Caerphilly Prospective Study (CaPS)

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

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics · − MRIS - Flagging Current Status Report; − MRIS - Members and Postings Report

Objective for processing

The University of Bristol is applying to NHS Digital to extend its current Data Sharing Agreement, retaining the identifiable Medical Research Information Service (MRIS) data previously disseminated by NHS Digital. The University of Bristol requires access to NHS England Data for the purpose of the following research programme: The Caerphilly Prospective Study (CaPS) study was initially set up in the late 1970s. The initial objective of the (CaPS) study was to establish the relation between specific biochemical and physiological variables and the prevalence and incidence of ischaemic heart disease (IHD). Over the years the number of outcome measures (phenotypes) has been enlarged with a specific focus on cognitive impairment, dementia and ageing traits in the later years. The Caerphilly Prospective Study (CaPS) The overall aim of the CaPS study is to enhance the understanding of life course influences on the aetiology of chronic disease and physiological traits by examining lifestyle, genetic and other exposures at various times in the life course and determine whether these predict a wide range of different outcomes. The following is a summary of the aims of the research programme provided by the University of Bristol: NHS Digital mortality and cancer data is required as a vital aspect in identifying relevant health outcomes in this study. For example, cardiovascular disease (CVD) may present with clinical symptoms or as sudden death, the latter outcome of which is only available to the study from NHS Digital data. “The Caerphilly Prospective Study (CaPS) was initially set up in the late 1970s. The initial objective of CaPS was to establish the relation between specific biochemical and physiological variables and the prevalence and incidence of ischaemic heart disease (IHD). Over the years the number of outcome measures has been enlarged with a specific focus on cognitive impairment, dementia and ageing traits in the later years. Over time the number of study outcomes has increased so it not only includes heart disease and stroke, but also encompasses age-related diseases such as dementia and Parkinson’s disease. Such diseases may not always be coded in the main cause of death but may appear in the death certificate, thereby enhancing case detection and confirming previously reported morbidity or indicating a change of diagnosis. For example, some individuals initially diagnosed as Parkinson’s disease may after further follow-up have this diagnosis changed to a related disorder such as multiple system atrophy, and this latter diagnosis may captured by the death certificate. The same applies with cancers and hence the valuable information provided by the cancer registry. In the future, the University of Bristol may seek hospital episode statistics (HES) data from NHS Digital which will further enhance the ability to detect non-fatal conditions and repeat episodes of the same condition e.g. heart failure as a measure of disease severity. The overall aim of CaPS is to enhance the understanding of life course influences on the causes of chronic disease and physiological traits by examining lifestyle, genetic and other exposures at various times in the life course and determine whether these predict a wide range of different outcomes.” The study population comprised of almost three thousand men aged 45-59 years selected at random from the electoral register of Caerphilly Urban District. The University of Bristol wish to collect outcome Data from NHS England to add to the variables collected from the cohort since the 1970s, with the intention of following the whole cohort until their death. This is unusual in most studies and scientifically valuable. The University of Bristol therefore wish to make this linked Data available to other researchers across the University; and also to make CaPS data linked to information derived from NHS England Data more widely available to other researchers, in order to pursue research projects compatible with the aims outlined above. The initial design attempted to contact all men aged 45 to 59 years from the town of Caerphilly and adjoining villages. 2512 subjects identified from the electoral register and general practice lists were examined between July 1979 and September 1983 (phase I). Men were initially seen at an evening clinic, where they completed a questionnaire, had anthropometric measures (measurements of the proportions, size, and weight of the human body) and an electrocardiogram (ECG) taken to check the heart’s rhythm and electrical activity. They also completed a food frequency questionnaire at home. They subsequently re-attended an early morning clinic to have fasting blood samples for a wide variety of tests. Any researcher at the University of Bristol who wishes to use linked CaPS and NHS England Data; or any researcher from another organisation who wishes to use CaPS data linked to information derived from NHS England Data; must submit a data access request form to the CaPS Data Access Committee (DAC). The expected number of such requests per year is 2-3 internal, and a further 2-3 external requests. Phase II of the study was undertaken between July 1984 and June 1988. An additional 447 new men were included who had moved into the study areas. This is known as the “reconstructed” cohort. In addition to the tests undertaken at phase I, new tests included audiometry (evaluation of hearing function). Membership of the DAC will include both academic and lay representation, and include the programme principal investigator alongside experts in epidemiology and data management. The DAC will seek an expert opinion from an independent member of staff at the University of Bristol or another academic centre of excellence for all requests arising from within the University of Bristol. Phase III of the study was undertaken between November 1989 and September 1993. It followed the same methods as Phase I and II. The main new features were a standardised battery of cognitive function tests as well as a variety of new platelet (blood clotting cells) and bleeding time tests. The Terms of Reference of the DAC are: Phase IV of the study was undertaken between October 1993 and February 1997. Audiometry measured at phase II was repeated as was cognitive function measured at phase III. 1. To review all data access requests based on the “Five Safes” framework (“Safe projects, people, setting, data, outputs”). Based on this Framework, the DAC will assess each project against the following criteria: After phase IV men have been contacted on two further occasions by post. This has enabled data on stroke events as well as new non-fatal myocardial infarctions (heart attacks) to be collected. (i). Is this an appropriate use of the data? For example, is there likely public benefit, in accordance with the National Data Guardian for health and social care guidance? Is there demonstrable analytical merit? Is the project feasible? Phase V was undertaken between August 2002 and June 2004. This repeated questionnaire data but also had a special memory clinic to assess men who scored poorly on the cognitive assessments to see if they may have any cognitive impairment or dementia. (ii). How trustworthy are the researchers? Since then men have received a postal questionnaire on the Warwick Edinburgh Well-Being scale (measuring mental well-being). (iii) Does the environment prevent misuse? All men have been followed up for incident Ischemic Heart Disease (IHD) through mortality flagging, self-reported information confirmed by medical records, positive history to the Rose angina questionnaire, checking hospital admissions and new evidence of ECG ischaemia (restriction in blood supply to parts of the body). The follow-up of the participants has since 1982 involved information from NHS Digital about vital status and if deceased, the causes of death as well as cancer registration and type of cancer. (iv) Is the data detail appropriate? Under previous versions of this Agreement and in line with permission from the Office for National Statistics which was the custodian of the data at that time, the University of Bristol has shared pseudonymised subsets of study data with third party researchers at the University College London (UCL) – London School of Hygiene and Tropical Medicine (LSHTM)-University of Edinburgh – University of Bristol (UCLEB) universities consortium. NHS Digital acknowledges that data was shared with appropriate permissions at the time of sharing. This Agreement does not retrospectively grant permission from NHS Digital for that sharing. (v) Is there any confidentiality risk from publication? The University of Bristol also formerly shared study data with the University of Cambridge and the University of Helsinki. In all instances, the data was mostly collected from other study sources and no NHS Digital data covered under this Agreement has been directly shared. Information derived from data shared under this Agreement has been shared. Derivation was guided by ONS processes. 2. To seek further clarifications from applicants if the DAC are concerned about any issues arising from the above framework – for example, relevant privacy implications; the scientific quality and the public health / clinical relevance of the application. Any data shared must be subject to the conditions that the receiving organisation: 3. Ensure that datasets will only be shared with bona fide researchers who are using the data for projects that are of potential scientific, public, or clinical value and who meet criteria above. i. must not combine it with other datasets which could potentially increase the risk of reidentification for individuals in the dataset; 4. Researchers will be asked to sign a Data Access Agreement to ensure Data are not misused and the projects have clear scope, are time bound and have a clear dissemination plan. The Data Access Agreement will include points related to the safe use and destruction of the Data. ii. must not attempt to re-identify individuals in the dataset; 5. Ensure the researchers are provided with disclosure control policies to reduce the accidental or deliberate identification of an individual, based on the Office for National Statistics’ Handbook on Statistical Disclosure Control (https://securedatagroup.org/sdc-handbook/). To ensure disclosure control, a copy of papers arising from new research based on the CaPS Data should be sent, prior to publication, for checking by the DAC. iii. must not onwardly share the dataset; Transparency will be maintained by registering all approved projects on the study website (https://www.bristol.ac.uk/population-health-sciences/projects/caerphilly/) with a brief lay description of the research being undertaken. iv. must use the dataset for a defined purpose in support of the CaPS Study's aims defined within this Agreement, and The following NHS England Data will be accessed: v. must not publish the data. • Civil Registration Mortality and Cancer Registrations – necessary to identify relevant health outcomes for the study Under the terms of this Agreement, the University of Bristol is responsible for ensuring compliance with the above conditions and for confirming destruction of the data by the receiving organisations once the data is no longer required for the purpose for which it was shared. • Demographics – necessary to track embarkations from the NHS which would prevent the study from following up on other health outcome data During the term of this Agreement, the University of Bristol must not share any data covered under this Agreement or data derived from data covered under this Agreement with any third party. The University of Bristol must agree with NHS Digital a mutually acceptable mechanism for sharing data and/or derived data and may only share data once an amended version of this Agreement has been signed by all parties. The level of the Data will be identifiable because the University of Bristol holds the identifying details and also requires return of date of birth in order to cross-check that events have been allocated to the correct individuals. The University of Bristol use data at an individual rather than aggregate level as it is impossible to undertake the research without record level information to enable sophisticated multivariable (statistical) modelling. For example, the University of Bristol may wish to model individual risk factor and outcome trajectories such as whether change in an individual’s body mass index (BMI) predicts change in their cognitive performance on memory tests. The Data will be minimised as follows: Data minimisation principles apply in that (i) Record level data are provided for the purpose of a specific hypothesis (ii) Filtering is undertaken if appropriate, for example subjects who are lost to follow up may be excluded. As the data set is relatively small, it is more normal to not filter on any factor other than missingness. (iii) Usually all episodes of clinical follow-up are required, as one of the strengths of this prospective cohort study is the repeat measures of risk factors which allows the researchers to model a trajectory. (iv) No further linkages are undertaken other than to mortality and cancer registration data. • Limited to a study cohort held by the University of Bristol comprising ~3000 men selected at random from the electoral register of Caerphillly Urban District Under a forthcoming amendment, the University of Bristol will be seeking new record level data (from April 2016) on cause of mortality and cancer registration to supplement its existing records, and also historical HES data (earliest to latest available). The new data requested from NHS Digital will be added to the existing dataset and will further the aims by providing more outcomes which in turn will enhance the statistical power of the study and enable sub-group analyses (e.g. comparing whether a risk factor is equally important in men with higher and lower educational level). The new mortality and cancer data will be the same type of data as already held, but covering the period since April 2016 to ensure full life-course follow-up of all cohort members. The minimisation per use will be reviewed and approved by the Data Access Committee as per the process specified above. The data is based on all men who lived in the Caerphilly area and a complete coverage of events since inception of the cohort will reduce any selection bias and maximise statistical power. There are no alternative methods to obtain these data as the vast majority of the original participants have died or are very old (80 years plus) and it is no longer appropriate to recontact them as it is now 40 years since the study commenced. The University of Bristol is the research sponsor and the Controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. The processing of these data are in the public interest (UK GDPR Article 6(1)(e)) as they contribute to a greater understanding of health related risks and how these may be tackled in terms of public health prevention and as such serve as public interest. Such research can identify new risk factors, be they environmental or genetic that may lead to new causes of disease with the potential for developing new interventions to prevent disease. In some cases, new genetic discoveries may lead to the reuse of existing therapeutics or the development of new drug targets. The lawful basis for processing personal data under the UK GDPR is: The University of Bristol are also processing the data in accordance with UK GDPR Article 9(2)(j) as ‘processing is necessary for archiving purposes in the public interest, scientific or historical research purposes’. The use of these data will add scientific knowledge to the existing evidence base around the aetiology and potential prevention of many common chronic diseases. It will also comparison of trends in disease and risk factor prevalence over time to see if the Public Health is or is not improving, for example the proportion of individuals meeting the World Health Organization recommendations on physical activity over time. The University of Bristol believe these useful activities justify the retention and processing of the NHS Digital data. 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 Bristol has considered the moral or ethical issues around the data processing. All participants were fully aware they were voluntarily participating in a longitudinal health research project and consented for the research team to have access to their medical records, though given the historical nature of this study, as was normal at that time, the participants were not formally informed that their vital status would be reported through NHS Digital. The participants were fully aware that the study collaborated with other researchers and wished to follow them until death. The lawful basis for processing special category data under the UK GDPR is: The University of Bristol is the data controller and also processes the data for the purpose described in this Agreement. There are no commissioners involved. 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 study does not currently receive any grant funding but is supported by the Population Health Sciences department, University of Bristol through staff time and support and infra-structure. It also requests data access costs as cost recovery from other studies using broader CaPS data (not NHS Digital data) when appropriate. This processing is in the public interest because it contributes to a greater understanding of health-related risks and how these may be tackled in terms of public health prevention. Such research can identify new risk factors, be they environmental or genetic that may lead to new causes of disease with the potential for developing new interventions to prevent disease. In some cases, new genetic discoveries may lead to the reuse of existing therapeutics or the development of new drug targets. The funding is provided by the Population Health Sciences Department at the University of Bristol and the Medical Research Council Integrative Epidemiology Unit based in the Department through staff time support and infrastructure. CaPS also requests data access charges from organisations requesting CaPS data when appropriate. The University of Bristol has shared pseudonymised subsets of study data with third party researchers at the University College London (UCL) – London School of Hygiene and Tropical Medicine (LSHTM) - University of Edinburgh – University of Bristol (UCLEB) universities consortium. NHS England acknowledges that data was shared with appropriate permissions at the time of sharing. This Data Sharing Agreement (DSA) does not retrospectively grant permission from NHS England for that sharing. The University of Bristol also shared study data with the University of Cambridge. The data was mostly collected from other study sources and no NHS England Data covered under this DSA has been directly shared. Information derived from Data shared under this DSA has been shared. The University of Bristol may share information derived from Data shared under this DSA with other organisations wishing to conduct research in line with the purposes of this research programme. Data will be accessed by Masters or PhD students enrolled with the University of Bristol. It is expected that no more than three Masters or PhD students will work on the Data at any one time. Any student working with the Data held under this Data Sharing Agreement must have completed relevant data protection and confidentiality training and are subject to the University of Bristol’s policies on data protection and confidentiality. Any students accessing the Data will do so under the supervision of a substantive employee of the University of Bristol. The University of Bristol would be responsible and liable for any work carried out by students. These students would only work on the Data for the purposes described in this Data Sharing Agreement. This study was set up before formal Patient and Public Involvement practices were commonplace, however all of the study participants volunteered to take part in this medical research project and were aware that their data was going to be used in collaborative research. The project was set up in 1979/1980, and the participants were kept aware of both the results of the research and future activities through regular newsletters. Around 600 subjects attended a 25th birthday party for CaPS where the Welsh Minister of Health gave a short speech about the value of medical research and the CaPS project. The new data access committee who will review requests for data use will include one or more lay members who can advise on the suitability of future research.

Processing activities

Under The University of Bristol will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Name and a previous iteration of this Agreement, NHS Digital received the flags unique person ID) for the cohort of participants to be linked with identifying information. The cohort is closed, and no additional cohort members will be sent to NHS Digital under this version of the Agreement. England Data. NHS Digital has previously sent identifying data (mortality and event notifications with names, address, date of birth, NHS number and sex) to the University of Bristol where it was processed and added to the master database. NHS England will provide the relevant records from the Civil Registrations Mortality, Cancer Registrations and Demographics datasets to the University of Bristol. The Data will contain date of birth and a unique person ID which can be used to link and cross-check the Data with other record level data already held by the recipient. Subsequent flows of data have occurred, whereby the University of Bristol have transferred derived NHS Digital data to external organisations. Other organisations who currently have CaPS data containing derived NHS Digital data variables are the University of Cambridge, University of Helsinki, UCL, LSHTM and the University of Edinburgh. This data was typically shared in conjunction with pseudonymised data obtained from the study's data collection and will have undergone statistical analyses as part of a project proposal approved by the University of Bristol. No further subsequent flows of data will occur under this Agreement. The University of Bristol is the only organisation authorised to process NHS Digital data under this Agreement. Data is processed to explore any hypotheses related to the overall aim of the CaPS study. The Data will not be transferred to any other location. There is no data linkage other than to research data collected by the University of Bristol (see https://www.bristol.ac.uk/population-health-sciences/projects/caerphilly/about/). These variables are numerous especially those derived from the biochemical analysis of blood samples. For simplicity, they can be grouped into the following sub-headings; demographic (e.g. age), lifestyle (e.g. smoking), environmental (e.g. noise exposure) psychosocial (e.g. Type A personality), clinical (e.g. blood pressure), biochemical (e.g. serum cholesterol), outcomes (e.g. heart disease, cognitive function etc). There is no matching to publicly available data. The Data will be stored on servers at the University of Bristol. All individuals processing the data at the University of Bristol are substantive employees or authorised PhD students, all of whom have received appropriate training in data protection and confidentiality. Data can be accessed either on University premises or from home using special VPN software. University of Bristol store the data on a Safe Haven following NHS Digital guidelines. This means that all access to the data is controlled by the Data Custodian who must request access on an individual level from IT. Access logs are kept for 12 months and audit reports are available monthly. The data are encrypted at rest on the server. To comply with data destruction notices from NHS Digital, the data stored on the Safe Haven is not backed-up by design. The Data will be accessed onsite at the premises of the University of Bristol. The Data will also be accessed by authorised personnel via remote access. 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). The University of Bristol must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. For remote access: - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA; - Access controls granting users the minimum level of access required are in place; - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect Data; - Multifactor authentication (MFA) is required for remote access; - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this agreement) and complies with the organisation’s remote access policy. The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose) Remote processing will be from secure locations within England/ Wales. The Data will not leave England/ Wales at any time. The core dataset will only be accessed by the principal investigators and database manager at the University of Bristol. All access to the data is controlled by the Principal Investigator who must request access on an individual level from the Information Technology Department. The Principal Investigator or Database Manager will produce subsets of the Data that will be accessed by other researchers at the University of Bristol, subject to successful requests to the CaPS Data Access Committee. The Data Access Request will specify and justify which subsets of Data are required. This will be checked and accepted or refuted by the Data Access Committee at the University of Bristol in line with the terms and conditions explained in ‘Objectives for Processing’. Access to the Data, including subsets, will be restricted to substantive employees of, and students enrolled by, the University of Bristol. 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 collected by the University of Bristol (see https://www.bristol.ac.uk/population-health-sciences/projects/caerphilly/about/). These variables are numerous especially those derived from the biochemical analysis of blood samples. For simplicity, they can be grouped into the following sub-headings; demographic (e.g. age), lifestyle (e.g. smoking), environmental (e.g. noise exposure) psychosocial (e.g. Type A personality), clinical (e.g. blood pressure), biochemical (e.g. serum cholesterol), outcomes (e.g. heart disease, cognitive function etc). There is no matching to publicly available data. 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. Researchers from the University of Bristol will use the Data to analyse trends as described in ‘Objective for Processing’. Employees or agents of other organisations who have made a successful application to the CaPS Data Access Committee are only permitted to access anonymised data including information derived from NHS England Data. The derived variables which have been shared with the University of Cambridge, and which may be shared with other organisations in combination with original CaPS data, are limited to the following variables approved under the specification shared with NHS England in June 2022: i. An indicator for whether a patient has died or not ii. Simplified cause of death (Death by any type of stroke; death by any type of cancer; death by any type of cardiovascular disease; death by any other cause) iii. Date of death with a random error term of +/- up to 182 days iv. Censor date with a random error term of +/- up to 182 days v. Date of first heart attack or first stroke with a random error term of +/- up to 15 days Any data (to be) shared must be subject to the conditions that the receiving organisation: i. must not combine it with other datasets which could potentially increase the risk of reidentification for individuals in the dataset; ii. must not attempt to re-identify individuals in the dataset; iii. must not onwardly share the dataset; iv. must use the dataset for a defined purpose in support of the CaPS Study's aims defined within this DSA, and v. must not publish the data. Under the terms of this DSA, the University of Bristol is responsible for ensuring compliance with the above conditions and for confirming destruction of the data by the receiving organisations once the data is no longer required for the purpose for which it was shared.

Expected output

The outputs produced from the data provided is new knowledge in relation to the epidemiology of cardiovascular disease (e.g. heart disease and stroke), cancers, dementia and other chronic diseases. These outputs are usually in the form of scientific publications in peer reviewed journals, book chapters, monographs etc. They are also expected to contribute to oral presentations and other media. The results presented in such outputs are summary tables e.g. percentage of smokers and effect estimates such as a measure of risk e.g. the risk ratio of dying from cardiovascular disease comparing obese with non-obese subjects. Any small number cells will be suppressed in line with the HES analysis guide so that no cells have fewer than 7 subjects. The expected outputs of the processing will be: The University of Bristol follows the following approaches to the dissemination and communications of results and outputs. Other researchers are targeted through publication in the most appropriate scientific journal which may be generic (e.g. Lancet) or specialist (e.g. Brain). Thus other researchers working in the same topic area are expected to be aware of the results. Depending on the importance of the findings for Public Health, the University Press Office (and sometimes the Journal itself) typically issue a Press Release to the general media. In this scenario, it is often the case that journalists contact the lead/senior author to discuss the results and gather a quote for a lay article. In some cases this may also lead to radio and/or television interviews. Some journals now host their own vlogs about papers of interest and may also commission an accompanying editorial. The University of Bristol will also submit abstracts for oral or poster presentations to both National (e.g. Society for Social Medicine) or International conferences where the work is hoped to be presented. University of Bristol researchers may also be invited to attend meetings or advise on policy formulation with relevant bodies. The outputs may contribute to policy formulation either through the citation and inclusion of results in clinical or public health guidelines (e.g. National Institute for Clinical Excellence, World Health Organisation, British Heart Foundation) or through other bodies that synthesise evidence for the purpose of commissioners and/or policy leaders (e.g. Lancet Commission). • Submissions to peer reviewed journals, book chapters, monographs etc, including generic journals (such as the Lancet) or specialist journals (such as ‘Brain’) The Caerphilly Prospective Study (CaPS) is a very detailed and richly phenotyped study that has data both on lifestyle, clinical, biochemical and genetic data. It is therefore used for a wide variety of hypotheses rather than a single specific one and can be used to examine a wide range of different outcomes such as heart disease, cancer and dementia. The research from CaPS has already resulted in over 150 publications and this is expected to continue to increase. Currently, derived data from CaPS contributes to various consortia that undertake meta-analyses across multiple epidemiological cohort studies (see below). In some of the meta-analyses the results are aggregated across many studies and the specific study cannot even be identified. • Presentations at appropriate national conferences (such as the Society for Social Medicine) or international conferences Variables derived from NHS Digital data were shared with the University of Cambridge as part of the Emerging Risk Factors Collaboration (EFRC), regarding approximate time of fatal heart attack/ death from other causes. A key output from the EFRC collaboration is the publication 'World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions (Kaptoge et al., 2019). This work was led by the cardiovascular disease epidemiology team based at the University of Cambridge, which includes data from CaPS as well as many other cohort studies. There are several different cardiovascular disease prediction risk scores that have been developed for high income countries (HIC) but far less for low middle income countries (LMIC). The team were able to develop risk prediction models (including CaPS data) which were then validated in further datasets and with particular potential use in LMICs. • Press releases to the general media Variables derived from NHS Digital data were shared with the University of Helsinki as part of the Biomarker for Cardiovascular Risk Assessment across Europe (BiomarCaRE) consortium, regarding approximate time of death relating to stroke, cancer, cardiovascular disease or other causes. • Meetings with relevant bodies (such as the National Institute for Clinical Excellence, World Health Organisation, British Heart Foundation or Lancet Commission) Variables derived from NHS Digital data were shared with the University College London - London School of Hygiene and Tropical Medicine - University of Edinburgh - University of Bristol (UCLEB) universities consortium in 2016 in line with approvals by the Office for National Statistics (ONS) at the time. NHS Digital derived variables covered broad categories of cause of death, time of death and cause of cancer for projects concerning biochemical metabolomic predictors of cardiovascular disease risk factors and outcomes. • A database to be utilised as a resource for health research 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 outputs will be communicated to relevant recipients through the following dissemination channels: • Journals • Social media • Press/media engagement • Direct bilateral engagement with organisations involved in policy formulation • Posters displayed at academic and public meetings such as events hosted by the British Heart Foundation or dementia charities • Briefing documents provided to relevant regulatory bodies and charities The outputs are expected on an ongoing basis throughout the life course of the research programme. CaPS has ethical approval for use as a research database until at least summer 2028. Research from CaPS has already resulted in over 150 publications and this is expected to continue to increase. Variables derived from NHS England Data were shared with the University of Cambridge as part of the Emerging Risk Factors Collaboration (EFRC), regarding approximate time of fatal heart attack/ death from other causes. A key output from the EFRC collaboration is the publication 'World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions (Kaptoge et al., 2019). This work was led by the cardiovascular disease epidemiology team based at the University of Cambridge, which includes data from CaPS as well as many other cohort studies. [2 paragraphs unchanged]

Expected measurable benefits

The types of benefit that may arise from the CaPS study are [23 words unchanged] care by allowing disease modellers and health economists to predict future disease trends through risk factor surveillance and the use of effect estimates for this research and other studies. trends. CaPS study findings are in the public interest in terms of enhancing understanding of how to prevent disease. Meta-analyses using derived CaPS data will look at the associations between a variety of different exposures and disease outcomes including death. Such research can identify new risk factors be they environmental or genetic that may lead to new causes of disease, with the potential for developing new interventions to prevent disease. The use of the Data could: Inclusion of research evidence from CaPS as well as other studies in policy documents is one way to document and measure the public benefit of this research. The timelines to see expected benefits are hard to predict as it depends both on the weight of pre-existing evidence (it is rare to see policy changes on the basis of one or two studies) and its political expedience. • lead to the identification or improvement of treatments or interventions The provision of NHS Digital data to the existing CaPS data can greatly enhance the value of the research by (i) validating self-reported diagnosis, (ii) correcting misdiagnoses (iii) identifying new cases (iv) enhancing statistical power to demonstrate associations (iv) reduce selection bias by only studying less severe cases who participate in follow-ups and are less likely to have died from the disease of interest. • advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations A potential benefit of the derived NHS Digital data shared for the Emerging Risk Factors Collaboration (ERFC) is in relation to cardiovascular disease and the publication of the revised World Health Organisation (WHO) risk scores. The new risk prediction models could enable the estimation of cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. Having such risk prediction models available could therefore help to achieve the following: (i) aid health care planning to rational provision of secondary and tertiary cardiovascular care (ii) examine trends both in the past and into the future of any natural experiments or policy changes to restrict adverse exposures e.g. banning smoking in public (iii) as a political lever to redistribute funding to support primary prevention. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). 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 organisations that synthesise evidence for the purpose of commissioners and/or policy leaders (such as the Lancet Commission); and organisations such as the National Institute for Clinical Excellence, World Health Organisation and British Heart Foundation who develop clinical or public health guidelines. Should the findings be considered of particular importance for public health, a Press Release may be issued to the general media, and the lead/senior author would typically discuss the results with journalists to gather a quote for a lay article. In some cases, this may also lead to radio and/or television interviews. Additionally, some journals now host their own vlogs about papers of interest and may commission an accompanying editorial.

Benefits reported

CaPS data has contributed to life course meta-synthesis studies that looks look at a risk factor or trait over the life course by merging datasets that have data over different life stages e.g. childhood, young adulthood adulthood, middle age, older age etc. This has shown the interesting pattern as to how blood pressure changes over the life course. This highlights important ages [13 words unchanged] sort of research has been the specific targeting of research funding by UKRI, NIHR UK Research and Innovation, the National Institute for Health and Care Research, and the Global alliance Alliance for chronic diseases Chronic Diseases on life course research and interventions targeting specific critical or sensitive time periods (see https://www.gacd.org/funding/current-call-for-applications/common-risk-factors). Knowing who, why and when individuals have died, as supplied from NHS Digital, England, is important to the validity of the research. This is because the [7 words unchanged] biased if one does not consider loss to follow-up due to death. The CaPS study has highlighted how men who have healthy life styles [44 words unchanged] into the evidence base for organisations such as UK Health Security Agency (UKHSA) for whom dementia is a major priority priority, as it will place ever increasing demands on both and health and social care services as our the population in the UK continues to get older. Its ability to test [5 words unchanged] disease are also linked to dementia is important to organisations like the UK Health Security Agency UKHSA and the British Heart Foundation, and is part of the basis of the "What's good for the heart is good for the brain" movement. [4 paragraphs unchanged] The WHO CVD Risk Chart Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health 2019; 7: e1332–45

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

Objective for processing

The University of Bristol is applying to NHS Digital to extend its current Data Sharing Agreement, retaining the identifiable Medical Research Information Service (MRIS) data previously disseminated by NHS Digital. [1 paragraph unchanged] The overall aim of the CaPS study is to enhance the understanding [10 words unchanged] and physiological traits by examining lifestyle, genetic and other exposures at various time times in the life course and determine whether these predict a wide range of different outcomes. The University of Bristol wishes to retain and process the identifiable Medical Research Information Service (MRIS) data received under previous iterations of this Agreement. NHS Digital mortality and cancer data is required as a vital aspect in identifying relevant health outcomes in this study. For example, cardiovascular disease (CVD) may present with clinical symptoms or as sudden death, the latter outcome of which is only available to the study from NHS Digital data. Over time the number of study outcomes has increased so it not only includes heart disease and stroke, but also encompasses age-related diseases such as dementia and Parkinson’s disease. Such diseases may not always be coded in the main cause of death but may appear in the death certificate, thereby enhancing case detection and confirming previously reported morbidity or indicating a change of diagnosis. For example, some individuals initially diagnosed as Parkinson’s disease may after further follow-up have this diagnosis changed to a related disorder such as multiple system atrophy, and this latter diagnosis may captured by the death certificate. The same applies with cancers and hence the valuable information provided by the cancer registry. In the future, the University of Bristol may seek hospital episode statistics (HES) data from NHS Digital which will further enhance the ability to detect non-fatal conditions and repeat episodes of the same condition e.g. heart failure as a measure of disease severity. [1 paragraph unchanged] The initial design attempted to contact all men aged 45 to 59 years from the town of Caerphilly and adjoining villages. 2512 subjects (response rate 89%) identified from the electoral register and general practice lists were examined between [11 words unchanged] at an evening clinic, where they completed a questionnaire, had anthropometric measures (measurements of the proportions, size, and weight of the human body) and an ECG taken. electrocardiogram (ECG) taken to check the heart’s rhythm and electrical activity. They also completed a food frequency questionnaire at home (Fehily et al 1994). home. They subsequently re-attended an early morning clinic to have fasting blood samples for a wide variety of tests. Quality control was examined using both "blind" split samples as well as a second repeat measure on a random sub-sample to examine intra-individual variation. Phase II of the study was undertaken between July 1984 and June 1988. An additional 447 new men were included who had moved into the study areas. This is known as the “reconstructed” cohort. In addition to the tests undertaken at phase I, new tests included audiometry (evaluation of hearing function). Phase II of the study was undertaken between July 1984 and June 1988. An additional 447 new men were included who had moved into the study areas. This is known as the “reconstructed” cohort. In addition to the tests undertaken at phase I, new tests included audiometry. Phase III of the study was undertaken between November 1989 and September 1993. It followed the same methods as Phase I and II. The main new features were a standardised battery of cognitive function tests as well as a variety of new platelet (blood clotting cells) and bleeding time tests. Phase III of the study was undertaken between November 1989 and September 1993. It followed the same methods as Phase I and II. The main new features were a standardised battery of cognitive function tests as well as a variety of new platelet and bleeding time tests. [1 paragraph unchanged] After phase IV men have been contacted on two further occasions by post. This has enabled data on stroke events as well as new non-fatal myocardial infarctions (heart attacks) to be collected. Phase V was undertaken between August 2002 and June 2004. This repeated questionnaire data but also now had a special memory clinic to assess men who scored poorly on the cognitive assessments to see if they have may have any cognitive impairment or dementia. Since then men have received a postal questionnaire on the Warwick Edinburgh Well-Being scale. scale (measuring mental well-being). All men have been followed up for incident Ischemic Heart Disease (IHD) [12 words unchanged] the Rose angina questionnaire, checking hospital admissions and new evidence of ECG ischaemia. ischaemia (restriction in blood supply to parts of the body). The World Health Organisation HO criteria were used to define cases follow-up of non-fatal myocardial infarction. the participants has since 1982 involved information from NHS Digital about vital status and if deceased, the causes of death as well as cancer registration and type of cancer. At each phase, 40-50 mls of blood were taken and stored at either -40 or -80 C. This insightful decision has enabled subsequent researchers to rapidly test new hypotheses (e.g. the role of H. Pylori, cytomegalovirus and C. Pneumoniae with respect to IHD risk: see Strachan et al 1999, 1999, 1998). A large amount and variety of samples (serum, plasma, sodium citrate, etc.) remain for future potential analyses. Under previous versions of this Agreement and in line with permission from the Office for National Statistics which was the custodian of the data at that time, the University of Bristol has shared pseudonymised subsets of study data with third party researchers at the University College London (UCL) – London School of Hygiene and Tropical Medicine (LSHTM)-University of Edinburgh – University of Bristol (UCLEB) universities consortium. NHS Digital acknowledges that data was shared with appropriate permissions at the time of sharing. This Agreement does not retrospectively grant permission from NHS Digital for that sharing. The research from the MRC (Medical Research Council) Caerphilly Prospective Study has already resulted in over 150 publications and this will continue to increase as currently data from CaPS contributes to various consortia that undertake meta-analyses across multiple epidemiological cohort studies. The University of Bristol also formerly shared study data with the University of Cambridge and the University of Helsinki. In all instances, the data was mostly collected from other study sources and no NHS Digital data covered under this Agreement has been directly shared. Information derived from data shared under this Agreement has been shared. Derivation was guided by ONS processes. Under previous versions of this Agreement and in line with permission from the Office for National Statistics which was the custodian of the data at that time, the University of Bristol has shared pseudonymised subsets of study data with third party researchers within and outside of the UK. The data was mostly collected by the University of Bristol from other sources and no data covered under this Agreement has been directly shared. Information derived from data shared under this Agreement has been shared. NHS Digital acknowledges that data was shared with appropriate permissions at the time of sharing. This Agreement does not retrospectively grant permission from NHS Digital for that sharing. The data shared has not been assessed by NHS Digital nor confirmed to be sufficiently derived such that a (a) it cannot be identified as originating or deriving from the Data and cannot be reverse-engineered such that it can be so identified; and (b) is not capable of use as a substitute for the Data. Any data shared must be subject to the conditions that the receiving organisation: i. must not combine it with other datasets which could potentially increase the risk of reidentification for individuals in the dataset; ii. must not attempt to re-identify individuals in the dataset; iii. must not onwardly share the dataset; iv. must use the dataset for a defined purpose in support of the CaPS Study's aims defined within this Agreement, and v. must not publish the data. Under the terms of this Agreement, the University of Bristol is responsible for ensuring compliance with the above conditions and for confirming destruction of the data by the receiving organisations once the data is no longer required for the purpose for which it was shared. [1 paragraph unchanged] The University of Bristol is the data controller and also process the data for the purpose described in this Agreement. The University of Bristol use data at an individual rather than aggregate level as it is impossible to undertake the research without record level information to enable sophisticated multivariable (statistical) modelling. For example, the University of Bristol may wish to model individual risk factor and outcome trajectories such as whether change in an individual’s body mass index (BMI) predicts change in their cognitive performance on memory tests. Data minimisation principles apply in that (i) Record level data are provided for the purpose of a specific hypothesis (ii) Filtering is undertaken if appropriate, for example subjects who are lost to follow up may be excluded. As the data set is relatively small, it is more normal to not filter on any factor other than missingness. (iii) Usually all episodes of clinical follow-up are required, as one of the strengths of this prospective cohort study is the repeat measures of risk factors which allows the researchers to model a trajectory. (iv) No further linkages are undertaken other than to mortality and cancer registration data. Under a forthcoming amendment, the University of Bristol will be seeking new record level data (from April 2016) on cause of mortality and cancer registration to supplement its existing records, and also historical HES data (earliest to latest available). The new data requested from NHS Digital will be added to the existing dataset and will further the aims by providing more outcomes which in turn will enhance the statistical power of the study and enable sub-group analyses (e.g. comparing whether a risk factor is equally important in men with higher and lower educational level). The new mortality and cancer data will be the same type of data as already held, but covering the period since April 2016 to ensure full life-course follow-up of all cohort members. [1 paragraph unchanged] The processing of these data are in the public interest (article 6(1e)) (UK GDPR Article 6(1)(e)) as they contribute to a greater understanding of health related risks and [57 words unchanged] the reuse of existing therapeutics or the development of new drug targets. The study has also contributed to life course meta-synthesis that looks at a risk factor or trait over the life course by merging datasets that have data over different life stages e.g. childhood, young adulthood middle age, older age etc. This has shown the interesting pattern as how blood pressure changes over the life course (see Wills et al 2011). The University of Bristol has considered the moral or ethical issues around the data processing. All participants were fully aware they were voluntarily participating in a longitudinal health research project and consented for the research team to have access to their medical records, though given the historical nature of this study, as was normal at that time, the participants were not formally informed that their vital status would be reported through NHS Digital. The participants were fully aware that the study collaborated with other researchers and wished to follow them until death. There is no obvious risk of potential harm to the public by the dissemination of the results which are always at an aggregate or summary level. The University of Bristol are also processing the data in accordance with UK GDPR Article 9(2)(j) as ‘processing is necessary for archiving purposes in the public interest, scientific or historical research purposes’. The use of these data will add scientific knowledge to the existing evidence base around the aetiology and potential prevention of many common chronic diseases. It will also comparison of trends in disease and risk factor prevalence over time to see if the Public Health is or is not improving, for example the proportion of individuals meeting the World Health Organization recommendations on physical activity over time. The University of Bristol believe these useful activities justify the retention and processing of the NHS Digital data. The study does not currently receive any grant funding but is supported by the Population Health Sciences department, University of Bristol through staff time and support and infra-structure. It also requests data access costs as cost recovery from studies when appropriate. The University of Bristol has considered the moral or ethical issues around the data processing. All participants were fully aware they were voluntarily participating in a longitudinal health research project and consented for the research team to have access to their medical records, though given the historical nature of this study, as was normal at that time, the participants were not formally informed that their vital status would be reported through NHS Digital. The participants were fully aware that the study collaborated with other researchers and wished to follow them until death. The University of Bristol is the data controller and also processes the data for the purpose described in this Agreement. There are no commissioners involved. The study does not currently receive any grant funding but is supported by the Population Health Sciences department, University of Bristol through staff time and support and infra-structure. It also requests data access costs as cost recovery from other studies using broader CaPS data (not NHS Digital data) when appropriate.

Processing activities

Under a previous iteration of this Agreement, NHS Digital received the flags [10 words unchanged] is closed, and no additional cohort members will be sent to NHS Digital. Digital under this version of the Agreement. NHS Digital has previously sent identifying data (mortality and event notifications) notifications with names, address, date of birth, NHS number and sex) to the University of Bristol where it is was processed and added to the master database. Subsequent flows of data have occurred, whereby the University of Bristol have transferred manipulated NHS Digital data to external organisations (including some organisations that fall outside the EEA). This data was typically shared in conjunction with pseudonymised data obtained from the studies data collection, or data collected from third parties. Subsequent flows of data have occurred, whereby the University of Bristol have transferred derived NHS Digital data to external organisations. Other organisations who currently have CaPS data containing derived NHS Digital data variables are the University of Cambridge, University of Helsinki, UCL, LSHTM and the University of Edinburgh. This data was typically shared in conjunction with pseudonymised data obtained from the study's data collection and will have undergone statistical analyses as part of a project proposal approved by the University of Bristol. No further subsequent flows of data will occur under this Agreement. The University of Bristol is the only organisation authorised to process NHS Digital data under this Agreement. Data is processed to explore any hypotheses related to the overall aim of the CaPS study. There is no data linkage other than to research data collected by the University of Bristol as specified above. There is no matching to publicly available data. All external parties are aware that there will be no attempt to re-identify individuals. Any data shared will be stored on a secure server (with appropriate password protection) hosted by the academic organisation and staff who undertake any analysis will have received training in data protection and confidentiality. There is no data linkage other than to research data collected by the University of Bristol (see https://www.bristol.ac.uk/population-health-sciences/projects/caerphilly/about/). These variables are numerous especially those derived from the biochemical analysis of blood samples. For simplicity, they can be grouped into the following sub-headings; demographic (e.g. age), lifestyle (e.g. smoking), environmental (e.g. noise exposure) psychosocial (e.g. Type A personality), clinical (e.g. blood pressure), biochemical (e.g. serum cholesterol), outcomes (e.g. heart disease, cognitive function etc). There is no matching to publicly available data. All individuals processing the data at the University of Bristol are substantive employees, all of whom have received appropriate training in data protection and confidentiality. All individuals processing the data at the University of Bristol are substantive employees or authorised PhD students, all of whom have received appropriate training in data protection and confidentiality. Data can be accessed either on University premises or from home using special VPN software. University of Bristol store the data on a Safe Haven following NHS Digital guidelines. This means that all access to the data is controlled by the Data Custodian who must request access on an individual level from IT. Access logs are kept for 12 months and audit reports are available monthly. The data are encrypted at rest on the server. To comply with data destruction notices from NHS Digital, the data stored on the Safe Haven is not backed-up by design. [1 paragraph unchanged]

Expected output

The outputs produced from the data provided is new knowledge in relation [24 words unchanged] of scientific publications in peer reviewed journals, book chapters, monographs etc. They will are also expected to contribute to oral presentations and other media. Such The results presented in such outputs may contribute to policy formulation either through groups are summary tables e.g. percentage of smokers and effect estimates such as a measure of risk e.g. the risk ratio of dying from cardiovascular disease comparing obese with non-obese subjects. Any small number cells will be suppressed in line with the HES analysis guide so that formulate clinical or public health guidelines (e.g. NICE, WHO, British Heart Foundation) or through other bodies that synthesise evidence for the purpose of commissioners and/or policy leaders (e.g. Lancet Commission). no cells have fewer than 7 subjects. The Caerphilly Prospective Study (CaPS) is a very detailed and richly phenotyped study that has data both on lifestyle, clinical, biochemical and genetic data. It is therefore used for a wide variety of hypotheses rather than a single specific one and can be used to examine a wide range of different outcomes such as heart disease, cancer and dementia. It is therefore impossible to pre-specify all hypotheses and for genetic research it is often used as part of a replication study to see if it can confirm new findings from discovery studies. The University of Bristol follows the following approaches to the dissemination and communications of results and outputs. Other researchers are targeted through publication in the most appropriate scientific journal which may be generic (e.g. Lancet) or specialist (e.g. Brain). Thus other researchers working in the same topic area are expected to be aware of the results. Depending on the importance of the findings for Public Health, the University Press Office (and sometimes the Journal itself) typically issue a Press Release to the general media. In this scenario, it is often the case that journalists contact the lead/senior author to discuss the results and gather a quote for a lay article. In some cases this may also lead to radio and/or television interviews. Some journals now host their own vlogs about papers of interest and may also commission an accompanying editorial. The University of Bristol will also submit abstracts for oral or poster presentations to both National (e.g. Society for Social Medicine) or International conferences where the work is hoped to be presented. University of Bristol researchers may also be invited to attend meetings or advise on policy formulation with relevant bodies. The outputs may contribute to policy formulation either through the citation and inclusion of results in clinical or public health guidelines (e.g. National Institute for Clinical Excellence, World Health Organisation, British Heart Foundation) or through other bodies that synthesise evidence for the purpose of commissioners and/or policy leaders (e.g. Lancet Commission). The results presented in such outputs are summary tables e.g. percentage of smokers and effect estimates such as a measure of risk e.g. the risk ratio of dying from cardiovascular disease comparing obese with non-obese subjects. Any small number cells will be suppressed in line with the HES analysis guide so that no cells have fewer than 7 subjects. In some of the meta-analyses the results are aggregated across many studies and the specific study cannot even by identified. The Caerphilly Prospective Study (CaPS) is a very detailed and richly phenotyped study that has data both on lifestyle, clinical, biochemical and genetic data. It is therefore used for a wide variety of hypotheses rather than a single specific one and can be used to examine a wide range of different outcomes such as heart disease, cancer and dementia. The research from CaPS has already resulted in over 150 publications and this is expected to continue to increase. Currently, derived data from CaPS contributes to various consortia that undertake meta-analyses across multiple epidemiological cohort studies (see below). In some of the meta-analyses the results are aggregated across many studies and the specific study cannot even be identified. Variables derived from NHS Digital data were shared with the University of Cambridge as part of the Emerging Risk Factors Collaboration (EFRC), regarding approximate time of fatal heart attack/ death from other causes. A key output from the EFRC collaboration is the publication 'World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions (Kaptoge et al., 2019). This work was led by the cardiovascular disease epidemiology team based at the University of Cambridge, which includes data from CaPS as well as many other cohort studies. There are several different cardiovascular disease prediction risk scores that have been developed for high income countries (HIC) but far less for low middle income countries (LMIC). The team were able to develop risk prediction models (including CaPS data) which were then validated in further datasets and with particular potential use in LMICs. Variables derived from NHS Digital data were shared with the University of Helsinki as part of the Biomarker for Cardiovascular Risk Assessment across Europe (BiomarCaRE) consortium, regarding approximate time of death relating to stroke, cancer, cardiovascular disease or other causes. Variables derived from NHS Digital data were shared with the University College London - London School of Hygiene and Tropical Medicine - University of Edinburgh - University of Bristol (UCLEB) universities consortium in 2016 in line with approvals by the Office for National Statistics (ONS) at the time. NHS Digital derived variables covered broad categories of cause of death, time of death and cause of cancer for projects concerning biochemical metabolomic predictors of cardiovascular disease risk factors and outcomes. Reference: Kaptoge, S., Pennells, L., De Bacquer, D., Cooney, M.T., Kavousi, M., Stevens, G., Riley, L.M., Savin, S., Khan, T., Altay, S., Amouyel, P., Assmann, G., Bell, S., Ben-Shlomo, Y., Berkman, L., Beulens, J.W., Björkelund, C., Blaha, M., Blazer, D.G. and Bolton, T. (2019). World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. The Lancet Global Health, [online] 7(10), pp.e1332–e1345. doi:10.1016/s2214-109x(19)30318-3.

Expected measurable benefits

The Caerphilly Prospective study (CaPS) has already contributed to a large volume of published research of high quality. There are several hundred papers that are either based on data from CaPS itself or more recently it has contributed to a wide variety of multi-study collaborations which combine data across many studies in what is known as meta-analysis. These sort of studies look at the associations between a variety of different exposures and disease outcomes including death. Such research can identify new risk factors be they environmental or genetic that may lead to new causes of disease with the potential for developing new interventions to prevent disease. It has also contributed to life course meta-synthesis that looks at a risk factor or trait over the life course by merging datasets that have data over different life stages e.g. childhood, young adulthood middle age, older age etc. This has shown the interesting pattern as how blood pressure changes over the life course (see Wills et al 2011). This highlights important ages where prevention strategies may have more impact on health. The types of benefit that may arise from the CaPS study are health related and may result in new methods of disease prevention or prediction. This may benefit the provision of health and/or adult social care by allowing disease modellers and health economists to predict future disease trends through risk factor surveillance and the use of effect estimates for this research and other studies. CaPS study findings are in the public interest in terms of enhancing understanding of how to prevent disease. Meta-analyses using derived CaPS data will look at the associations between a variety of different exposures and disease outcomes including death. Such research can identify new risk factors be they environmental or genetic that may lead to new causes of disease, with the potential for developing new interventions to prevent disease. Inclusion of research evidence from CaPS as well as other studies in policy documents is one way to document and measure the public benefit of this research. The timelines to see expected benefits are hard to predict as it depends both on the weight of pre-existing evidence (it is rare to see policy changes on the basis of one or two studies) and its political expedience. The provision of NHS Digital data to the existing CaPS data can greatly enhance the value of the research by (i) validating self-reported diagnosis, (ii) correcting misdiagnoses (iii) identifying new cases (iv) enhancing statistical power to demonstrate associations (iv) reduce selection bias by only studying less severe cases who participate in follow-ups and are less likely to have died from the disease of interest. A potential benefit of the derived NHS Digital data shared for the Emerging Risk Factors Collaboration (ERFC) is in relation to cardiovascular disease and the publication of the revised World Health Organisation (WHO) risk scores. The new risk prediction models could enable the estimation of cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. Having such risk prediction models available could therefore help to achieve the following: (i) aid health care planning to rational provision of secondary and tertiary cardiovascular care (ii) examine trends both in the past and into the future of any natural experiments or policy changes to restrict adverse exposures e.g. banning smoking in public (iii) as a political lever to redistribute funding to support primary prevention.

Benefits reported

The University of Bristol have contributed to a number of important meta-analyses with other studies that have looked at genetic and metabolomic risk factors for chronic diseases. In addition, the Caerphilly study has highlighted how men who have healthy life styles (non-smoking, not obese, high fruit and vegetable intake, regular physical activity and low or moderate alcohol intake) have increased disease free survival as well as reduced risk of cognitive impairment and dementia (Elwood et al PLoS One 2013). Such work is important from a public health perspective and can feed into the evidence base for organisations such as Public Health England for whom dementia is a major priority as it will place ever increasing demands on both and health and social care services as our population in the UK continues to get older. Its ability to test how risk factors for cardiovascular disease are also linked to dementia is important to organisations like PHE and the British Heart Foundation and is part of the basis of the "What's good for the heart is good for the brain" movement. CaPS data has contributed to life course meta-synthesis that looks at a risk factor or trait over the life course by merging datasets that have data over different life stages e.g. childhood, young adulthood middle age, older age etc. This has shown the interesting pattern as how blood pressure changes over the life course. This highlights important ages where prevention strategies may have more impact on health. One impact of this sort of research has been the specific targeting of research funding by UKRI, NIHR and the Global alliance for chronic diseases on life course research and interventions targeting specific critical or sensitive time periods (see https://www.gacd.org/funding/current-call-for-applications/common-risk-factors). Knowing who, why and when individuals have died, as supplied from NHS Digital, is important to the validity of the research. This is because the results and hence policy implications may be biased if one does not consider loss to follow-up due to death. Some exemplars of important work that have come from CaPS (with other studies) is for example the importance of hearing loss as a predictor of future dementia. This was one of the risk factors identified by the Lancet Commission on dementia (Livingston et al 2017) as a potentially modifiable risk factor for dementia. The inclusion of CaPS in the MRC Dementia Platform UK (https://portal.dementiasplatform.uk/) will enable a large international community of researchers access to CaPS data to further our understanding of dementia risk. The CaPS study has highlighted how men who have healthy life styles (non-smoking, not obese, high fruit and vegetable intake, regular physical activity and low or moderate alcohol intake) have increased disease free survival as well as reduced risk of cognitive impairment and dementia. Such work is important from a public health perspective and can feed into the evidence base for organisations such as UK Health Security Agency for whom dementia is a major priority as it will place ever increasing demands on both and health and social care services as our population in the UK continues to get older. Its ability to test how risk factors for cardiovascular disease are also linked to dementia is important to organisations like the UK Health Security Agency and the British Heart Foundation, and is part of the basis of the "What's good for the heart is good for the brain" movement. Other examples include identifying new genetic pathways to disease or risk factors. CaPS was one of 13 cohorts that were used to identify the FTO gene, the first major genetic determinant of obesity, which is a growing public health issue for children and young adults. CaPS has also been a contributor to the Emerging Risk Factors Collaboration (ERFC) that have looked at cardiovascular risk factors. Recently the ERFC have produced new World Health Organisation (WHO) CVD algorithms cardiovascular disease risk models for application in multiple global regions and CaPS was one of the datasets included in this large piece of work. Recently variations in genetics The ERFC outputs have been used already provided WHO and country specific health ministries the ability to study environmental exposures using an approach known as Mendelian Randomization. CaPS has contributed to the publication testing whether an inflammatory marker, C-Reactive Protein, was associated with coronary heart disease (CHD). It was also included in a large meta-analysis of pulse wave velocity and CHD to see if this new measure can improve risk prediction of CHD over and above normal integrate routinely collected surveillance data on risk factors such as blood pressure. These results obesity and cheaper technology have apply the potential respective algorithms to change estimate the way doctors practice medicine and by better risk stratification has the potential to improve health care delivery. future 10 year burden of cardiovascular disease. CaPS data also contributed to a meta-analysis which discovered the importance of hearing loss as a predictor of future dementia. This was one of the risk factors identified by the Lancet Commission on dementia (Livingston et al., 2017) as a potentially modifiable risk factor for dementia. Reference: Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. PMID: 28735855.

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

Objective for processing

[1 paragraph unchanged] The overall aim of the CaPS study is to enhance the understanding of life course influences on the aetiology of chronic disease and physiological traits by examining life style, lifestyle, genetic and other exposures at various time in the life course and determine whether these predict a wide range of different outcomes. The University of Bristol wishes to obtain retain and process the identifiable Medical Research Information Service (MRIS) data for received under previous iterations of this study, covering different outcomes, such as cardiovascular disease, dementia, cancer, ageing traits and mortality. Agreement. [2 paragraphs unchanged] Quality control was examined by the use of using both "blind" split samples as well as a second repeat measure on a random sub-sample to examine intra-individual variation. [6 paragraphs unchanged] All men have been followed up for incident IHD Ischemic Heart Disease (IHD) through mortality flagging, self-reported information confirmed by medical records, positive history to [16 words unchanged] Organisation HO criteria were used to define cases of non-fatal myocardial infarction. [1 paragraph unchanged] The research from the MRC (Medical Research Council) Caerphilly Prospective Study has [17 words unchanged] contributes to various consortia that undertake meta-analyses across multiple epidemiological cohort studies. (e.g. Emerging Research Factor Collaboration, University of Cambridge). This Agreement permits the University of Bristol to continue to hold the data on cause of death and cancer registration that has been released since 1980 and to receive new data on any events since 2016 to update the database. These data currently contain identifying information but the University of Bristol has agreed a strategy in the future to move to a fully pseudonymised dataset. Mortality and cancer data enables the study team to examine associations between their exposures and health related outcomes such as cause specific mortality and cancers (fatal and non-fatal). Under previous versions of this Agreement and in line with permission from the Office for National Statistics which was the custodian of the data at that time, the University of Bristol has shared pseudonymised subsets of study data with third party researchers within and outside of the UK. The data was mostly collected by the University of Bristol from other sources and no data covered under this Agreement has been directly shared. Information derived from data shared under this Agreement has been shared. NHS Digital acknowledges that data was shared with appropriate permissions at the time of sharing. This Agreement does not retrospectively grant permission from NHS Digital for that sharing. The data shared has not been assessed by NHS Digital nor confirmed to be sufficiently derived such that a (a) it cannot be identified as originating or deriving from the Data and cannot be reverse-engineered such that it can be so identified; and (b) is not capable of use as a substitute for the Data. During the term of this Agreement, the University of Bristol must not share any data covered under this Agreement or data derived from data covered under this Agreement with any third party. The University of Bristol must agree with NHS Digital a mutually acceptable mechanism for sharing data and/or derived data and may only share data once an amended version of this Agreement has been signed by all parties. The University of Bristol is the data controller and also process the data for the purpose described in this Agreement. [1 paragraph unchanged] The processing of these data are in the public interest (article 6(1e)) [129 words unchanged] blood pressure changes over the life course (see Wills et al 2011). This highlights important ages where prevention strategies may have more impact on health and would be covered by GDPR section 9(2)(i). The University of Bristol does not see any has considered the moral or ethical issues around the data processing as all the processing. All participants were fully aware they were voluntarily participating in a longitudinal health [78 words unchanged] of the results which are always at an aggregate or summary level. By obtaining new data to add onto the existing dataset, the study will be able to enhance its statistical power and will be unusual in having such a long follow-up period. This should lead to better public information on health risks and potential prevention strategies. The University of Bristol is the sole data controller and also processes the data for this study. No other organisations process the data for this purpose. Under previous versions of this Agreement and in line with permission at the time, the University of Bristol has shared pseudonymised subsets of the data with third party researchers within and outside of the UK. The data was mostly collected by the University of Bristol from other sources and no data covered under this Agreement has been directly shared. Information derived from data under this Agreement has been shared. Under this Agreement, the University of Bristol is not permitted to share any further data covered under this Agreement or derived from data covered under this Agreement. To permit such data sharing in the future, the University of Bristol will be required to apply for and receive approval for an amendment to this Agreement granting such permissions. Most of the cohort have now died, the exact percentage of survivors is not known. A decision was made a few years ago not to try and recontact the cohort (current age range is between 82-98 years) as most are likely to be frail and some will have dementia. In addition, some will no longer be residing at home having moved to family or care homes so it is unlikely the participants could be found. It is therefore believed that linkage is the least intrusive approach to obtain these valuable data. NHS Digital already hold the original study ID that was established when the cohort was originally flagged. In the future the University of Bristol team propose to add a new study member identifier to replace the original one thereby ensuring a fully pseudonymised study. [1 paragraph unchanged]

Processing activities

Under a previous iteration of this Agreement, NHS Digital already hold received the flags for the cohort of participants with identifying information. The cohort is closed so closed, and no additional cohort members will be sent to NHS Digital. NHS Digital has previously sent identifying data (mortality and event notifications) to the University of Bristol where it is processed and added to the master database. Under this Agreement, the University of Bristol requires a Members and Posting report which will include identifying data, to ensure the cohort is reconciled and correctly flagged. The University of Bristol is also requesting back-dated events and mortality data, including identifying data, from September 2016. The University of Bristol will then provide a new study member identifier to NHS Digital and request a second members and posting list including the new study member ID, as well as the original member ID, to ensure that linkage has been successful with the new identifier. Once this is in place, the University of Bristol will proceed to an amendment whereby they will move to a pseudonymised dataset where all personal identifying data are removed, other than a new unique identifier which will replace the old identifier so data cannot be linked to existing paper records. NHS Digital has previously sent identifying data (mortality and event notifications) to the University of Bristol where it is processed and added to the master database. The department of Population Health Sciences at the University of Bristol will not hold the link file (old ID and new ID) so will not be able to back-link the data but this link file will be kept by three independent bodies for safety reasons (DPUK, NHS Digital and Data Bris who are the University of Bristol Research Data Repository) so that any newly derived data from stored blood or DNA samples can be added to the database using the link file. All previously supplied identifying details, supplied by NHS Digital, will be destroyed and evidenced by a Certificate of Data Destruction. Subsequent flows of data have occurred, whereby the University of Bristol have transferred manipulated NHS Digital data to external organisations (including some organisations that fall outside the EEA). This data was typically shared in conjunction with pseudonymised data obtained from the studies data collection, or data collected from third parties. There is no data linkage other than to research data collected by [17 words unchanged] parties are aware that there will be no attempt to re-identify individuals. Such Any data shared will be stored on a secure server (with appropriate password protection) hosted [7 words unchanged] undertake any analysis will have received training in data protection and confidentiality. All individuals processing the data at the University of Bristol are substantive employees, all of whom have received appropriate training in data protection and confidentiality. [1 paragraph unchanged]

Unchanged: Expected output, Expected measurable benefits, Benefits reported.