The applicant is only requesting mortality data and a bridge file: HES to Civil Registration mortality data under this application. [4 paragraphs unchanged] The data approved under this data sharing agreement Data Sharing Agreement will not be linked further by the applicant and the only data linkages are those permitted in this application. further.

Expected output

The main purpose of this demonstration study is to assess the feasibility of large scale record linkage of blood donor records to health records. The findings of this pilot study will be reported in peer-reviewed medical journals. Readers of medical journals include clinicians, decision-makers and academic scientists. It is anticipated that the outputs of this research will be presented at blood donor research conferences to inform the wider blood donors research community and will also be communicated to donors via NHSBT newsletters and a publicly accessible website: https://www.nhsbt.nhs.uk/research-and-development/current-research/clinical-research/donor-health/. Initial study outputs are expected by 2019-2020. 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. Data was supplied for the purpose of a demonstration study aiming to assess the feasibility of large scale record linkage of blood donor records to health records. When applying for the data, the applicant stated that the findings of this pilot study will be reported in peer-reviewed medical journals and that it was anticipated that the outputs of this research will be presented at blood donor research conferences to inform the wider blood donors research community and will also be communicated to donors via NHSBT newsletters and a publicly accessible website: https://www.nhsbt.nhs.uk/research-and-development/current-research/clinical-research/donor-health/. The applicant stated that initial study outputs were expected by 2019-2020. The applicant has reported that the design and initial results of this study were communicated at the European Conference on Donor Health and Management in 2016, the largest international conference on blood donor health. Preliminary findings of the effects of whole blood donation on hospital episode statistics have also been presented to blood donors and NHSBT researchers at the National Institute for Health Research (NIHR) Blood and Transplant Research Unit Training Day in Cambridge in 2017. There is no evidence of any outputs being produced between 2018 and 2021. Any further extension of this Data Sharing Agreement will be conditional on the applicant demonstrating the necessity for further retention and reuse of the data and providing realistic time frames for delivery of specific outputs.

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. [2 paragraphs unchanged]

Benefits reported

Stated in the previous version and removed here.

Thus far, the design and initial results of this study have been communicated at the European Conference on Donor Health and Management in 2016, the largest international conference on blood donor health. Preliminary findings of the effects of whole blood donation on hospital episode statistics have also been presented to blood donors and NHSBT researchers at the National Institute for Health Research (NIHR) Blood and Transplant Research Unit Training Day in Cambridge in 2017.

These presentations have fostered exciting discussions with blood donor researchers and international blood donation organizations about the methods used for long term follow-up of blood donors to improve their health. As further results of these discussions, various methods have been explored to improve our pilot study and enhance the feasibility of creating a large scale donor health follow-up study.