General Health Outcomes in Subfertile Men: a UK register-based cohort study

University College London (UCL) requires access to NHS England data for the purpose of the following research project: General Health Outcomes in Sub fertile Men: a UK register-based cohort study.

The following is a summary of the aims of the research project provided by UCL:

To investigate the risks of long-term malignant and non-malignant health outcomes, as well as early death, in men with known subfertility in the UK.

The proposed study will utilize routinely collected administrative health records to investigate the risk of long-term malignant and non-malignant health outcomes, as well as early death, in subfertile men in the UK and compare them with men with similar demographic and socioeconomic characteristics from the general population. This project will link data held in several large existing national databases and will not involve any direct patient/participant contact. Records of males with known subfertility will be identified through the Human Fertilisation and Embryology Authority (HFEA) Register of couples who underwent non-donor assisted fertility treatments in UK clinics between August 1991 and September 2009. These will then be linked to hospital admissions, cancer, and mortality data held by NHS England to allow investigation of longitudinal health outcomes in this cohort.

The following NHS England Data will be accessed:

• Hospital Episode Statistics Admitted Patient Care, Critical Care, Accident & Emergency, and Outpatients – necessary to, for example, estimate the risk of non-oncological morbidities such as diabetes or cardiovascular disease, other chronic diseases such as urogenital systemic infections, endocrinopathies and metabolic disorders, respiratory disease, autoimmune diseases and also to estimate the risk of hospital admissions (e.g., rates per year, causes of admission, and length of hospital stay).

• Civil Registrations of Death - necessary to estimate, for example, mortality rates and risk of early death

• Cancer Registration Data - necessary to, for example, estimate the risk of oncological conditions such as testicular or prostate cancer and other types of cancers such as urinary or digestive system cancers, cancers of the lymphatic or circulatory systems etc.

The level of the Data will be:

• Pseudonymised

The Data will be minimised as follows:

• Limited to a study cohort identified by HFEA - ART cohort of males with known subfertility identified through the Human Fertilisation and Embryology Authority (HFEA) Register of couples who underwent non-donor assisted reproduction treatments in UK clinics between August 1991 and September 2009.

• Hospital data -1997/98 to latest available

• Cancer Registration Data and Mortality data- up to latest available

The majority of outcome measures (e.g., malignancies, chronic non-malignant health conditions, early death) being examined in this study are conditions that develop in later life. Accessing data up to the most recent year available will allow UCL to investigate the health effects of subfertility/infertility using a life-course approach. It will provide valuable insight into the longitudinal health of these men which, in turn, can help identify opportunities for early detection and intervention.

UCL is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The 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.

This study is funded by a Wellcome Investigator Award in Science awarded to the principal investigator.

The funder will have no ability to suppress or otherwise limit the publication of findings.

Amazon Web Services (AWS) is the processors acting under the instructions of UCL. AWS’ role is limited to secure back-up of data stored in UCL’s Data Safe Haven.

UCL uses offsite data centre services provided by VIRTUS data centre. VIRTUS does not have access to the data.

The data will be accessed by substantive employees of the Great Ormond Street Institute of Child Health, University College London (GOS ICH, UCL).

The proposed research was developed in conjunction with members of the British Fertility Society (consisting of andrologists, counsellors, embryologists, endocrinologists, nurses, and other professional groups working in this field) and the Fertility Network UK (the largest fertility patient support network in the UK).

Additionally, UCL also invited men in the general public to share their views by completing a short anonymous survey (available at: https://liftresearchucl.com/surveys/), with the aim of understanding their (1) awareness and concerns about potential adverse health effects associated with male fertility problems and (2) their views on studies such as ours. The survey was distributed via newsletters, social media, and a study-specific website. The group members and survey respondents supported a study of this nature and recognised the importance of collecting data for this purpose and also felt that, in addition to providing critical insight into the health consequences of subfertility, a study of this nature could be considered as an important starting point in addressing the stigma around male subfertility.

HFEA will transfer cohort data to NHS England. The data will consist of identifying details specifically Name and Date of Birth to allow linkage of the cohort to NHS England data.

The flow of identifying data from HFEA to NHS England is permitted under the Human Fertilisation and Embryology (Disclosure of Information for Research Purposes) Regulations 2010 which enables HFEA to lawfully share this data with NHS England for the purpose of this research.

NHS England will provide the relevant records from the Civil Registrations of Death, Cancer Registration Data and HES datasets to UCL. The Data will contain no direct identifying data items but will contain a unique person ID which can be used to link with other record level data already held by the recipient (i.e., pseudonymised background fertility data for the males – provided by HFEA and transferred directly to UCL).

The Data will not be transferred to any other location.

The data will be stored in the UCL Data Safe Haven (DSH).

Amazon Web Services provides cloud hosting services to UCL and will store the data as contracted by UCL. UCL uses offsite data centre services provided by VIRTUS data centre.

The Data will be accessed by authorised personnel via remote access and onsite.

UCL must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

The Data will not leave England at any time.

Access to pseudonymised data is restricted to individuals within the Population, Policy and Practice unit of the GOS ICH, who have authorisation from the Principal Investigator. All such individuals are substantive employees of UCL.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will be linked at person record level with a pseudonymised dataset containing background fertility information for the males. This dataset, provided by the HFEA, will be transferred to UCL directly and will contain the same study id numbers as the dataset obtained from NHS England. This will allow researchers at UCL to link the two datasets for analysis without the need for access to identifiable data.

The UCL research team will not have access to any personal identifiable data at any stage. The identifying details are held by HFEA. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to re-identify individuals when using the pseudonymised dataset.

Analysts and researchers at GOS ICH, UCL will analyse the Data for the purposes described above.

The expected outputs of the processing will be:

• Peer-reviewed publications in medical journals. The main results of the study will be submitted for publication in a high-impact general medical journal (such as The Lancet, The Journal of the American Medical Association (JAMA), or the British Medical Journal (BMJ)). Publications will be Open Access as per UCL policy, and freely available via both journal websites and UCL webpages.

• National and international conference presentations.

• Dissemination of findings via the UCL press department and through the study-specific website (https://liftresearchucl.com/)

• Report for the study funder (Wellcome Trust) which will be publicly available via their study webpage on the Wellcome Trust website.

• Lay summary report which will be made publicly available via the websites of stakeholder organizations (HFEA, Fertility Network UK; NHS England's Fertility Treatments Advisory Group; the Royal Colleges including Royal College of Obstetrics and Gynaecology and Royal College of Paediatrics and Child Health; Wellcome Trust; and UCL)

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 datasets from which the information was derived.

Dissemination of the research findings to researchers and scientists will involve presentations at national and international conferences and publications in peer review medical journals, as detailed above. Dissemination of the research findings to the public (key stakeholders being sub fertile males) will be facilitated through existing collaborations with the HFEA and Fertility Network UK (the leading patient organization supporting people suffering from infertility). Dissemination of the research findings to a lay audience will be in the form of a brief research report and a video shared via the websites, newsletters, and social media channels of stakeholder organizations (HFEA, Fertility Network UK, Welcome Trust, and UCL). Research regarding fertility treatments, including previous work published by the research team, has attracted a high level of media interest, and the team anticipates that this will be the case for the proposed study. The team is acutely aware of the potentially harmful effect of inaccurate or sensational reporting of research findings in this sensitive area, and the confusion and anxiety this can cause for couples and parents. The team will work closely with the HFEA, Fertility Network UK, & UCL to coordinate press releases and ensure that information is conveyed accurately and responsibly.

The research team will commence analysing the data as soon as it has been made available. The team would anticipate that the process of data analysis, interpretation, and report writing would take approximately 18 months, and outputs will be generated by early 2025 although this estimate is dependent upon the timeframe for data access approvals being obtained and the data linkage being completed.

The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients.

The use of the data could:

• help the system to better understand the health and care needs of subfertile males.

• Identify opportunities and develop strategies for early detection and prevention of particular conditions in this population.

• inform planning health services and programmes to improve outcomes.

• inform decisions on how to effectively allocate and evaluate funding according to health needs.

• lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

• support knowledge creation and exploratory research.

There will be no direct benefits to the study participants. However, the study will have wider benefits to various assisted reproduction technologies (ART) stakeholder groups by addressing the gap in scientific knowledge regarding the long-term health outcomes of sub fertile males. Dissemination of the research findings to researchers and scientists will involve presentation at national and international conferences and publications in peer reviewed medical journals. This will benefit the medical and scientific community by addressing the gaps in knowledge regarding risks associated with infertility. It can also potentially facilitate further research and influence early detection and prevention policy decisions. Dissemination of the research findings to the public (key stakeholders being sub fertile males) will be facilitated through existing collaborations with the HFEA and Fertility Network UK (the leading patient organization supporting people suffering from infertility). This will benefit patients and families affected by subfertility, commissioners and providers, and staff caring for people needing fertility 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.

The results will further the understanding of the long-term health outcomes of subfertility in males which, in turn, will allow patients and families affected by subfertility to make informed decisions. It will also enable clinicians and staff caring for people requiring fertility treatments to develop a better understanding of prognosis and provide targeted treatment and appropriate support. Finally, it will allow researchers and health care services to develop strategies for prevention or early identification of high-risk individuals, thereby reducing the potential impact on the NHS burden.

Yielded Benefits is not a requirement for new applications.