Establishing predictors of long-term health outcomes in the NewKI CKD cohort.

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

Datasets: + Cancer Registration Data; + Civil Registrations of Death · − HES:Civil Registration (Deaths) bridge

Objective for processing

The University of Oxford requires access to NHS England data for the purpose of a longitudinal observational study: the following research project: Establishing predictors of long-term health outcomes in the New Onset Kidney Impairment Study (NewKI) Chronic Kidney Disease (CKD) cohort. The aim of this study is to identify predictors of adverse health outcomes in an older primary care population with chronic kidney disease or transiently impaired renal function. The investigators at the Nuffield Department of Primary Care Clinical Trials Unit aim to identify which people with CKD are most likely to develop health problems, to help to plan preventive treatments. CKD is a worldwide health problem associated with high morbidity and mortality and its prevalence is increasing. Decreased renal function is a well-known predictor of hospitalisation, cognitive dysfunction and poor quality of life. Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in this population. Glomerular Filtration Rate (GFR) is a test used to check how well the kidneys are working. Specifically, it estimates how much blood passes through the glomeruli each minute. Glomeruli are the tiny filters in the kidneys that filter waste from the blood. Usually GFR is estimated using an equation and a simple blood test to calculate the estimated GFR (eGFR). As GFR decreases, and CKD progresses, the risk of poor health outcomes increases, including end stage renal disease, cardiovascular events and mortality. CKD is characterised by decreased kidney function, measured as a GFR of less than 60 ml/min/1·73 m2 or markers of kidney damage present for at least 3 months duration. CKD prevalence increases with age, therefore older people may be those who benefit most from screening for CKD or closer monitoring of other health conditions. However, despite how common CKD is, and the inevitable decline in renal function over time, little is known about what predicts more rapid decline in renal function seen by some people, and therefore which patients should be monitored more closely or when interventions should be considered. This study will provide novel data in this area. The following is a summary of the aims of the research project provided by The University of Oxford: The Oxford Renal Longitudinal Cohort Study (OxRen) is a prospective observational longitudinal cohort study established in 2013 in the Thames Valley area of the UK. It recruited 3200 primary care participants aged 60 years and older from 13 GP Practices across the Thames Valley region. The study collected data on prevalence of CKD through a targeted screening programme. During the study, participants without a diagnosis of CKD were re-screened after two years to collect data on incidence. Patients who were diagnosed with CKD or had transiently impaired renal function (n=902) received baseline assessment visits where detailed information on participants health and lifestyle were collected. Blood and urine samples were also collected for analysis. Since then, these participants have attended study visits every year to monitor their general health and kidney function. • Provide objective estimates of the mortality rate and Cardiovascular disease (CVD) incidence of CKD patients. OxRen closed in 2017, but the population has been followed up in the NewKI study (New Onset Kidney Impairment Study) to continue to collect data on CKD incidence and disease progression through annual follow-up visits or two yearly screening visits for CKD. Now, the investigators want to establish whether any of these participants have gone on to develop more serious health problems, were admitted to hospital or died. The investigators will use statistical models to identify the people who went on to develop health problems or died, at an earlier stage. This work will help the investigators to understand which people are at greatest risk of poor health outcomes, so their doctors can monitor their health more closely and make sure they are taking the right medications. • Estimate and compare the mortality rates and CVD incidence for CKD patients identified routinely by clinical practice, and for CKD patients identified by means of screening. The study has now been awarded funding from the National Institute for Health Research School for Primary Care Research (NIHR SPCR) towards linking NewKI participants with NHS Digital data. This will enable the investigators to establish predictors of adverse health outcomes in the NewKI CKD cohort by obtaining data on new diagnoses, hospital admissions and death. • Identify predictors for mortality and CKD incidence to help clinicians identify those at greatest risk for closer monitoring, medication review or other medical interventions. Annual follow-up visits will continue to collect data on progression of CKD through laboratory measurements. In addition to scheduled study visits, the study team have begun linking NewKI participant data with the Royal College of General Practitioners Research Surveillance Centre (RCGP RSC) database in a feasibility study. Full linkage with the RCGP RSC will allow the investigators to prospectively follow up participants using their routine primary care records, and will be able to continue to follow up participants who are no longer able to attend study visits. • Identify people at the lowest risk of adverse outcomes who do not need close follow up. Over the long term this will help to guide the clinical management of people with CKD, especially those with early-stage renal disease in primary care. As the NewKI population continues to age, the risk of adverse health outcomes will increase. In 2020 it will be seven years since the first participant was recruited to the study. However, in order to capture data on hard outcomes, such as new diagnoses, end stage renal disease, hospitalisations, cardiovascular events and death, the investigators now need to link patient data with NHS Digital and Civil Registration mortality data. • Evaluate the effectiveness of screening for chronic kidney disease (CKD) in primary care. Collecting these data will allow the investigators to: • Establish predictors of adverse health outcomes in the NewKI CKD cohort. 1) provide objective estimates of the mortality rate and CVD incidence of CKD patients, • Determine the incidence of CKD from routinely collected health records and determine whether there are associations with adverse events for those without CKD. 2) estimate and compare the mortality rates and CVD incidence for CKD patients identified routinely by clinical practice, and for CKD patients identified by means of screening, and • Understand which people are at greatest risk of poor health outcomes including cancer and renal disease so their doctors can monitor their health more closely and make sure they are taking the right medications. 3) identify predictors for mortality and CKD incidence in order to help clinicians identify those at greatest risk for closer monitoring, medication review or other medical interventions. • Compare prognosis of those known to have CKD to those with screening-identified, transient CKD, and no CKD to inform the clinical effectiveness of a CKD screening programme. It will also identify people at the lowest risk of adverse outcomes who do not need close follow up. Over the long term this will help to guide the clinical management of people with CKD, especially those with early stage renal disease in primary care. The following NHS England data will be accessed: Ethical approval for NHS Digital follow-up was received in July 2019 by Yorkshire & The Humber - Bradford Leeds Research Ethics Committee (REC reference: 17/YH/0429), and participants have now consented to share their NHS Digital data to allow follow-up for life. • Hospital Episode Statistics: Admitted Patient Care – Necessary to establish predictors of adverse health outcomes in the NewKI CKD cohort; and determine the incidence of CKD from routinely collected health records and determine whether there are associations with adverse events for those without CKD. This is a consented study and Article 6 (1) (e) and 9 (2) (j) are used as this work is research in the public interest as it aims to improve care for patients with CKD in the future. It will also help GP’s to identify patients at greater risk so they can be monitored more closely. • Civil Registrations of Death – necessary to provide objective estimates of the mortality rate and CVD incidence of CKD patients; and estimate and compare the mortality rates and CVD incidence for CKD patients identified routinely by clinical practice, and for CKD patients identified by means of screening. The data will be pseudonymised when stored and analysed at the University of Oxford Nuffield Department of Primary Care Health Sciences (data controller and processor). • Cancer Registrations – will provide cancer diagnoses, as malignancies are also an important cause of CKD. Access is necessary to inform the effectiveness of screening for CKD, including harms and benefits associated with it, by exploring how the population already known to have CKD compare to those newly identified as having CKD (or transient CKD) through screening. Only aggregated data with small numbers suppressed will be used in publications; no identifiable individual level data will be published. Patients will have provided fully informed written consent for the data linkage. Patients can withdraw their consent for these activities at any time. In such cases no further data will be requested for the patient. Existing data will continue to be used, in accordance with the consent provided. The level of the data will be Identifiable. The HES, Cancer Registrations, and Civil Registrations of Death data flowing from NHS Digital is pseudonymised, however the study team holds a participation ID to link the HES, Cancer Registrations, and Civil Registrations of Death data to data already held by the study team. By means of this re-identification, the data provided by NHS England is therefore considered identifiable. The data will be minimised as follows: • Limited to a study cohort of 1490 NewKI participants who are aged 60+, registered with GP practices in Oxfordshire or Berkshire, who are at highest risk of developing adverse health outcomes and who consented to participate in the study. • Limited to data between 2013 and 2023. The University of Oxford is the sole the data controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. Only the University of Oxford will process the data. The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. As a higher education establishment, the University of Oxford conduct research to improve health care and service and the linkage requested is necessary for the performance of a task carried out in the public interest. The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. The funding is provided by National Institute for Health Research (NIHR) School for Primary Care Research. The funding is allocated by the University of Oxford specifically for the study described. There are no other organisations acting in an advisory capacity or as part of an oversight or steering committee. The data will be accessed by substantive employees of the University of Oxford and PhD students affiliated with the University of Oxford. PhD students will complete mandatory data protection and confidentiality training, and are subject to the University of Oxford policies on data protection and confidentiality. Individuals accessing the data will do so under the supervision of a substantive employee of the University of Oxford. The University of Oxford would be responsible and liable for any work carried out by the individual. PhD students would only work on the data for the purposes described in this Agreement.

Processing activities

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data). The University of Oxford will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Name, Date of Birth, and a unique person ID) for the cohort to be linked with NHS England data. University of Oxford will submit a file containing the identifiers of the consented participants who had a diagnosis of CKD and were recruited to the study (minus any patients that withdraw from the study) to NHS Digital using its secure electronic file transfer system. Identifiers will include: DOB, NHS number. Each participant record will also contain the unique study participant ID number. The CKD cohort will include 902 patients. NHS England will provide the relevant records from the Cancer Registrations, Civil Registrations of Death, and HES Admitted Patient Care datasets to the University of Oxford. The data returned to the University of Oxford will contain no direct identifying data items but will contain a unique person ID which can be used to link the data with participant study already held by the recipient. HES and mortality data to include date and cause of death for each participant identified in the file submitted by the study team will be returned to the study team. The HES and mortality data flowing from NHS Digital is pseudonymised, however the study team has a participation ID to link the HES and mortality data to data the study team already holds. By means of this re-identification, the HES and mortality data is therefore considered identifiable. The data will not be transferred to any other location. The returned data will be processed and stored by the study team at the University of Oxford who will be undertaking the study analyses to achieve the stated purpose. Access to this data will be limited to authorised personnel from the study team. Datasets will be stored on secure University of Oxford Servers located within the University’s Medical Science Division in a University-owned and managed facility at the John Radcliffe Hospital site in Oxford. The flow of data would involve University of Oxford securely transferring name, NHS number and date of birth to NHS digital to link records. Backup storage is located in two separate locations owned by the University of Oxford. Backups should be useable in the event of a disaster at the main site and will be accorded the same physical & electronic protections as live data. Linked data from NHS Digital would be transferred back to study team. The data will be accessed onsite at the premises of University of Oxford, Nuffield Department of Primary Care Sciences. Pseudonymised data is processed and only aggregate data will be used to describe the population. Remote processing will only be through a secure electronic network and organisational controls prohibit personnel from downloading or copying data to local devices. No record level data falling under this agreement will be shared with any third-party. Remote processing will be subject to the following being in place: Only substantive employees of the University of Oxford will undertake data processing activities. Standard employment contractual agreements are in place to cover general data confidentiality requirements of all staff. In addition staff will be required to undergo specific data protection training in accordance with relevant local policies • Multifactor authentication (MFA); • Access controls granting users the minimum level of access required; • Secure connections (e.g., VPNs or secure protocols) to protect data during remote access; • Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls. All remote access is undertaken within the scope of the relevant organisations’ DSPT per this Data Sharing Agreement (DSA). The data will not leave England at any time. Access to this data is restricted to authorised personnel from the study team. All such individuals are substantive employees of the University of Oxford or PhD students affiliated with the University of Oxford. All personnel accessing the data have been appropriately trained in data protection and confidentiality. The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset. Researchers from the University of Oxford’s Medical Science Division in a University-owned and managed facility at the John Radcliffe Hospital site in Oxford will process the data for the purposes described above.

Expected output

Apart from direct outputs in terms of new evidence to help identify predictors of adverse health outcomes in an older primary care population with CKD, other outputs will be generated which may include, reports, submissions to peer reviewed journals such as the BMJ, presentations and dashboards. There are 3 potential conferences for presenting the outputs from this work in 2022, Society for Academic Primary Care conference in the UK, NAPCRG – North America Primary Care Research Group conference – Arizona, US and WONCA Europe (World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians), London 2022. A lay summary of results will also be made available to participants. The expected outputs of the processing will be: All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide. • Submissions to peer reviewed journals such as such as the British Medical Journal. The study team will facilitate the dissemination of the research and/or scientific work to stakeholders during the project and after its completion. It is expected that the NewKI study will generate a high number of high impact manuscripts to include the following: Progression and rapid decline of CKD, Biomarkers for the progression of renal decline, Biomarkers for the identification of CVD risk and cost effectiveness of screening for CKD. Dissemination mechanisms will be used appropriate to the relevant audience. • Presentations at conferences throughout 2023 such as the Society for Academic Primary Care conference in the UK, NAPCRG – North America Primary Care Research Group conference – Arizona, US and WONCA Europe (World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians). The investigators will ensure that the results of the study are communicated with all relevant parties using multiple channels. The investigators have support from the University of Oxford media team to maximise reach and impact. The study team have also produced a study newsletter for participants to outline key findings from the baseline paper. Participants can also request for a copy of the lay summary of results at the end of the study. • Publication on the University of Oxford’s website: https://www.phc.ox.ac.uk/research/kidney-disease/studies/oxren The NIHR SPCR as funders have clear (standard) expectations for data sharing which the University of Oxford are contractually obliged to follow, any onward sharing of data will only be data which is aggregated with small numbers suppressed. The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. Publications will continue throughout the study. The outputs will be communicated to relevant recipients through the following dissemination channels: Two PPI representatives have been involved in the NewKI study steering committee to monitor recruitment and oversee the management of the study. At each stage, the study team have discussed overall study findings, recruitment figures, any planned changes to data collection and the proposed publications with the PPI representatives. The plain English summary of the funding application for this current project to link patient data with NHS Digital was reviewed by the two PPI representatives and they were involved in identifying outcomes which are important to patients. • Journals such as the British Medical Journal As the study team generate results from the NewKI study, they have been sharing results with study participants in regular newsletters. • Social media: X - @oxprimarycare For this current analysis, the study team will be sharing results with the PPI representatives at the regular NewKI study steering committee meetings. When the analysis is complete, the study team will share results in a newsletter to all NewkI study participants.’ • Publications covering the impact of CKD screening on prognosis: mortality, cardiovascular disease (CVD), cancer, ESRD, hospitalisations and health-related quality of life. Production and dissemination of outputs is expected throughout 2024.

Expected measurable benefits

The planned dissemination will help to guide the clinical management of people with early stage renal disease in primary care. This work will establish predictors of adverse health outcomes and identify those at greatest risk to be prioritised for closer monitoring, medication review or other medical interventions. It will also provide evidence as to whether CKD screening helps to identify additional patients at risk of death, CVD or other poor health outcomes, who may otherwise have been missed. The findings of this research study are expected to contribute to evidence-based decision-making for policymakers, local decision-makers such as doctors, and patients, to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study. Dissemination is in the public interest as CKD affects around 3 million people in the United Kingdom and some patients with CKD are more likely to go on to develop adverse health outcomes, including cardiovascular disease, than the general population. Despite how common CKD is, and the inevitable decline in renal function over time, little is known about what predicts more rapid decline in renal function seen by some people, and therefore which conditions should be monitored more closely or when interventions should be considered. Publications focussing on predictors of long term adverse health outcomes in patients with CKD will help raise awareness amongst general practitioners and may lead to changes in practice so that those who are most at risk can be prioritised for closer monitoring and preventative treatments. The use of the data could: Collecting these data will allow the investigators to 1) provide objective estimates of the mortality rate and CVD incidence of CKD patients, 2) estimate and compare the mortality rates and CVD incidence for CKD patients identified routinely by clinical practice, and for CKD patients identified by means of screening, and 3) identify predictors for mortality and CKD incidence in order to help clinicians identify those at greatest risk for closer monitoring, medication review or other medical interventions. It will also identify people at the lowest risk of adverse outcomes who do not need close follow up. Over the long term this will help to guide the clinical management of people with CKD, especially those with early stage renal disease in primary care. • help the system to better understand the health and care needs of populations. The research aims to benefit patients with CKD and the investigators will also carry out a more limited analysis of the remainder of the cohort who did not have CKD on screening (n=1709) to establish whether the screening data the study team have collected (age, sex, estimated GFR and urinary albumin-creatinine ratio) has any associations with adverse events. This does not include NHS Digital data. • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. The controller will benefit from recognition associated with the peer review publications. • inform planning health services and programmes, for example to improve equity of access, experience and outcomes. • inform decisions on how to effectively allocate and evaluate funding according to health needs. • advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as obesity and diabetes. CKD affects around 3 million people in the United Kingdom and some patients with CKD are more likely to go on to develop adverse health outcomes, including cardiovascular disease, than the general population. Publications focussing on predictors of long-term adverse health outcomes in patients with CKD will help raise awareness amongst general practitioners and may lead to changes in practice so that those who are most at risk can be prioritised for closer monitoring and preventative treatments. It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients. Policymakers, local decision-makers such as doctors, and patients will need to take action based on the information provided to them in order to realise the potential improvement opportunities. For example, screening policy change could lead to prioritisation of preventative treatments for CKD patients who are most at risk of developing adverse health conditions. Including a wider population of patients without CKD enables a better understanding about the risks to patients having CKD compared to patients without CKD. If findings highlight improvements to screening are required, the University of Oxford will publish and disseminate to health professionals at conferences.

Benefits reported

Yielded Benefits is not a requirement for new applications. Publications from the OxRen/NewKI cohort have provided a reliable estimate of the prevalence of CKD in UK primary care. Analyses from the study data have also provided an estimate of the number of people who will be living with undiagnosed CKD, the types of comorbidity people with CKD will be living with, and how rapidly kidney function in an older primary care population deteriorate. It is hoped these data will enable clinicians to provide more targeted care for their conditions. Findings have indicated that quality of life for patients with early-stage kidney disease was similar to those without kidney disease.