MR706 - SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

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Objective for processing

[2 paragraphs unchanged] The data under this Agreement is treated as identifiable because the data controller continue to retain the patient identifiers which will be provided to NHS Digital. England. [10 paragraphs unchanged] The study team have previously received data from NHS Digital. England. Under this Agreement further data are requested and the data controller wish to retain all data previously disseminated. [9 paragraphs unchanged] The study team request linkage of individual participants by their identifying information (name, NHS number, date of birth, gender) by NHS Digital. England. NHS Digital England will return data to the Nuffield Department of Population Health at the [6 words unchanged] trial identity number with data from the linkage, i.e. pseudonymised record-level data. [3 paragraphs unchanged] Linking participants to their data held by NHS Digital England is the least intrusive way of achieving the study's purpose. The data [68 words unchanged] is applied at the point of disclosure and does not apply retrospectively. [4 paragraphs unchanged] The study team have three similar studies with common aims but for which three separate data sharing agreements are held with NHS Digital. England. Due to the similarities between the studies and the cohorts used, where [56 words unchanged] of variables on major health events such as stroke, MI & dementia. [2 paragraphs unchanged] The study team intend to link data from participant DNA analyses to NHS Digital England data. Linkage to longer-term outcomes (including those identified from NHS Digital England data) is of considerable importance in fully understanding response to statins and [35 words unchanged] contribute to the development of better patient treatments and precision medicine approaches. [6 paragraphs unchanged] All processing of NHS Digital England data will take place within the University of Oxford, therefore Oxford are listed as sole data processor under this Agreement. [2 paragraphs unchanged]

Processing activities

[6 paragraphs unchanged] NHS Digital England will link the identifiers with the following data-sets: [7 paragraphs unchanged] NHS Digital England will not return any identifiers to the data controller. Only the pseudonymised Study ID and pseudonymised data from the data-sets listed above will be returned. The data controller will retain the pseudonymised data for at least 25 [13 words unchanged] will be required to maintain an active Data Sharing Agreement with NHS Digital. England. The applicant will only hold and analyse data-sets with trial numbers, the [16 words unchanged] Controller’s NDPH NHS DSP Toolkit compliant environment via an encrypted transfer method. Participants who have applied the National Opt Out will be excluded from the flow of data from NHS Digital. England. In addition, participants who have read the privacy notice (available on the [62 words unchanged] remove any participant from future analysis who has requested to be withdrawn. Once data from NHS Digital England is held by the University of Oxford, NHS Digital England data will be linked to data collected from participants during the trial, [29 words unchanged] NDPH is used for large meta-analysis of trial data. No pseudonymised NHS Digital England or identifiable data will be shared other than with substantive employees of the data controller. [1 paragraph unchanged] Other than the linkages already described within this Agreement, researchers will not link NHS Digital England data to other datasets. No attempt will be made to re-identify participants from the NHS Digital England data. [4 paragraphs unchanged]

Expected output

[3 paragraphs unchanged] It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). England). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 [10 paragraphs unchanged]

Benefits reported

[12 paragraphs unchanged] Updated 27/08/2024. There are no additional Yielded Benefits to report at this time.

Unchanged: Expected measurable benefits.

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

Datasets: + Bridge file: Hospital Episode Statistics to Mental Health Minimum Data Set; + Cancer Registration Data; + Civil Registrations of Death; + Demographics; + Hospital Episode Statistics Admitted Patient Care (HES APC); + Mental Health Minimum Data Set (MHMDS); + Mental Health Services Data Set (MHSDS); + Mental Health and Learning Disabilities Data Set (MHLDDS)

Objective for processing

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides background to the study: [1 paragraph unchanged] SEARCH was a randomised, multi-centre, factorial trial of LDL (low-density lipoprotein) cholesterol lowering lowering, comparing higher versus standard dose simvastatin, simvastatin (a drug used to lower cholesterol for people diagnosed with high blood cholesterol), and homocysteine (an amino acid) lowering comparing folic acid and vitamin B12 supplementation versus placebo in 12,064 patients with an average age of 64 and with a history of myocardial heart attacks (myocardial infarction (MI). (MI)). It was run in 88 UK clinical centres for ten years. Participants [10 words unchanged] and October 2001, with all final follow-up assessments completed by June 2008. The initial trial results were published in 2010. This study, in combination with other available data, showed that additional LDL cholesterol lowering with a high dose statin further reduced major vascular events, but that folic acid and vitamin B12 supplementation did not have beneficial effects on vascular outcomes. NDPH has a strong research interest in the more reliable assessment of the effects of LDL cholesterol lowering. The data under this Agreement is treated as identifiable because the data controller continue to retain the patient identifiers which will be provided to NHS Digital. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (apoE) that binds to receptors in low-density lipo-protein and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. The initial SEARCH trial results have shown that: In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because of reverse causal effects of the incipient dementia leading to lower levels. However, raised mid-life levels of LDL cholesterol have been found to be associated with increased risk of dementia 15-20 years later. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. - The allocation to simvastatin 80mg daily versus 20mg daily reduced LDL-cholesterol by 0.35 mmol/L and reduced major vascular events (i.e. heart attacks, strokes or coronary or non-coronary revascularisation) by 6% (95% CI 12% to +1%). This reduction was in line with expectations and contributed to the Cholesterol Trialists’ Collaboration (CTT) meta-analysis that showed that more intensive LDL-cholesterol lowering produces additional benefits. - Supplementation with folic acid plus vitamin B12 significantly reduced homocysteine levels and is safe, but did not reduce the risk of major vascular events or cancer. - Simvastatin 80mg daily was associated with an increased risk of myopathy (muscle symptoms with raised blood creatine kinase) with 53 vs 2 cases respectively among those allocated 80mg vs 20mg simvastatin daily. - In a nested genetic case-control a genetic marker in the SLCO1B1 gene was shown to increase the risk of statin-induced myopathy. - The SEARCH database continues to provide valuable information on other risk factors for myopathy. Data from SEARCH contributed to the CTT meta-analyses and the B Vitamin Treatment Trialists’ Collaboration (BVTTC) analyses. On-going investigations include looking at the long-term effects (over 10 years) of homocysteine-lowering on vascular and non-vascular deaths and cancers using data from electronic health records. NDPH has a strong research interest in the more reliable assessment of the effects of LDL cholesterol lowering. This long-term follow-up will add important data about the effects of LDL cholesterol lowering on important chronic health outcomes. In addition to the effects of randomly allocated treatment, the study team will look at the effect of clinical, genetic, and biomarker data on future health. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (apoE) that binds to receptors in low-density lipo-protein and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides (a type of fat found in blood) than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because incipient dementia leads to lower levels. However, raised levels of LDL cholesterol 15-20 years before the development of dementia have been found to be associated with increased risk of dementia. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. [1 paragraph unchanged] The study team have previously received data from NHS Digital. Under this Agreement further data are requested and the data controller wishes wish to retain all data previously disseminated. The data subjects are all be participants of the original randomised controlled trial. Additionally, the data controller now has Section 251 support to request hospital episodes, cancers, demographics and mental health datasets for the cohort. This data will enable the data controller to examine the effect of baseline clinical, genetic and biomarker variables on major health events, including major vascular events (including, but not limited to strokes of different types and myocardial infarction), cancers, renal disease and dementia. The data controller will ascertain these The legal basis for processing and storing data under this Agreement is Article 6(1)e (GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long term effects of cholesterol-lowering treatments in the UK population and is therefore in the public interest. events, through ICD-10 coding in hospital admission, death records, and mental health records. The study team have found in previous work that the majority of cases of chronic disease (including dementia) can be found in admitted patient care, death and mental health records. In addition, processing and storage of special category (sensitive) personal data is being done under Article 9(2)(j) (GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long term effects of cholesterol-lowering treatments on important health outcomes. The purpose of requesting the data under this Agreement is to determine factors that contribute to the health of trial participants in the longer-term. The research team have taken the opinion of the West of Scotland Research Ethics Service, who have granted approval to the study in its current form. Furthermore, potential harm to the public will be limited by data pseudonymisation, data minimisation, and technical and organisational safeguards. Analysis will occur in a safe, IG Toolkit/DPST compliant environment and identifiers will not be included in the analysis. The study team have asked for the opinion of available participants in these and similar studies, and they have agree that the use of the data in the way that the study team have proposed is reasonable. The research objectives are: 1. To determine whether participants randomly allocated to treatments leading to lower levels of LDL cholesterol or lower homocysteine levels have a lower risk of dementia. 2. To determine whether participants randomly allocated to treatments leading to lower levels of LDL cholesterol or lower homocysteine levels have other long-term health effects. 3. To measure the association between baseline and in-trial vascular risk measures with future dementia. 4. To determine the association between deoxyribonucleic acid (DNA) and plasma markers with dementia and other long-term health effects. In order to determine the occurrence of the diagnosis of particular illnesses, the study team, who are all substantive employees of the University of Oxford, will need to link trial participants to hospitalisation, mental health, death and cancer records. The study team will therefore request linkage to Hospital Episode Statistics (HES) for Admitted Patient Care, the Mental Health Datasets, Demographics, Civil Registration - Deaths, and Cancer data sets. The study team request linkage of individual participants by their identifying information (name, NHS number, date of birth, gender) by NHS Digital. NHS Digital will return data to the Nuffield Department of Population Health at the University of Oxford with each participant's trial identity number with data from the linkage, i.e. pseudonymised record-level data. The data subjects will all be participants of the original randomised controlled trial. The study team will obtain data from each participant from the time they began to take part in the trial (the first participant was randomised in 1st September 1998) to the date of linkage. This allows researchers to: (i) compare the occurrence of events recorded by the study during follow up with events recorded by electronic health records; (ii) compare the very long-term incidence of major disease by randomised treatments and baseline factors. Further data releases will allow the study team to continue follow-up of participants for their entire lifespan including cause of death. Participants were resident in and recruited from across the UK, and may have moved between nations since recruitment, and therefore the study team would like to link all participants (including those in Scotland) to data held across England and Wales. Linking participants to their data held by NHS Digital is the least intrusive way of achieving the study's purpose. The data controller believes that re-approaching participants for further consent would lead to potentially very large biases in ascertainment of major health conditions (because of non-responder biases particularly amongst those in poorest health, or those who have died) and potentially lead to distress. Therefore, the data controller has obtained Section 251 support from the Health Research Authority (HRA) Confidentiality Advisory Group (CAG) for this linkage. The national data opt out is applied at the point of disclosure and does not apply retrospectively. The research team have taken the opinion of the West of Scotland Research Ethics Service, who have granted approval to the study in its current form. Furthermore, potential harm to the public will be limited by data pseudonymisation, data minimisation, and technical and organisational safeguards. Analysis will occur in a safe, NHS Data Security and Protection (DSP) Toolkit compliant environment and identifiers will not be included in the analysis. Although the study is not in direct contact with participants, at the time the study team asked for the opinion of available participants in these and similar studies, they agreed that the use of the data in the way that the study team have proposed is reasonable. The study team request linkage only to those datasets and data fields relevant to the research that contain information on medical diagnoses, for only the participants of the study. The study team will also link to equivalent datasets received from Digital Health & Care Wales (DHCW), the Scottish NHS Central Register (NHSCR) and Public Health Scotland. The study team have three similar studies with common aims but for which three separate data sharing agreements are held with NHS Digital. Due to the similarities between the studies and the cohorts used, where any one study (this Agreement, in addition DARS-NIC-147885-0TV66 (HPS2-THRIVE) and DARS-NIC-148069-ZB4GM (HPS)) does not give sufficient power for an analysis, the study team will perform meta-analyses to a common protocol from each study. Where the randomised allocations are similar, the study team will perform study level and individual participant data meta-analyses to look at the effect of variables on major health events such as stroke, MI & dementia. The first planned analyses will be based on at least 20 years’ follow-up from trial initiation with further analyses planned at approximately 5 yearly intervals based on on-going linkage to NHS records. Participants who consented to have their medical records followed up also consented to providing blood samples for the genomic arm of this study. The genomic analyses will be undertaken at specialist laboratories. This will involve sending pure DNA samples. DNA is not a relevant material under the Human Tissue Authority (HTA) and all samples will be sent with only the participant study identifier and no personal data. All data will be returned to Oxford for statistical analyses. The study team intend to link data from participant DNA analyses to NHS Digital data. Linkage to longer-term outcomes (including those identified from NHS Digital data) is of considerable importance in fully understanding response to statins and cardiovascular risk and its consequences as a whole. Genetic data may be able to add insights into our understanding of the effects of statins, determinants and mechanisms of risk factors and disease outcomes, that can contribute to the development of better patient treatments and precision medicine approaches. Although the University of Oxford is not asking for personal identifiers under this Agreement, the remaining supplied data will still be linked to the existing long-term follow-up study database, which does store the identifying data. There is an ongoing need to retain identifying data to enable further data linkages, such as that which will take place under this Data Sharing Agreement. Direct identifiers will need to be retained whilst linkages are made between datasets before all data are identified primarily with the study ID, in order to pseudonymise the long-term follow-up dataset. The intention is to keep a pseudonymised dataset for future analysis for as long as is necessary, and this will be reviewed on a yearly basis. In addition, it is NDPH policy to retain research data for at least 25-years after the end of a the trial as per the 2014 Clinical Trials Regulation (EU) No 536/2014: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf To address the GDPR principle of data minimisation the University of Oxford only request fields that are deemed necessary for the purpose of this research, and only receive data that relates to a specific cohort of ~12,064 individuals (minus any withdrawals). The legal basis for processing and storing data under this Agreement is Article 6(1)e (UK GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long-term effects of cholesterol and homocysteine lowering treatments in the UK population and is therefore in the public interest. In addition, processing and storage of special category personal data is being done under Article 9(2)(j) (UK GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long-term effects of cholesterol and homocysteine lowering treatments on important health outcomes. [1 paragraph unchanged] One of the Investigators investigators for the study is employed by both the University of Edinburgh and the University of Oxford. The applicant has confirmed this investigator will analyse the data under this Agreement solely in his role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. The applicant has confirmed that this individual will analyse the data under this Agreement solely in his role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. [1 paragraph unchanged]

Processing activities

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information about processing activities permitted under previous iterations of this Agreement. The SEARCH study team will resupply the following identifiers for the original randomised UK cohort (12,064 minus any participants who have withdrawn from the study: NHS Digital previously received the identifiers for this cohort and as recruitment ended in 2001, the identifiers that NHS Digital currently hold are: [3 paragraphs unchanged] - Date of death - Postcode [2 paragraphs unchanged] In turn the University of Oxford received identifiable MRIS Cause of Death, Members and Posting, Flagging Current Status and Cohort Event Notification reports, which they wish to retain . NHS Digital will link the identifiers with the following data-sets: There were no subsequent flows of data. - HES APC No linkage is proposed to datasets containing personal identifiers. No linkage to publicly available data is proposed. No attempt will be made to re-identify participants from the NHS data. - Mental Health datasets NDPH researchers, substantively employed by the University of Oxford, are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. The NDPH servers are protected against unauthorised external access by an appropriate strength firewall. - Demographics Access to patient identifiable information is protected by the appropriate authentication procedures (user IDs and passwords). Authentication is only given to personnel with a need to access the required data. NDPH has a Corporate Level Security Policy that has been fully adopted by management and will apply fully to the long-term follow-up study. - Civil Registration - deaths - Cancer Registrations Historic data will be supplied for HES, cancer and mental health data-sets from 1998 (where available) to present. For the Demographics and Civil Registration - Deaths, latest available data will be provided. NHS Digital will not return any identifiers to the data controller. Only the pseudonymised Study ID and pseudonymised data from the data-sets listed above will be returned. The data controller will retain the pseudonymised data for at least 25 years after the end of a the trial, as per NDPH guidelines, and will be required to maintain an active Data Sharing Agreement with NHS Digital. The applicant will only hold and analyse data-sets with trial numbers, the identifiers and linkage key will be held separately. The data will be sent to the Data Controller’s NDPH NHS DSP Toolkit compliant environment via an encrypted transfer method. Participants who have applied the National Opt Out will be excluded from the flow of data from NHS Digital. In addition, participants who have read the privacy notice (available on the study website: https://www.searchtrial.org/) and have decided that they do not wish their data to be used in this study will be able withdraw their consent to participate in the study and their data will not be included in future analysis. Although the SEARCH long-term research is being conducted with Section 251 support, the University of Oxford consider it appropriate and ethical to remove any participant from future analysis who has requested to be withdrawn. Once data from NHS Digital is held by the University of Oxford, NHS Digital data will be linked to data collected from participants during the trial, including baseline clinical, genetic and biomarker data. All processing of data will be performed within the Nuffield Department of Population Health at the University of Oxford. Data held within NDPH is used for large meta-analysis of trial data. No pseudonymised NHS Digital or identifiable data will be shared other than with substantive employees of the data controller. Using existing ICD-10 code lists for different clinical phenotypes, the study team will define the date and the nature of disease events for each participant. Researchers will link the list of processed disease outcomes with existing datasets of baseline clinical, genetic and biomarkers data (including those received from Scotland and Wales), and the occurrence of disease events within trial. Data linkage takes place within the NDPH NHS DSP Toolkit compliant environment. Data are pseudonymised prior to analysis. Other than the linkages already described within this Agreement, researchers will not link NHS Digital data to other datasets. No attempt will be made to re-identify participants from the NHS Digital data. NDPH researchers are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. The NDPH servers are protected against unauthorised external access by an appropriate strength firewall. Access to patient identifiable information is protected by the appropriate authentication procedures (user IDs and passwords). Authentication is only given to personnel with a need to access the required data. Only personnel involved in the long-term follow-up of these studies (processing and analysing data) will have access to this data. NDPH has a Corporate Level Security Policy that has been fully adopted by management and will apply fully to the long-term follow-up study. [2 paragraphs unchanged]

Expected output

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides details of Outputs described under previous iterations of this Agreement: The primary outputs from this data will be academic, and will include submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. The primary outputs from any data to be requested in the future will be academic and will include submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. [3 paragraphs unchanged] The study team will also share outputs via all of the listed channels: [8 paragraphs unchanged] SEARCH related publications: Outputs for the SEARCH study so far include multiple publications in peer-reviewed journals and presentations at international conferences. Information about the publications can be found on the SEARCH website https://www.searchtrial.org/ • Offer A, Arnold M, Clarke R, Bennett D, Bowman L, Bulbulia R, Haynes R, Li J, Hopewell JC, Landray M, Armitage J, Collins R, Parish S; Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Collaborative Group. Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Netw Open. 2019 Mar 1;2(3):e190223. https://www.ncbi.nlm.nih.gov/pubmed/30821829 DOI: 10.1001/jamanetworkopen.2019.0223. • Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy Lancet. 2016 Nov 19;388(10059):2532-2561. Epub 2016 Sep 8. https://www.ncbi.nlm.nih.gov/pubmed/27616593 DOI: 10.1016/S0140-6736(16)31357-5 • Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group None., Armitage J., Bowman L., Wallendszus K., Bulbulia R., Rahimi K., Haynes R., Parish S., Peto R., Collins R. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010 Nov 13;376(9753):1658-1669. Epub 2010 Nov 8 https://www.ncbi.nlm.nih.gov/pubmed/21067805 DOI: 10.1016/S0140-6736(10)60310-8 • Cholesterol Treatment Trialists' (CTT) Collaboration; C Baigent, L Blackwell, J Emberson, L E Holland, C Reith, N Bhala, R Peto, E H Barnes, A Keech, J Simes, R Collins Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials Lancet. 2010 Nov 13;376(9752):1670-1681 https://pubmed.ncbi.nlm.nih.gov/21067804/ doi: 10.1016/S0140-6736(10)61350-5 • Armitage J., Clarke R., Collins R., Effects of Folic Acid Plus Vitamin B-12 vs Placebo in Myocardial Infarction Survivors - Reply JAMA. 2010 Oct 27;304(16):1783-1784 https://jamanetwork.com/journals/jama/fullarticle/186782 DOI: 10.1001/jama.2010.1474 • Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA, 2010 Jun 23;303(24):2486-2494 https://www.ncbi.nlm.nih.gov/pubmed/20571015 DOI: 10.1001/jama.2010.840 • The SEARCH Collaborative Group SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study N Engl J Med. 2008 Aug 21;359(8):789-99 Epub 2008 Jul 23 https://www.ncbi.nlm.nih.gov/pubmed/18650507 DOI: 10.1056/NEJMoa0801936 • SEARCH Study Collaborative Group Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): Characteristics of a randomized trial among 12064 myocardial infarction survivors Am Heart J. 2007 Nov;154(5):815-823.e1-6 Epub 2007 Sep 6 https://www.ncbi.nlm.nih.gov/pubmed/17967584 DOI: 10.1016/j.ahj.2007.06.034

Expected measurable benefits

This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information described in previous iterations of this Agreement: The research may help decisions about treatments for patients with vascular disease, or who are considering treatment with lipid lowering agents such as statins. The any future research may help decisions about treatments for patients with vascular disease, or who are considering treatment with lipid lowering agents such as statins. The study of data for the SEARCH trial has the advantage of: large size; very detailed baseline data collection; and information on several genetic and blood biomarkers which will inform researchers' knowledge of the effects of LDL-cholesterol lowering. The study of data for the SEARCH trial has the advantage of: large size; very detailed baseline data collection; and information on several genetic and blood biomarkers which will inform our knowledge of the effects of LDL-cholesterol lowering. The data controller intends to produce data that other organisations (for example, The National Institute for Health and Care Excellence (NICE) guideline committees) will be able to use to better advise on the effect of LDL-cholesterol lowering on the incidence of dementia and other long term health conditions, so that patients can better judge the impact of medicines on their health. The data controller will produce data that other organisations (for example NICE guideline committees) will be able to use to better advise on the effect of LDL-cholesterol lowering on the incidence of dementia and other long term health conditions, so that patients can better judge the impact of medicines on their health. Statins which lower LDL cholesterol are some of the most commonly prescribed medications, so the results of this study are likely to affect many people. In England, there are about 6 million prescriptions a month of lipid regulating drugs (~2 million for simvastatin, ~4 million for atorvastatin) Statins which lower LDL cholesterol are some of the most commonly prescribed medications, so the results of this study are likely to affect many people. In England, there are about 6 million prescriptions a month of lipid regulating drugs (~2 million for simvastatin, ~4 million for atorvastatin). SEARCH is the largest randomised trial to assess directly the efficacy and safety of lowering LDL cholesterol more than is typically done. Initial results showed that during an average of 6.7 years of treatment, the 80mg simvastatin regimen lowered LDL cholesterol by an average of 14mg/dl (0.35 mmol/l) more than the 20mg simvastatin regimen. This additional reduction in LDL cholesterol was associated with 6% fewer heart attacks, strokes or revascularisations. Researchers will achieve these benefits first through communication of risk. If this study leads to a change in the apparent benefits of LDL-lowering, then this will be communicated first through published literature, and then into risk scores by the study group and other academics. Although not statistically significant on its own, the risk reduction in SEARCH is entirely consistent with the benefit observed in previous statin trials. When it was combined in a meta-analysis with the 4 previous trials that had directly compared more versus less intensive statin regimens, lowering LDL cholesterol further by an average of 20mg/dl was shown to produce highly significant 15% further reductions in heart attacks, strokes and revascularisation procedures. Researchers hope to achieve further benefits first through communication of risk. If this research shows our study leads to a long term change in the apparent benefits of LDL-lowering, then researchers this will measure the impact of their work in citations, in guidelines, be communicated first through published literature, and work then into risk scores by our group and other academics. Any benefits found are expected to be realised within 5-10 years after the end of study. If the research shows a long-term benefits of LDL-lowering, then the research team will measure the impact of the work in citations, in guidelines, and work by other academics. The researchers expect to show any benefit found within 5-10 years after the end of study.

Benefits reported

[1 paragraph unchanged] The SEARCH study conducted by the University of Oxford’s Clinical Trial Service Unit (CTSU) within the Nuffield Department of Population Health (NDPH) (NDPH), has strongly influenced the labelling of statin medication internationally, treatment guidelines, and [63 words unchanged] Health Economic Research Centre has provided clear evidence of cost-effectiveness of statins. Some of the main points realised from the outputs and publications are: The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies. SEARCH results contributed to large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in the trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens. Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. The study team have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. SEARCH contributed to the strong recommendation that lower LDL-cholesterol is better for prevention of heart attack and stroke, which has led to more than 6 million prescriptions of lipid lowering drugs per year in England. SEARCH contributed to knowledge that folic and homocysteine do not substantially reduce the risk of heart attack and stroke. Due to this knowledge, these medicines are not recommended for prevention of cardiovascular disease in the UK. SEARCH should provide reliable evidence about the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy and, separately, of folate-based homocysteine-lowering therapy in a high-risk population.

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

Datasets: − Bridge file: Hospital Episode Statistics to Mental Health Minimum Data Set; − Hospital Episode Statistics Admitted Patient Care (HES APC); − Mental Health Minimum Data Set (MHMDS); − Mental Health Services Data Set (MHSDS); − Mental Health and Learning Disabilities Data Set (MHLDDS)

Objective for processing

Mortality and Cancer data were supplied to the University of Oxford by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as ‘SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine’. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides background to the study: This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) study is led by the Nuffield Department of Population Health (NDPH) at the University of Oxford. The University of Oxford are sole data controller for the purpose of this Agreement. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated and destruction of the data will be required. SEARCH was a randomised, multi-centre, factorial trial of LDL cholesterol lowering comparing higher versus standard dose simvastatin, and homocysteine lowering comparing folic acid and vitamin B12 supplementation versus placebo in 12,064 patients with an average age of 64 and with a history of myocardial infarction (MI). It was run in 88 UK clinical centres for ten years. Participants in SEARCH were recruited to the trial between September 1998 and October 2001, with all final follow-up assessments completed by June 2008. The following provides background information on the purpose of the original study: The initial trial results were published in 2010. This study, in combination with other available data, showed that additional LDL cholesterol lowering with a high dose statin further reduced major vascular events, but that folic acid and vitamin B12 supplementation did not have beneficial effects on vascular outcomes. NDPH has a strong research interest in the more reliable assessment of the effects of LDL cholesterol lowering. 10,389 men and women who have had a heart attack were invited to take part in the SEARCH study. SEARCH is a study of long term treatment to prevent further heart attacks and the need for heart surgery. Cholesterol levels are of particular interest in relation to dementia because a genetic risk factor for Alzheimer’s disease is the APOE4 variant of the APOE gene. APOE is the genetic code for a protein (apoE) that binds to receptors in low-density lipo-protein and is involved in the transport of cholesterol in the brain. People with the APOE4 variant have higher levels of total cholesterol and triglycerides than those without, and therefore higher blood LDL cholesterol is one potential mechanism for the effect of the gene. Heart attacks are the leading cause of death in Great Britain. One of the leading causes is having too much cholesterol in the blood. Lowering cholesterol has been shown clearly to reduce the chances of having another heart attack or of needing heart surgery. However, more intensive lowering of cholesterol might have some unsuspected adverse effects that counterbalance any further reduction in heart attacks. In observational studies, there is a link between higher cholesterol and dementia. In the short-term (up to 10 years) lower cholesterol has been associated with an increased risk of dementia, which may be because of reverse causal effects of the incipient dementia leading to lower levels. However, raised mid-life levels of LDL cholesterol have been found to be associated with increased risk of dementia 15-20 years later. There is little data, however, on whether raised levels of cholesterol and other cardiovascular risk factors at older ages are associated with an increased risk of dementia 15-20 years later. Continued follow-up for dementia in studies in older people initiated many years ago is therefore extremely valuable for investigating such effects. The main aim of SEARCH is to find out whether lowering cholesterol to a greater extent with a higher dose of the statin call simvastatin, rather than with a standard dose, produces worthwhile benefits. Participants would be asked to take two tablets each day, initially for 2 months; 20mg dose of simvastatin or a placebo and a 80mg dose of simvastatin or a placebo. By taking both tablets each day, the participant would receive either 20mg or 80mg simvastatin. Dementia is a leading cause of death in the UK and it is likely that by now many of the SEARCH participants may have developed dementia. This study now constitutes a uniquely rich resource for study of the relationships of vascular risk factors to dementia incidence many years later. This study will look at the association of vascular risk factors measured at baseline with dementia incidence at various times into the future, with longer delays between measurement of risk factors at recruitment and incidence of dementia being particularly valuable. SEARCH will also help determine if certain vitamins, such as folic acid and vitamin B12 can help protect against heart attacks. Participants would be asked to take one tablet containing either 20mg folic acid plus 1mg vitamin B12, or a matching placebo. The study team have previously received data from NHS Digital. Under this Agreement the data controller wishes to retain all data previously disseminated. Following the initial 2 months treatment period, participants were seen in clinic after 2, 4, 8 and 12 months in the first year and then every 6 months for the next 4 years. The data subjects are all be participants of the original randomised controlled trial. The legal basis for processing and storing data under this Agreement is Article 6(1)e (GDPR), i.e. it is a task carried out in the public interest. The aim of the study is to provide reliable evidence about the very long term effects of cholesterol-lowering treatments in the UK population and is therefore in the public interest. In addition, processing and storage of special category (sensitive) personal data is being done under Article 9(2)(j) (GDPR) exemption, i.e. that the processing of the data is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes. The scientific research aim of the study is to provide reliable evidence about the very long term effects of cholesterol-lowering treatments on important health outcomes. The research team have taken the opinion of the West of Scotland Research Ethics Service, who have granted approval to the study in its current form. Furthermore, potential harm to the public will be limited by data pseudonymisation, data minimisation, and technical and organisational safeguards. Analysis will occur in a safe, IG Toolkit/DPST compliant environment and identifiers will not be included in the analysis. The study team have asked for the opinion of available participants in these and similar studies, and they have agree that the use of the data in the way that the study team have proposed is reasonable. All processing of NHS Digital data will take place within the University of Oxford, therefore Oxford are listed as sole data processor under this Agreement. One of the Investigators is employed by both the University of Edinburgh and the University of Oxford. The applicant has confirmed that this individual will analyse the data under this Agreement solely in his role as a substantive employee of the University of Oxford, and therefore the University of Edinburgh are not listed as a data controller under this Agreement. Funding for this study is provided internally from the University of Oxford.

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. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information about processing activities permitted under previous iterations of this Agreement. The study data, including data provided by NHS Digital under previous agreements, are currently held by the University of Oxford. Under this interim extension all devices containing data will be securely locked away in a locked cabinet at the University of Oxford storage address specified in this Agreement. NHS Digital previously received the identifiers for this cohort and as recruitment ended in 2001, the identifiers that NHS Digital currently hold are: The following provides background on the processing activities undertaken for the original study: - Name Identifying data was shared with ONS to carry out the linkage between the study data and civil registration data. Participants records were ‘flagged’ with the Office for National Statistics (ONS). ONS notified the study team at the University of Oxford of participants’ deaths (date and cause) and cancer events when they occurred. The ‘flagging for long-term follow up’ service transferred from ONS to the HSCIC in 2008. Data was last supplied in September 2016. - NHS Number - Date of birth - Date of death - Postcode - Gender - Study ID In turn the University of Oxford received identifiable MRIS Cause of Death, Members and Posting, Flagging Current Status and Cohort Event Notification reports, which they wish to retain . There were no subsequent flows of data. No linkage is proposed to datasets containing personal identifiers. No linkage to publicly available data is proposed. No attempt will be made to re-identify participants from the NHS data. NDPH researchers, substantively employed by the University of Oxford, are experienced in handling confidential and participant sensitive data and have appropriate training in information governance. The NDPH servers are protected against unauthorised external access by an appropriate strength firewall. Access to patient identifiable information is protected by the appropriate authentication procedures (user IDs and passwords). Authentication is only given to personnel with a need to access the required data. NDPH has a Corporate Level Security Policy that has been fully adopted by management and will apply fully to the long-term follow-up study. All information is stored securely by the University of Oxford and is kept confidential. Access to the computer database is by unique combinations of usernames and passwords and only authorised study personnel can access information about participants. The building is secure with authorised swipe card access only. No individuals will be identified in any study reports. 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).

Expected output

No new outputs will be produced under this Data Sharing Agreement. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides details of Outputs described under previous iterations of this Agreement: In any future application, the applicant will be required to provide details of the outputs that were produced and disseminated by the study as well as details of any future outputs planned. The primary outputs from any data to be requested in the future will be academic and will include submissions to peer reviewed journals such as New England Journal of Medicine and the Lancet, and conferences such as the American Heart Association meeting. The study team will only present data at an aggregated level with small numbers suppressed. The study team will present actual and modelled data in graphical and tabular format. The NDPH contributes widely to health policy, particularly in the area of vascular risk prevention. It contributes to debate with academic papers, conference participation, lectures to the public and advice to government (including NHS Digital). Examples of the impact of the work performed by NDPH up to 2014 is available from: https://results.ref.ac.uk/(S(ep5gbndxsprqnc0kork3mjyu))/Submissions/Impact/728 The study team will share outputs via all of the listed channels: - Study website - Open lectures and talks - Exhibition at public events - Posters - Press/media engagement and other public promotion of the research The data controller aims to issue the next publication by Spring 2023. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. SEARCH related publications: • Offer A, Arnold M, Clarke R, Bennett D, Bowman L, Bulbulia R, Haynes R, Li J, Hopewell JC, Landray M, Armitage J, Collins R, Parish S; Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Collaborative Group. Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Netw Open. 2019 Mar 1;2(3):e190223. https://www.ncbi.nlm.nih.gov/pubmed/30821829 DOI: 10.1001/jamanetworkopen.2019.0223. • Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R. Interpretation of the evidence for the efficacy and safety of statin therapy Lancet. 2016 Nov 19;388(10059):2532-2561. Epub 2016 Sep 8. https://www.ncbi.nlm.nih.gov/pubmed/27616593 DOI: 10.1016/S0140-6736(16)31357-5 • Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group None., Armitage J., Bowman L., Wallendszus K., Bulbulia R., Rahimi K., Haynes R., Parish S., Peto R., Collins R. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010 Nov 13;376(9753):1658-1669. Epub 2010 Nov 8 https://www.ncbi.nlm.nih.gov/pubmed/21067805 DOI: 10.1016/S0140-6736(10)60310-8 • Cholesterol Treatment Trialists' (CTT) Collaboration; C Baigent, L Blackwell, J Emberson, L E Holland, C Reith, N Bhala, R Peto, E H Barnes, A Keech, J Simes, R Collins Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials Lancet. 2010 Nov 13;376(9752):1670-1681 https://pubmed.ncbi.nlm.nih.gov/21067804/ doi: 10.1016/S0140-6736(10)61350-5 • Armitage J., Clarke R., Collins R., Effects of Folic Acid Plus Vitamin B-12 vs Placebo in Myocardial Infarction Survivors - Reply JAMA. 2010 Oct 27;304(16):1783-1784 https://jamanetwork.com/journals/jama/fullarticle/186782 DOI: 10.1001/jama.2010.1474 • Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA, 2010 Jun 23;303(24):2486-2494 https://www.ncbi.nlm.nih.gov/pubmed/20571015 DOI: 10.1001/jama.2010.840 • The SEARCH Collaborative Group SLCO1B1 Variants and Statin-Induced Myopathy — A Genomewide Study N Engl J Med. 2008 Aug 21;359(8):789-99 Epub 2008 Jul 23 https://www.ncbi.nlm.nih.gov/pubmed/18650507 DOI: 10.1056/NEJMoa0801936 • SEARCH Study Collaborative Group Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): Characteristics of a randomized trial among 12064 myocardial infarction survivors Am Heart J. 2007 Nov;154(5):815-823.e1-6 Epub 2007 Sep 6 https://www.ncbi.nlm.nih.gov/pubmed/17967584 DOI: 10.1016/j.ahj.2007.06.034

Expected measurable benefits

In any future application, the applicant will be required to provide details of the expected benefits resulting from the study. This Data Sharing Agreement permits the retention, but no other processing, of data provided under previous iterations of this Agreement. The following provides information described in previous iterations of this Agreement: The any future research may help decisions about treatments for patients with vascular disease, or who are considering treatment with lipid lowering agents such as statins. The study of data for the SEARCH trial has the advantage of: large size; very detailed baseline data collection; and information on several genetic and blood biomarkers which will inform our knowledge of the effects of LDL-cholesterol lowering. The data controller will produce data that other organisations (for example NICE guideline committees) will be able to use to better advise on the effect of LDL-cholesterol lowering on the incidence of dementia and other long term health conditions, so that patients can better judge the impact of medicines on their health. Statins which lower LDL cholesterol are some of the most commonly prescribed medications, so the results of this study are likely to affect many people. In England, there are about 6 million prescriptions a month of lipid regulating drugs (~2 million for simvastatin, ~4 million for atorvastatin). Researchers will achieve these benefits first through communication of risk. If this study leads to a change in the apparent benefits of LDL-lowering, then this will be communicated first through published literature, and then into risk scores by the study group and other academics. If this research shows a long term benefits of LDL-lowering, then researchers will measure the impact of their work in citations, in guidelines, and work by other academics. Any benefits found are expected to be realised within 5-10 years after the end of study.

Benefits reported

In any future application, the applicant will be required to provide details of the actual benefits achieved as a result of the study The SEARCH main study, in combination with other available data, showed that additional LDL cholesterol lowering with a high dose statin further reduced major vascular events, but that folic acid and vitamin B12 supplementation did not have beneficial effects on vascular outcomes. The SEARCH study conducted by the University of Oxford’s Clinical Trial Service Unit (CTSU) within the Nuffield Department of Population Health (NDPH) has strongly influenced the labelling of statin medication internationally, treatment guidelines, and the resulting changes in prescribing have contributed to reductions in mortality and morbidity from heart attack and ischaemic stroke in many countries. CTSU’s randomised trials and meta-analyses of trials have shown that lowering low density lipoprotein (LDL) cholesterol safely reduces the risk of heart attacks, strokes and revascularisation procedures in a wide range of people, and work conducted in collaboration with the NDPH’s Health Economic Research Centre has provided clear evidence of cost-effectiveness of statins.

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

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.