ADDITION: Anglo-Danish-Dutch study of Intensive Treatment of people with newly diagnosed diabetes in primary care - ten year follow up

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

Datasets: − MRIS - List Cleaning Report

Objective for processing

The HES data was requested for the ADDITION-ten year follow-up study which is part of the larger ADDITION-Europe trial. The ADDITION-Europe trial is a four centre trial – Cambridge, Leicester, Denmark and the Netherlands (with Cambridge being the lead Trial centre) – assessing the effectiveness and cost effectiveness of intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes. BACKGROUND This study aims to collect 10 year follow up information on cardiovascular events and risk factors, treatment and mortality for the cohort of participants of the ADDITION study who enrolled in the UK. People with diabetes have an increased risk of developing cardiovascular disease (CVD). However, there can be a delay between the onset of diabetes and a person experiencing symptoms, making it difficult to detect diabetes early. It would be logical to suggest that if people were found earlier in the disease trajectory and treated before symptoms developed, the risk of them suffering from an early death or CVD would be reduced. For background regarding the ADDITION studies overall; approximately 36000 people in or near Cambridge were invited to screening (the ADDITION-Cambridge screening cohort, MR798/NIC-147750-8GS7S). Until recently the effect of intensive treatment of multiple risk factors earlier in the course of diabetes was unknown. Results from the ADDITION-Europe trial (a four centre trial – Cambridge, Leicester, Denmark and the Netherlands - with Cambridge being the lead Trial centre), which assessed the effectiveness and cost effectiveness of intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes, demonstrated that, compared to routine care, an intervention to promote intensive management of patients with diabetes detected by screening was associated with significant differences in prescribed treatment and levels of cardiovascular risk factors at five years. These differences were associated with a 17% reduction in risk of cardiovascular events which was considered not statistically significant - in other words it may have been due to chance. Of these, 867 were diagnosed with diabetes as a result of screening and make up the ADDITION-Cambridge main cohort which this Data Sharing Agreement pertains to. (MR1406/NIC-28744-S4F8H). The lower than expected event rate (the frequency of occurrence of an event in a population) among screen-detected patients and the apparent divergence of event rates between groups suggested that further follow up of this cohort was justified to establish whether early treatment reduces long-term cardiovascular risk. Resolving this uncertainty could be important in assessing the costs and benefits of screening for diabetes and for informing early treatment decisions. Further to this, 239 of the participants from the ADDITION-Cambridge main cohort were included in a sub-study called ADDITION-plus. 239 extra, new participants were also recruited for ADDITION-plus. These 478 participants form the ADDITION-plus cohort (MR1417/NIC-34907-D9R3N). Any data requests for the ADDITION Plus study will be considered under a separate application. For background regarding the ADDITION studies overall - approximately 36,000 people in or near Cambridge were invited to screening (the ADDITION-Cambridge screening cohort, covered under DARS-NIC-147750-8GS7S). University of Cambridge is the lead site for a Europe-wide study called ADDITION-Europe, which pools data from Cambridge and three other centres across Europe. However, none of the data from MR798, MR1406, or MR1417 will be shared with the wider European study, it will be used in Cambridge only. Of these, 867 were diagnosed with diabetes as a result of screening and make up the ADDITION-Cambridge main cohort which this Data Sharing Agreement pertains to (DARS-NIC-28744-S4F8H). Only the University of Cambridge will have access to the data shared under this Agreement and are the sole Data Controller who also process data. Further to this, 239 of the participants from the ADDITION-Cambridge main cohort were included in a sub-study called ADDITION-plus. 239 extra participants were also recruited for ADDITION-plus. These 478 participants form the ADDITION-plus cohort (covered under DARS-NIC-34907-D9R3N). The ADDITION study (which this agreement pertains to) aims to collect follow up information for a subset of the 1212 participants recruited in Cambridge (n=867) originally recruited under patient consent. As aforementioned, the University of Cambridge is the lead site for a Europe-wide study called ADDITION-Europe, which pools data from Cambridge and three other centres across Europe. However, none of the NHS England data disseminated under NIC-147750-8GS7S, NIC-28744-S4F8H or NIC-147750-8GS7S has been shared with the wider European study; it has been used in Cambridge only. Section 251 support has been granted to permit the study to obtain up to date address details for all participants in order to inform them of the 10 year follow up (and if they wish, speak to the study team about the study); invite them to fill in questionnaires, and to update the study team of their current GP practice in order to complete the follow up, as well as obtaining linked Hospital Episode Statistics (HES) data. AIMS AND OBJECTIVES The University of Cambridge also holds MINAP (Myocardial Ischemia National Audit Project) data (access provided by the National Institute for Cardiovascular Outcomes Research (NICOR)) and Sentinel Stroke National Audit Programme (SSNAP) (access to provided via the Royal College of Physicians) and Section 251 support permits linkage of HES data to this audit data. The purpose of the ADDITION: ten-year follow-up study has been to assess whether the differences in intensity of treatment achieved in the first five years after diagnosis are associated with a reduction in cardiovascular risk and mortality over ten years for a subset of the 1212 participants recruited in Cambridge (n=867). This study will allow an assessment of the long term effects of the differences in intensity of treatment achieved during the first five years after diagnosis. One of the objectives of the current follow up phase is to evaluate whether follow-up through GP notes can be replaced with follow-up through HES for a potential 15-year follow-up of this cohort. Follow-up through GP notes is a very time-consuming process both for the researchers and for the many GP surgeries involved in ADDITION, and has taken about 2 years. This is exacerbated by the gradual movement of participants to new surgeries over the study, meaning that for 10-year follow-up many GP surgeries who were contacted for notes were never originally involved with the study. The amount of work involved in follow-up through GP notes will only increase as the time since the start of the study increases. Furthermore, questionnaire response rate was approx. 50% meaning that trying to attempt to collect this data via postal means will greatly reduce the power of the study. Also due to the dispersal of participants around the country as well as their advancing years would mean it would take a great deal of resource to be able to follow these participants. The University of Cambridge’s primary objective has been to evaluate the effect of early intensive treatment of multiple risk factors among people with screen-detected diabetes on time to first CVD event over ten years (a composite CVD endpoint including CVD death, non-fatal myocardial infarction (heart attack), non-fatal stroke, revascularisations (procedure that can restore blood flow in blocked arteries or veins) and amputation). In order to assess whether follow-up through routine sources alone would be practical, the University of Cambridge research team need to work out whether the events captured through HES data match up with the events captured through GP note follow-up. Therefore the research team need HES data covering the whole duration of the study. The first ADDITION participants were recruited in March 2002, and so we need data from the 2001-2002 HES data sets (where available) to the present (therefore 15 years of data is required). The study’s secondary objectives have been to evaluate the effect of early intensive treatment of multiple risk factors on (i) each of the components of the primary composite endpoint and all-cause mortality; (ii) microvascular (retinopathy (damage to back of eye caused by high blood sugar levels), neuropathy (damage to nerves in body’s extremities such as hands and feet) and nephropathy (deterioration of kidney function) outcomes and intermediate outcomes (such as height, weight, blood pressure, diet, physical activity). With the HES data, the University of Cambridge plan to extract study outcome data (such as inpatient admission for a heart attack). This will then form part of the master dataset which will also include similar outcome data that has been extracted from other sources (MINAP, SSNAP, Questionnaires & GP records). The data will be fully anonymised and will not be released on an individual level. DATA SUMMARY The University of Cambridge also plan to use all data sources to provide data for the health economics assessment of cost-utility of the study intervention. Again, this will be at aggregated with small numbers suppressed in line with the HES Analysis Guide. The University of Cambridge received Hospital Episode Statistics (HES) Admitted Patient Care (2001/2002 – 2016/2017), HES Outpatients (2003/2004 – 2016/2017), HES A&E (2007/2008 – 2016/2017) and MRIS-List Cleaning Report data (up to August 2016). In order to assess whether follow-up through routine sources alone would be practical, the University of Cambridge research team needed to work out whether the events captured through HES data match up with the events captured through GP note follow-up. Therefore, the research team required HES data covering the whole duration of the study. The first ADDITION participants were recruited in March 2002, and so data was required from the 2001-2002 (where available) to 2016/2017 (15 years of data). The University of Cambridge contacted all ADDITION Cambridge participants in the UK with a self-report questionnaire to assess health behaviour and patient-reported outcomes. NHS England data was required for the following purposes: Prior to sending any questionnaires, the participant list was cross-checked with available records from MRIS to minimise the risk of sending questionnaires to participants who are deceased. (1) to cross reference the currently-held address and GP data with data held by NHS England (via MRIS-List Cleaning Report data) to ensure the participant records were up to date and to allow follow-up of participants who have moved since last follow-up (completed). The purposes for data processing are: (2) to identify CVD outcomes recorded in HES data by scrutinising inpatient, A&E and outpatient admissions for the cohort in order to quantify completeness of follow-up. Events identified through HES records were compared with events identified through previously collected, self-reported data, GP record data and with data from the Myocardial Ischaemia National Audit Project (MINAP) and the Sentinel Stroke National Audit Programme (SSNAP) to establish whether it was feasible to conduct future follow-ups of this cohort through HES data alone (completed). (1) cross reference the currently-held address and GP data with those held by NHS Digital (via MRIS) to ensure the participant records are up to date and to allow follow-up of participants who have moved since last follow-up (this has already been completed). (3) to assess the cost-effectiveness of screening using HES data by identifying and costing all hospital admissions, including hospital admissions for reasons other than the primary end point (not yet completed). (2) identify CVD (cardiovascular disease) outcomes recorded in HES data by scrutinising inpatient, outpatient and A&E admissions for this cohort, to quantify completeness of follow-up. Events identified through HES records will be compared with events identified through already-collected self-reported data and GP record data, and with data from Myocardial Ischaemia National Audit Project (MINAP) and the Sentinel Stroke National Audit Programme (SSNAP), to establish whether it is feasible to conduct future follow-ups of this cohort through HES data alone. Purpose (1) - MRIS-List Cleaning Report data was required as the University of Cambridge needed to contact all ADDITION Cambridge participants in the UK with a self-report questionnaire to inform the management of newly diagnosed patients and to establish the size and nature of the benefits of detecting and treating diabetes earlier. Prior to sending any questionnaires, the participant list was cross-checked with available records from MRIS to minimise the risk of sending questionnaires to deceased participants. 10-year follow-up of the trial participants will add to the existing research base concerning early treatment of type 2 diabetes and inform NHS policy decisions concerning whether population-based diabetes screening programmes should be established in Europe and worldwide. (3) assess cost-effectiveness of screening using HES data by identifying and costing all hospital admissions, including hospital admissions for reasons other than the primary end point. This purpose has been met by the University of Cambridge and therefore the MRIS-List Cleaning Report data is no longer required. To that end, the MRIS data has been destroyed and a data destruction certificate supplied to NHS England. Purpose (1) data was needed to complete 10-year follow-up of this cohort with as high a follow-up rate as possible, in order to inform the management of newly diagnosed patients and to establish the size and nature of the benefits of detecting and treating diabetes earlier. Ten year follow-up of the trial participants will add to the existing research base concerning early treatment of type 2 diabetes and inform NHS policy decisions concerning whether population-based diabetes screening programmes should be established in Europe and worldwide. As detailed, this has already been completed. Purpose (2) – HES data was needed to allow the study to establish whether future follow-up of this cohort could be conducted using HES data alone, which would greatly simplify the process of data collection and reduce costs and time needed for future follow-up. One of the objectives of the current follow up phase is to evaluate whether follow-up through GP notes can be replaced with follow-up through HES for a potential 15-year follow-up of this cohort. Follow-up through GP notes has been a very time-consuming process, both for the researchers and for the many GP surgeries involved in the ADDITION studies, and has taken about 2 years. This has been exacerbated by the gradual movement of participants to new surgeries over the course of the study which has meant that, for the 10-year follow-up, many GP surgeries who were contacted for notes were never originally involved in the study. The questionnaire response rate was also approx. 50% which meant that attempting to collect this data via postal means would have greatly reduced the power of the study. Purpose (2) will allow the study to establish whether future follow-up of this cohort can be conducted using HES data alone, which could greatly simplify the process of data collection and reduce costs and time needed for future follow-up. Purpose (3) hopes to allow the study to quantify the total healthcare costs following diabetes diagnosis and establish whether costs are reduced by early intensive treatment. Purpose (3) will allow the study to quantify the total healthcare costs following diabetes diagnosis, and establish whether they are reduced by early intensive treatment. Section 251 support from the Health Research Authority (HRA) Confidential Advisory Group (CAG) was sought and approved to permit the University of Cambridge to obtain up to date address details for all participants in order to inform them of the 10 year follow up (and if they wish, speak to the study team about the study); invite them to fill in questionnaires, and to update the study team of their current GP practice in order to complete the follow up, as well as obtaining linked HES data. These studies are part of the University of Cambridge and as such the legal basis to hold and use personal data is covered under the General Data Protection Regulation “Article 6(1) (e) processing is necessary for the performance of a task carried out in the public interest”. To hold special categories of personal data our lawful basis is for pursuing scientific research under “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 University of Cambridge already hold MINAP (Myocardial Ischemia National Audit Project) data (access provided by the National Institute for Cardiovascular Outcomes Research (NICOR)) and Sentinel Stroke National Audit Programme (SSNAP) (access provided via the Royal College of Physicians) and Section 251 support permits linkage of HES data to this audit data. Ethical approval for the study continues to be in place (14/EE/1129). DATA MINIMISATION The data has been minimised as follows: • Limited to a study cohort identified by University of Cambridge. With the following criteria. - Diagnosed with type 2 diabetes at the ADDITION-Cambridge screening (867 participants). • HES A + E: Only 8% of the fields were requested. • HES OP: Only 6% of the fields were requested. • HES APC: Only 9% of the fields were requested. CONTROLLERSHIP/FUNDING The University of Cambridge is the sole Data Controller that also processes the NHS England data disseminated. Although The University of Cambridge collaborated with the University of Leicester, University of Aarhus, Holbæk Hospital and University Medical Centre Utrecht for previous rounds of the ADDITION study. The University of Leicester, University of Aarhus, Holbæk Hospital and University Medical Centre Utrecht will not make any decisions regarding processing of the data. The University of Cambridge will make all the decisions regarding the processing of data. The others will be informed of the processes we choose and will only be able to comment. Offsite Archive Storage and Integrated Services (UK) Limited (Oasis) is a data processor only as they provide backup storage facilities for the NHS England data disseminated. Oasis has no decision-making responsibility for the processing of NHS England data. Funding is provided by the Medical Research Council. The Medical Research Council has no decision-making responsibility regarding the processing of NHS England data, nor do they have any means to access or process the NHS England data held. LEGAL BASIS FOR PROCESSING DATA The University of Cambridge has a legal basis to process personal data and special categories of personal data under the following provisions of the General Data Protection Regulation (GDPR): Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller - 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 data are required for research purposes in the public interest, meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4), which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. The ways in which the processing of data will be of benefit to the public, thereby demonstrating that the processing is in the public interest, are described in section 5d.

Processing activities

Purpose 1 has been completed. Purpose 2 and 3 are yet to fully complete. It is for this reason University of Cambridge wish to extend the data sharing agreement so Purpose 2 and 3 can be completed. HES data has been released for purposes 2 and 3 and preliminary data analysis by the research team at Cambridge is underway. The University of Cambridge submitted a file containing the identifiers of the 867 participants recruited in Cambridge (minus participants who have withdrawn from the study fully or from access to medical records) to NHS England via Secure Electronic File Transfer (SEFT). This included: The University of Cambridge has submitted (under a previous iteration of this agreement) a file containing the identifiers of the 867 participants recruited in Cambridge (minus participants who have withdrawn from the study fully or from access to medical records) to NHS Digital using its secure electronic file transfer system. This included; [5 paragraphs unchanged] The cohort was linked to HES, with HES records extracted patient identifiers for the cohort for each participant. were linked to HES and MRIS-List Cleaning Report data. No additional filters were be applied to the data, nor were any additional derived fields provided. The HES data flowing flowed from NHS Digital is England was originally considered pseudonymised, however, the University of Cambridge has used the Study ID to link the HES data to the data previously disseminated (i.e. the List clean data MRIS-List Cleaning Report data) and the data the University of Cambridge holds). already holds. By means of this re-identification, the HES data to be disseminated is therefore has been considered Identifiable. identifiable. The data was downloaded at the University of Cambridge’s MRC Epidemiology Unit and transferred immediately to an independent, physically-separated network that is isolated from public network systems and can only be accessed locally, with a managed access system including both password and procedural controls. This ‘other network’ is still on the Unit premises but is known as the ‘private network’ where all of the Unit's patient data is stored. It is not connected to the internet and can only be accessed by being at the Unit. Access to this network must be approved by both local senior management and the ADDITION study CI. All study team members accessing the data have a contract of employment with the Unit. Prior to the COVID-19 pandemic the University of Cambridge’s MRC Epidemiology Unit (referred to as ‘the unit’ hereafter) stored personal identifiable data on an air-gapped, isolated network that was only accessible via the unit offices and only on certain PCs. During and since the COVID-19 pandemic the unit has employed the use of The Secure Research Domain (SRD) - a collection of tightly controlled systems/services that includes a secure remote access mechanism with multifactor authentication. The SRD is recognised by the School of Clinical Medicine as a “safe haven” for collecting, storing and processing personal identifiable data from ethically approved research studies. Registered users are only permitted access via unique usernames and complex passwords which are not used elsewhere across the University of Cambridge or the unit. The SRD is a designated safe haven within the School of Clinical Medicine at the University of Cambridge and has been assessed against the Department of Health Information Governance Toolkit. The service can only be accessed from within the unit’s network. Tight firewall controls are employed on all systems involved in the SRD. Outbound access from within the service is blocked by default. Only the bare minimum (and prior agreed) specific endpoints across wider networks required for the proper management of studies are permitted and configured outbound. All staff and students must attend the internal IT and data inductions provided by the unit. Where relevant this will also cover uses and rules relating to the SRD. In addition, the e-learning courses on the GDPR and Cyber Security must be completed. Oasis provides IT back up services to the University of Cambridge and will store copies of the data as contracted by the University of Cambridge. [1 paragraph unchanged] This purpose has now been fulfilled. fulfilled and the MRIS-List Cleaning Report data supplied by NHS England destroyed. The address and GP data has been was used to to: (1) re-contact participants who were lost to follow up, up and to (2) contact their participants’ registered GP surgery to enable the collection of recent endpoint and clinical measures. Where NHS Digital England data identifies identified changed contact details for participants, the data has left the MRC Epidemiology Unit unit in one of two ways: (a) Individual letters have been were sent to participants informing them of the 10-year follow-up process, reminding them of their right to withdraw from the study, providing them with an up to date up-to-date study Participant Information Sheet, and inviting them to fill in study questionnaires. Data shared in this way will necessarily involve involved sharing the participant’s name and address, but will did not include any other data from NHS Digital, England, nor will did the letters include linkage to any other study data. (b) Individual letters have been were sent to GPs asking them to provide data from relevant consenting participants' medical notes. Data shared in this way must needed to be sufficient to allow the GP surgery to identify the correct person, but will be was limited to the participant’s name, date of birth, and NHS number. The letters will did not include any other study data. Address and GP details have been were linked to the University of Cambridge's existing contact records via Pseudo/Anonymised pseudonymised study identifier. The address and GP data supplied by NHS Digital will England was never be released for analysis; it has was only been used for locating participants and their GPs to enable them to so they could be asked if they wish wished to take part in the 10-year follow-up. follow-up study. Personal identifiable data provided for this purpose has been was stored on a physically separate server in the Unit unit offices and can could only be accessed and used on site by those who have permission had the appropriate permissions within the research team. Other than this contact with individual participants who were previously lost to follow-up and their GPs, no personal identifiable data will be was used by or given to any other third party, and no record-level data will be was shared outside the Unit. unit. The List Clean data has been used to update the University of Cambridge ADDITION participant contact database with current address details. Addresses have been updated to send participants information on the current wave of data collection. Unless a participant specifically requests requested to opt out, following receipt of the current participant information sheet, their consent to hold and collect future study-related health data continues continued based on their original consent taken at baseline and the study’s current s251 approval. The University of Cambridge will retain retained updated addresses in the database to enable continued correspondence with participants to keep them updated on future waves of data collection. The Given the MRIS-List Cleaning Report data has now been destroyed the research team also plan will be using what address information they currently hold to continue sending Christmas cards and newsletters to participants as has been done throughout the course of the study and will use the updated addresses for this purpose also. keep in contact with participants. The team will also hold further public meetings to disseminate the results of the study and would will invite participants through letter letters to these. Prior to the start of another follow-up phase of the study, the research team will also send a newsletter to participants to inform them. The list clean MRIS-List Cleaning Report data is was not linked to study questionnaires, MINAP or SSNAP data. The ADDITION contacts [6 words unchanged] held separately to any outcome data and linked only by ID numbers. [1 paragraph unchanged] This purpose is in progress; has now been fulfilled. As a result of the comparison of the different data has been provided by HES and preliminary data analysis is underway. The sources collected during the study, the ADDITION research team at the University of Cambridge plan to use has verified the HES data in comparison to verify data from other sources and to ensure ensured completeness of the data set where a source has missing data. The study’s main outcome This is whether someone has had a cardiovascular event. Whilst significant as although, for example, the team have access to participant’s GP records records, there may be cases where hospital discharge summaries relating to an event [8 words unchanged] filed with the notes. In these cases, the event may be captured on one of in the requested datasets to HES data which would enable the study to have accurate and complete data. This will prevent incorrect conclusions being drawn based on incomplete data. In future, The ADDITION research team at the team would like University of Cambridge will continue to continue following follow up the ADDITION cohort for a further 5 years (15 year follow up). If up) as the data provided by NHS digital/MINAP/SSNAP provides as England/MINAP/SSNAP has provided a comprehensive data set as GP records at this 10 year follow up up. This will reduce the team would not use this resource-intensive (to both researchers and GPs) approach of searching through GP records in future rounds of data collection and rely place reliance solely on the secondary care data sets. Personal identifiable data provided for this purpose will be has been kept on a physically separate server in the Unit unit offices and can has only be been accessed and used on site by those who have permission the appropriate permissions within the research team. No personal identifiable HES data will has been/will be used by or given to any other third party, and no record-level HES data will has been/will be shared outside the Unit. unit. Aggregated data with small numbers suppressed in line with the HES analysis guidelines will be published in papers describing the proportion of events identified through each data source, to aid other researchers in deciding on the best sources to use for data collection; all data published will be aggregated in such a way that individuals cannot be identified from it. Data used during this analysis will be pseudonymised- has been pseudonymised - HES events will be were classified into broad categories and only month and year of event will be be/have been released for analysis intended for publication. Pseudonymised data may be released from the Unit’s physically separate server onto the Unit’s main network, and may be accessed on site or by remote access. All individuals with access to this data will either be substantively employed by were substantive employees of the University of Cambridge, or will have a Visiting Worker honorary contract. Cambridge. No personal identifiable HES data will be was used by or given to any other third party, and no record-level HES data will be was shared outside the Unit. [1 paragraph unchanged] This purpose is in progress; data has been provided by HES and progress - preliminary data analysis is underway. underway and still ongoing (hence the request for an extension to the Data Sharing Agreement with NHS England). HES data will be used to identify all hospital admissions, admissions and linked to NHS cost codes to quantify the total healthcare costs following diabetes diagnosis, diagnosis and to establish whether they are reduced by early intensive treatment. This data will be linked to the Unit's unit's existing records (self-report data and data directly collected by the study team, e.g. heights/weights/blood sugar levels) via the study identifier. Data used during analysis will be pseudonymised- pseudonymised - only month and year of event will be released for analysis intended for publication, and details of HES events will be reduced to the minimum necessary to be able in order to identify the appropriate NHS cost code. [1 paragraph unchanged] All individuals with access to this data will, working under appropriate supervision on behalf are substantive employees of data controller(s) / processor(s) within this agreement, are subject to the same policies, procedures and sanctions as substantive employees. University of Cambridge. All outputs will be restricted to aggregate data with small numbers supressed in line with the HES Analysis Guide. All personnel accessing the data have been appropriately trained in data protection and confidentiality. The data from NHS Digital will not be used for any other purpose other than that outlined in this Agreement. The data will not leave England/Wales at any time. The data from NHS England will not be used for any other purpose other than those outlined in this Agreement. [1 paragraph unchanged] All outputs and publications contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide. NHS Digital reminds all organisations party to this agreement of the need to comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data).

Expected output

The outputs achieved from using the List Cleaning service are: In respect of study outputs, it is essential for the University of Cambridge to have access to the NHS England data for two reasons: (1) Informed living participants of the 10-year follow-up process; reminded them of their right to withdraw from the study; provided them with an up to date study Participant Information Sheet, and invited them to fill in study questionnaires; (2) Requests have been sent to participants’ GPs asking them to provide data from consenting participants’ medical notes; (3) Medical notes passed to the ADDITION Study Research Assistant who has reviewed the notes to look for CVD endpoints and clinical measures (during surgery visits or remotely, with remote electronic access approved by the surgery). (4) Use HES data as another method to ascertain CVD outcomes to ensure completeness of the data. Outputs 1, 2 and 3 have been completed. Preliminary data analysis for output 4 is underway. Once the analysis of the HES data is complete (which the extension to the agreement will help to achieve) more publications and outputs will be possible as described below. The aim of contacting participants is to enable the study to continue collecting information to be used in the ADDITION-Europe study. It is essential for the study to have up to date events for two reasons; [2 paragraphs unchanged] The ADDITION–Europe study has so far led to the publication of 76 papers in peer-reviewed scientific journals, with a further 4 under review or in press. Data from ADDITION has also contributed to 12 PhD theses and 52 oral presentations or posters at international conferences. The primary analysis of 5 year outcomes was published in the Lancet (Griffin et al. (2011). Lancet, 378 (9786), 156–167). The results of the 10 year analysis will be submitted to this or a similar leading medical journals (subject to the completion of the processing activities described above). Findings were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September 2016. Secondary analyses including cost-utility analysis and mechanistic analyses will be published in leading medical or disease-specific peer-reviewed journals such as the Lancet, BMJ, Diabetalogia, Diabetes Care, and International Journal of Obesity. All publications will be open access, in line with the University of Cambridge open-access policy, and can be accessed by clinicians, academics, policy makers and interested members of the public. Outputs presented and/or reported will contain aggregate level data with small numbers supressed in line with the HES analysis guide. No personal identifiable data will be released or published. The expected outputs of the processing will be: • A report of findings to various stakeholders including fellow researchers at the various involved Universities • Submissions to peer reviewed journals targeted for high impact. • Presentations to future appropriate conference's and events. For example initial findings were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September 2016. The results of the 10 year analysis will be submitted to leading medical journals. Secondary analyses including cost-utility analysis and mechanistic analyses will be published in leading medical or disease-specific peer-reviewed journals such as the Lancet, BMJ, Diabetalogia, Diabetes Care, and International Journal of Obesity. All publications will be open access, in line with the University of Cambridge open-access policy, and can be accessed by clinicians, academics, policy makers and interested members of the public. These publications and presentations are expected to be produced throughout the lifespan of this Agreement and are expected until the study closes. The outputs will not contain NHS Digital data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

Expected measurable benefits

The benefits of collecting information about the participants are achieved through the wider study. Many of the benefits expected to be achieved at the outset of the study have now been realised and are therefore listed in section 5.d.iii. All benefits listed below either relate to purpose 3 of the study, which is yet to be completed, or benefits of data processing in relation to purposes 1 and 2 which have yet to be achieved. The 10 year follow up main results paper, which includes data collected after re-contact of participants and their GPs which was made possible by the list clean data in this application, looks at the difference in cardiovascular events between the control and intervention arms. This will add to the evidence of treatment and screening options for diabetes and will influence NHS policy makers and clinician decisions nationally on the best way to care for this population. This paper has been drafted and is under review at Lancet Diabetes and Endocrinology. It is estimated that 1 in 16 UK adults have (diagnosed or undiagnosed) type 2 diabetes and this creates a substantial burden of suffering and health service use. Treatment of type 2 diabetes and related complications (cardiovascular disease, amputation, blindness, kidney failure) account for 10% of the NHS budget. This is expected to rise as the number of people in the UK who have type 2 diabetes is estimated to rise to 6.25 million by 2035. The HES data will also be used to inform the cost-utility analysis of the ADDITION intervention. Completeness [9 words unchanged] crucial to enable a true cost to the NHS to be determined and hence to, in turn, influence implementation decisions on the course of treatment for the population. This could lead to reductions in NHS spending on treatments without proven effectiveness or to invest and/or investment in treatments that will generate savings in the future through reduced NHS service use. Finally, the HES data will also be used to look at how researchers can maximise efficiency in research data collection to minimise burden on the NHS. The HES data will be cross-checked with that which has already obtained from individual primary care records. The results of the agreement of these two sources will be analysed by the team. If HES provides a complete dataset of outcomes, in future, there will be no need to burden GP practices with requests for medical notes for research purposes as secondary care data will be proven reliable and comprehensive. This will free up substantial practice staff time which can be then refocused on their main activities – providing frontline care to their patients. The University of Cambridge has existing responsibility for the organisation and delivery of diabetes care both locally and nationally (e.g. guideline development, managed care networks, expert review group for diabetes Quality and Outcomes Framework indicators, National Screening Committee Advisory Group, UK Department of Health Vascular screening programme) and therefore have established mechanisms for influencing policy and practice in these and related fields. Results from this study hope to inform care early in the course of the disease and provide information on whether people in middle-age should be offered screening for diabetes in the UK and worldwide. It is estimated that 1 in 16 UK adults has (diagnosed or undiagnosed) type 2 diabetes, and this creates a substantial burden of suffering and health service use. Treatment of type 2 diabetes and related complications (cardiovascular disease, amputation, blindness, kidney failure) accounts for 10% of the NHS budget. This is expected to rise as the number of people in the UK who have type 2 diabetes is estimated to rise to 6.25 million by 2035. Other expected benefits include: Type 2 diabetes is frequently asymptomatic, with the true onset occurring several years before diagnosis. While detection of the condition may be improving, around 30-50% of people with diabetes remain undiagnosed, and when patients are diagnosed, around 20-30% have evidence of diabetic complications. Long-term follow-up of the ADDITION-Europe trial will inform the management of newly diagnosed patients and to establish the size and nature of the benefits of detecting and treating diabetes earlier. • Direct effects for individuals of trial participation, the study has previously reported lower than expected rates of cardiovascular evets and premature mortality among trial participants. Participation in the trial has facilitated earlier diagnosis and treatment of diabetes. The ADDITION trial has shown that this is not associated with adverse consequences in terms of anxiety and depression. Data from one year follow-up show that overall trial participants had lower levels of risk factors at one year than at the time of diagnosis. Furthermore, one year data suggest that, compared with routine care, intensive treatment is associated with reduced CVD risk, reduced anxiety, increased functional status and treatment satisfaction, with no detriment to quality of life. • Impact on clinical practice, policy makers and researchers which we monitor through metrics such as citations in scientific papers and guidelines/policy documents. For example, the results of ADDITION (the only published trial of screening for type 2 diabetes) and related studies form a key contribution of original research cited in UK policy documents (National Screening Committee review) and international guidelines (US Preventive Services Task Force), that recommend risk stratified rather than universal screening for type 2 diabetes, which is standard practice in health systems worldwide. The intervention promoting target driven, intensive management of patients with screen-detected type 2 diabetes in ADDITION-Cambridge was associated with a non-significant relative reduction (17%) in the incidence of cardiovascular events and a reduction in all-cause mortality at 5 years. The lower than expected event rate during the trial suggests five years of follow up may have been insufficient to detect a potentially important difference. Furthermore, the apparent divergence of event rates from four years indicates that further follow up of this cohort is justified to establish whether early intensive multifactorial treatment reduces long term cardiovascular risk. Modelling work suggests that there might be a difference in cardiovascular risk over the long term. Significant reductions in myocardial infarction and all-cause mortality associated with glucose lowering were only observed after ten years of follow up in the UKPDS trial. Whether such a legacy effect might be seen in ADDITION Europe is unclear. Resolving this uncertainty is important in assessing the costs and benefits of screening for diabetes. No other trials of screening for diabetes or intensive treatment of screen detected cases have been reported and no others are underway in Europe. First line treatment for diabetes has changed following results from the UKPDS. While newly diagnosed individuals were previously offered lifestyle advice for six months and then prescribed metformin, metformin is increasingly being prescribed from diagnosis. Long term follow up of the ADDITION-Europe trial will allow examination of the potential legacy effect of a health service intervention that targeted practices and patients, and whether differences in the intensity of the intervention of the routine care and intensive treatment practices remain. Results will add evidence to decisions about treatment from diagnosis and the balance between treatment and disease burden. ADDITION-Cambridge has existing responsibility for organisation and delivery of diabetes care both locally and nationally (e.g. guideline development, managed care networks, expert review group for diabetes QOF indicators, National Screening Committee Advisory Group, UK Department of Health Vascular screening programme) and therefore have established mechanisms for influencing policy and practice in these and related fields. Results from this study will help inform care early in the course of the disease and will provide information on whether people in middle-age should be offered screening for diabetes in the UK and worldwide.

Benefits reported

The primary benefits processing of using NHS Digital's List England's MRIS-List Cleaning service are that it Report data has enabled ADDITION-Cambridge to continue the University of Cambridge to collect information about its the participants of the ADDITION-10-year follow-up study fairly and transparently by giving participants the option to withdraw from the study should they wish. wish to. Furthermore, knowing receiving information on which participants are deceased has enabled ensured that the study team do not to avoid attempting contact and potentially causing distress to living relatives. relatives which may cause emotional distress. Being able to track and trace participants has meant that the study team has been able to collect more information from the respective GP practices (as stated in Purpose 1b above) which has greatly improved the power of the study, thus making it more useful for planning NHS resource allocation and best practice in the treatment of type 2 diabetes. The extra information collected as a result of the track and trace data has been included in a paper which is under review at Lancet Diabetes and Endocrinology. Type 2 diabetes is frequently asymptomatic, with the true onset occurring several years before diagnosis. While detection of the condition may be improving, around 30-50% of people with diabetes remain undiagnosed, and when patients are diagnosed, around 20-30% have evidence of diabetic complications. Participation in the trial has facilitated earlier diagnosis and treatment of diabetes. The ADDITION-10-year follow up study has shown that this is not associated with adverse consequences in terms of anxiety and depression. Data from one year follow-up shows that, in general, trial participants had lower levels of risk factors at one year than at the time of diagnosis. Furthermore, one year data suggested that, compared with routine care, intensive treatment is associated with reduced CVD risk, reduced anxiety, increased functional status and treatment satisfaction, with no detriment to quality of life. As analysis of HES data is still in preliminary stages, no benefits have been yielded from this yet. The intervention promoting target driven, intensive management of patients with screen-detected type 2 diabetes in the study was associated with a non-significant relative reduction (17%) in the incidence of cardiovascular events and a reduction in all-cause mortality at 5 years. The lower than expected event rate during the trial suggests five years of follow up may have been insufficient to detect a potentially important difference. Furthermore, the apparent divergence of event rates from four years indicates that further follow up of this cohort was justified to establish whether early intensive multifactorial treatment reduces long term cardiovascular risk. Modelling work suggests that there may be a difference in cardiovascular risk over the long term. Significant reductions in myocardial infarction and all-cause mortality associated with glucose lowering were only observed after ten years of follow up in the UK Prospective Diabetes Study (UKPDS) trial. Whether such a legacy effect might be seen in ADDITION-Europe is unclear. Resolving this uncertainty is important in assessing the costs and benefits of screening for diabetes. No other trials of screening for diabetes or intensive treatment of screen detected cases have been reported and no others are underway in Europe. First line treatment for diabetes has changed following results from the UKPDS. While newly diagnosed individuals were previously offered lifestyle advice for six months and then prescribed metformin, metformin is increasingly being prescribed from diagnosis. Long term follow up of the ADDITION-Europe trial has allowed for an examination of the potential legacy effect of a health service intervention that targets practices and patients, and whether differences in the intensity of the intervention of the routine care and intensive treatment practices remain. Results have added evidence to decisions about treatment from diagnosis and the balance between treatment and disease burden. Being able to track and trace participants has meant that the study team has been able to collect more information from the respective GP practices (as stated in Purpose 1b above) which has greatly improved the power of the study, thus making it more useful for: (1) planning NHS resource allocation and best practice in the treatment of type 2 diabetes and (2) influencing NHS policy makers and clinician decisions nationally on the best way to care for this population. Additionally, the HES data received has shown a good correlation with the records collected from GP practices. Therefore the study team will utilize secondary care data for future follow ups, reducing the burden not only on the GP practices but also on the University of Cambridge study team. The wider ADDITION–Europe study has so far led to the publication of over 80 papers in peer-reviewed scientific journals. Data from the wider ADDITION studies has also contributed to more than a dozen PhD theses and over 50 oral presentations or posters at international conferences. In relation to the ADDITION ten-year follow-up study, the primary analysis of 5 year outcomes was published in the Lancet (https://pubmed.ncbi.nlm.nih.gov/21705063/). The results of the 10 year analysis were submitted and published in the Lancet Diabetes Endocrinology (https://pubmed.ncbi.nlm.nih.gov/31748169/). Previous findings were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in September 2016. Other publications include: Examining the association between primary care practitioner (physician and nurse) empathy and incidence of CVD events and all-cause mortality among patients with type 2 diabetes. This showed that positive patient experiences of practitioner empathy in the year after diagnosis of type 2 diabetes may be associated with beneficial long-term clinical outcomes - //www.annfammed.org/content/17/4/311.long. In the year following diabetes diagnosis, small reductions in alcohol use were associated with a lower risk of CVD and small reductions in calorie intake were associated with a lower risk of all-cause mortality. The achievement of moderate behaviour change targets is possible outside of treatment programs and may reduce long-term risk of CVD complications - https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0902-5. Furthermore, a loss of up to 5% body weight in the year following diabetes diagnosis was associated with improvements in blood glucose levels and blood lipids and a lower risk of CVD at 10 years compared with maintaining weight - https://link.springer.com/article/10.1007/s00125-019-4886-1#citeas. Reducing fat intake was associated with lower long-term CVD risk. This evidence may raise concerns about low-carbohydrate, high-fat diets to achieve weight loss following type 2 diabetes diagnosis when participants were followed up over a 10 year period - https://onlinelibrary.wiley.com/doi/10.1111/dme.14646. Secondary analyses including cost-utility analysis and mechanistic analyses hope to be published in leading medical or disease-specific peer-reviewed journals such as the Lancet, British Medical Journal, Diabetalogia, Diabetes Care and the International Journal of Obesity. All publications will be/are open access, in line with the University of Cambridge’s open-access policy, and can be accessed by clinicians, academics, policy makers and interested members of the public. Outputs presented and/or reported have contained/will contain aggregate level data with small numbers supressed in line with the HES analysis guide.