MR287 - Study of Twins

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling The Institute of Cancer Research to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). This Agreement permits the secure retention of the data only and no other processing. The Institute of Cancer Research (ICR) will store the data with the intention to run updated analyses in 2028. The following provides background information on the purpose of the original study: ICR already hold the following NHS England data Civil Registration Mortality, Cancer Registration & Demographics for the purpose of a national cohort study of cancer in twins. The Institute of Cancer Research (ICR) requires mortality, cancer incidence and demographic data for the purpose of a national study of cancer in twins. This study is being conducted by the ICR on a larger scale than elsewhere, to provide the best, most powerful, data available to patients and their doctors about long-term health risks. This will lead to better information for patients in general and their families; to improved prognostic data for patient advice, and to improved clinical follow-up, and where needed, screening. Finding the causes of cancer is important to enabling its prevention and identifying high risk groups for screening and early detection. Cancer now accounts for 31% of death in men and 26% of deaths in women in England, so is a major public health problem. Gaining information on familial and genetic risks of cancer is important, because these are questions that matter greatly to patients, and to health care and screening of their relatives, and also because they can give important insights more widely into the causes, and hence prevention, of cancer. Information on genetic risks is also important to health service planning and service provision of genetics and high risk clinics, and of high risk screening services. A cohort study is the methodologically most rigorous study design that can be undertaken of long-term cancer and mortality risks in such patients, and the ICR believes it is the only cancer study of its type in the UK, and for several cancers (e.g. testicular cancer, premenopausal breast cancer) it is much the largest of its type internationally. Twin studies have unique potential to investigate both genetic and environmental/behavioural and prenatal aspects of disease aetiology, as well as to provide data to test hypothesised models of carcinogenesis. Such studies have made only a small contribution to investigation of cancer aetiology, however, reflecting the great difficulty of identifying large enough numbers of twins with cancer for site-specific analyses. Limited population-based data on monozygous (MZ) and dizygous (DZ) concordance for some [50 words unchanged] a catchment population of >50 million and all births over many decades. The ICR therefore inaugurated, Therefore with the help of ONS, the Office for National Statistics (ONS), a national study of cancer in twins. This study has been running for over 20 years and has contributed unique data on several aspects of genetic and environmental/ prenatal aetiology of cancer. twins was inaugurated. This study has been running for over 20 years and has contributed unique data on several aspects of genetic and environmental/ prenatal aetiology of cancer. Several papers have been published from it (see section 5d(ii) for list or previous publications and number of times these publications have been cited in the scientific literature). The study needs to be maintained so that in 5 years time ICR can run updated analyses, to be updated in the future with additional follow-up, which would lead to future publications. 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. The processing is record linkage to NHS-England deaths and cancer notifications for scientific analyses. The processing is record linkage to NHS-Digital deaths and cancer notifications for scientific analyses. The standard statistical analyses are those for cohort studies comparing rates in the cohort with published rates in the general population. Results are presented as summary measures or regression coefficients from statistical models. No identifiable level data would be published and results are reviewed for small number suppression to protect confidentiality. BACKGROUND: [2 paragraphs unchanged] 1) A cohort study of cancer incidence and of mortality in 29,500 patients in the UK with insulin-treated diabetes diabetes. 2) A cohort study of 48,000 patients with cytogenetic disorders from across Britain diagnosed up to 40 years ago… ago. 3) A cohort study of patients with paediatric endocrine diseases diseases. 4) A national study of cancer in twins twins. [1 paragraph unchanged] A cohort study is the methodologically most rigorous study design that can be undertaken of long-term cancer and mortality risks in such patients, and the ICR believes it is the only cancer study of its type in the UK, and for several cancers (e.g. testicular cancer, premenopausal breast cancer) it is much the largest of its type internationally. Several papers have been published from it, and it needs to be extended by updated and future follow-up. The cohort is fully flagged and no new patients will be identified or flagged. Therefore, ICR will not be sending direct identifiable data to NHS-England. ICR only received downloads from NHS-England for data items required for analysis. The direct identifiable data ICR hold for the study is retained to ensure Medical Research Council good practice guidelines have been met on data retention for veracity in research. These guidelines are an important ethical and scientific obligation on researchers because of the requirement to be able to respond, should the need arise, to queries regarding alleged fraud and scientific inveracity, and to prove that the results published from this study are indeed as they purport to be and data were correctly collected and analysed: this requirement could not currently be met in this study without the ability to go back to original records via their direct identifiers. ICR have reviewed this again during the year (2022), and it remains the case that the current NHS systems would not enable data files to be linked and paper records to be reliably found without identifiers. Conducting such a study, on a larger scale than elsewhere, will provide the best, most powerful, data available to patients and their doctors about the long-term hazards of these conditions. This will lead to better information for patients and their families; to improved prognostic data for patient advice, and to improved clinical follow-up, and where needed, screening. This is the objective and why the Institute of Cancer Research (ICR) is undertaking the study. The Institute of Cancer Research is the sole controller who will also process the data. No other organisations are involved in the project. The study is generating new data on cancer risks in order to: The study was originally set-up with funding by Office of Population Censuses and Surveys (OPCS) and the Cancer Research Campaign (Now Cancer Research UK). Funding is no longer received from these organisations and the minimal maintenance costs for the study come from discretionary funds held by the Principal Investigator (at ICR). 1. Provide information for patients and their relatives (especially twins, but also more widely), and from which clinicians can base advice, about familial and genetic risks of cancer. The likely risks of cancer in close members of their family is a major concern for cancer patients, on which they desire rigorous information. 2. Provide information for guidance on follow-up strategies of relatives who may need preventive actions or early detection e.g. by enhanced screening protocols. 3. Provide information for health service planning and service provision of genetics and high risk clinics and screening services for cancer patients and their families. 4. Improve understanding of disease aetiology and hence prevention by illuminating the extent to which familial cancer risks are explicable by genes already known, which model of genetic aetiology would fit with twin data, and the extent of potentially modifiable, environmental/behavioural and prenatal causes of these cancers.

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. The study subjects were identified and flagged on the OPCS (now NHS England) and Scottish NHS Central Register computer systems more than 20 years ago and flagged for cancer incidence, mortality, and exits from risk. They had mainly been identified internally at OPCS by matching national cancer registry files on all cancer registrations for residents of England and Wales born since 29th September 1939 and registered incident in England and Wales during 1971-1984 with the National Health Service Central Register (NHSCR) and the national birth register. Cancer patients born in Scotland (i.e., with Scottish NHS numbers) were similarly traced at the Scottish NHSCR in Edinburgh, to determine their twin status and birth order. Also, for breast cancer, testicular cancer and ovarian cancer, this was extended to earlier years using birth microfiches from OPCS and by sending the identified records to OPCS for flagging. The study data, including data provided by NHS Digital under previous agreements, are currently held by The Institute of Cancer Research. ICR holds the data on the twin study subjects and follow-up data up to the present (sent by NHS England and predecessor organisations over the last >20 years). There is no requirement for new data under this Agreement. At a later date, under a future iteration of the Agreement, ICR would seek updated follow-up data on cancer incidence, mortality and other losses to follow-up to enable analyses of cancer incidence and cause-specific mortality risks over longer periods for the benefit of current and future patients, and their health care. The following provides background on the processing activities undertaken prior to this Agreement: No new data will be shared with NHS England. NHS England routinely supplies data to the ICR and these data are stored and processed in the Epidemiology secure data safe haven, a part of the ICR network with additional security to meet Data Security and Protection (DSP) Toolkit requirements. These data are used only for analyses for the approved medical research project identified above. The data are not linked to datasets other than the ONS/NHS England data. The study subjects were identified and flagged on the OPCS (now NHS Digital) and Scottish NHSCR computer systems more than 20 years ago and flagged for cancer incidence, mortality, and exits from risk. They had mainly been identified internally at OPCS by matching national cancer registry files on all cancer registrations for residents of England and Wales born since 29th September 1939 and registered incident in England and Wales during 1971-1984 with the National Health Service Central Register (NHSCR) and the national birth register. Cancer patients born in Scotland (i.e., with Scottish NHS numbers) were similarly traced at the Scottish NHSCR in Edinburgh, to determine their twin status and birth order. Also, for breast cancer, testicular cancer and ovarian cancer, this was extended to earlier years using birth microfiches from OPCS and sent the identified records to OPCS for flagging. For historical purposes, after the data sent by NHS England have been linked, the analysis was conducted on pseudonymised files within the data safe haven. The data would be accessed and analysed by authorised researchers at ICR, in order to produce the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS England. Data would only be accessed by individuals within the ICR who have authorisation from the Principal Investigator at the ICR. Access will only be authorised for the purposes described and for individuals who are substantive employees of the ICR. ICR already holds the data on the twin study subjects and follow-up data up to the present (sent by NHS Digital and predecessor organisations over the last >20 years) and needs continuing follow-up data on cancer incidence, mortality and other losses to follow-up to enable analyses of cancer incidence and cause-specific mortality risks over longer periods for the benefit of current and future patients, and their health care. No new data will be shared with NHS digital. NHS Digital routinely supplies data to the ICR. These data are used only for analyses for the approved medical research project identified above. The standard statistical analyses are those for cohort studies comparing rates in the cohort with published rates in the general population. Results are presented as summary measures or regression coefficients from statistical models. No identifiable level data would be published and results are reviewed for small number suppression to protect confidentiality. The data are not linked to datasets other than the ONS/NHS Digital data. Identifiable data are required to ensure accurate linkages of individual patients’ data. After the data sent by NHS Digital have been linked, the analysis is conducted on pseudo-anonymised files. The data will be accessed and analysed by authorised researchers at ICR, in order to produce the analyses described above, which are the purpose of the study and the purpose of obtaining the data from NHS Digital. For clarity, Deepstore do not process the data. Deepstore are a secure off-site storage facility where ICR stores backup tapes. Any access by Deepstore Ltd to data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. Data will only be accessed by individuals within the ICR who have authorisation from the Chief Investigator, who is the Head of the Epidemiology Team at the ICR. Access will only be authorised for the purposes described and for individuals who are substantive employees of the ICR. All organisations party to this Agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract - i.e. employees, agents and contractors of the Data Recipient who may have access to that data).

Expected output

This Agreement permits the secure retention of the data only and no other processing. There is no intention to produce any new outputs under this Data Sharing Agreement. No new data is being requested under this agreement. ICR intend to acquire the latest available follow-up information in 2028 and will then evaluate if there was sufficient new results to justify new analyses and publication. No new outputs will be produced under this Data Sharing Agreement. However it is planned that future outputs will include published papers with longer follow-up over the next 20 years in high-profile peer-reviewed scientific journals on the risks of site-specific cancer incidence and cause-specific mortality in twins. In 2028, ICR intend to acquire the latest available follow-up information on the cohort. There should sufficient new events, and there will be longer follow-up, to allow new scientific analyses and publications. The research was initially funded by OPCS and the Cancer Research Campaign (now Cancer Research UK). It has produced several high-profile publications, so NHS England can be assured that it will do so again with longer follow-up and hence more valuable results to inform patients and clinicians on risks. It will also enable far longer-term risks to be assessed than has previously been possible. However it is planned that future outputs will include published papers with longer follow-up over the next 20 years in high-profile peer-reviewed scientific journals on the risks of site-specific cancer incidence and cause-specific mortality in twins. The research was initially funded by OPCS and the Cancer Research Campaign (now Cancer Research UK). It has produced several high-profile publications, so NHS Digital can be assured that it will do so again with longer follow-up and hence more valuable results to inform patients and clinicians on risks. It will also enable far longer-term risks to be assessed than has previously been possible. ICR will publicise the results to patients and society more widely by press releases and blogs, to professional standard, from the Institute’s very active communications department, information sent to patient-centred charities and help groups and put on the ICR’s website, and by talks given to patient and lay groups as well as to appropriate medical specialty conferences, meetings and seminars. Results would be presented as summary measures or regression coefficients from statistical models. No identifiable level data would be published, and results would be reviewed for small number suppression to protect confidentiality. ICR will publicise the results to patients and society more widely by press releases and blogs, to professional standard, from the Institute’s very active communications department, information sent to patient-centred charities and help groups and put on the ICR’s website, and by talks given to patient and lay groups as well as to appropriate medical specialty conferences, meetings and seminars. Below are a list of publications, with the number of times the paper has been cited in square brackets (from Google Scholar). Swerdlow et al., A population-based study of cancer risk in twins: relationships to birth order and sexes of the twin pair. Int J Cancer. 1996; 67:472-8 [34] Swerdlow et al., Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 1997;350:1729-8 [247] Swerdlow et al., Risk factors for testicular cancer: a case-control study in twins. Br J Cancer. 1999;80:1098-102 [78] Swerdlow et al., Risk factors for breast cancer at young ages in twins: an international population-based study. J Natl Cancer Inst. 2002;94:1238-46 [59]

Expected measurable benefits

[1 paragraph unchanged] Twin studies have unique potential to investigate both genetic and environmental/behavioural genetic, environmental, behavioural and prenatal aspects of disease aetiology, as well as to provide data [120 words unchanged] good reason to be concerned about long-term serious risks for family members. Overall the study would enable patients, their families and clinicians to undertake [8 words unchanged] of cancer, and hence to embark on a more personalised care pathway. In particular: 1. The study will contribute to information on relative and absolute risks of cancer incidence and site-specific mortality, for the benefit of patients and their relatives (especially twins, but also more generally), and from which clinicians can base advice, about familial and genetic risks of cancer. The likely risks of cancer in close members of their family is a major concern for cancer patients, on which they desire rigorous information. The likely risks of cancer in close members of their family is [82 words unchanged] patient-centred and effective follow-up, earlier diagnosis of adverse events, and improved outcomes. In particular: 2. Information on genetic risks is also important to health service planning and service provision of genetics and high risk clinics, and of high risk screening services as well as for health service resource distribution and costings for these services. 1) The study will contribute to information on relative and absolute risks of cancer incidence and site-specific mortality, for the benefit of patients and their relatives (especially twins, but also more generally), and from which clinicians can base advice, about familial and genetic risks of cancer. 3. The study will improve understanding of disease aetiology and hence prevention by illuminating the extent to which familial cancer risks are explicable by genes already known, which model of genetic aetiology would fit with twin data, and the extent of potentially modifiable, environmental/behavioural and prenatal causes of these cancers. 2) Provide information for guidance on follow-up strategies of relatives who may need preventive actions or early detection e.g. by enhanced screening protocols. Previous outputs from this study have been widely used, as evidenced by the citation rates of the papers (in square brackets below): 3) Information on genetic risks is also important to health service planning and service provision of genetics and high risk clinics, and of high risk screening services as well as for health service resource distribution and costings for these services. Swerdlow et al., Lancet 1997;350:1729-8 [204] 4) The study will improve understanding of disease aetiology and hence prevention by illuminating the extent to which familial cancer risks are explicable by genes already known, which model of genetic aetiology would fit with twin data, and the extent of potentially modifiable, environmental, behavioural, and prenatal causes of these cancers. Swerdlow et al., J Natl Cancer Inst. 2002;94:1238-46 [47] One measure of the success will be the number of times new scientific publications from the study are cited in the scientific or medical literature (as measured by Google Scholar). One previous publication from the study has over 200 citations and we expect future output to also have an impact. However, we do not plan further publications until the follow-up time in the cohort has increased by around another five years. Swerdlow et al., Int J Cancer. 1996; 67:472-8 [27] Previous outputs from this study have been widely used in reference (citation) in papers. Swerdlow et al., Br J Cancer. 1999;80:1098-102 [65]

Benefits reported

The next set of publications are planned for 5 years from now when the follow-up has accrued. Scientific publications from this study have provided information on the risks of cancer in twins and the aetiology of cancers, the results have contributed to the body of scientific knowledge on the causes of cancer (as evidenced by the number of times each paper has been cited). Online publications can be seen on the below web-links: A population-based study of cancer risk in twins: relationships to birth order and sexes of the twin pair. - https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0215(19960807)67:4%3C472::AID-IJC2%3E3.0.CO;2-P Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. - https://www.sciencedirect.com/science/article/pii/S0140673697055268?via%3Dihub Risk factors for testicular cancer: a case-control study in twins. - https://www.nature.com/articles/6690470 Risk factors for breast cancer at young ages in twins: an international population-based study. - https://academic.oup.com/jnci/article/94/16/1238/2912270?login=true The scientific results from this twins cancer cohort have given novel, objective data relating to prenatal and infectious disease aetiology of cancer risk in relation to birth order and sex of twins. The results have increased ICR’s understanding of the aetiology of some cancers that higher risks of breast and testicular cancers in dizygotic than in monozygotic twins support a prenatal aetiology. The risk associated with cryptorchidism in the twins accords with the hypothesis that cryptorchidism is causally associated with testicular cancer because it is a cause of the malignancy, rather than because the same maternal factors experienced in utero cause both conditions. Childhood growth before puberty may affect the risk of premenopausal breast cancer and the distribution of body fat in young adulthood may also be related to breast cancer risk. The results for twins of probands with cancer have implications for genetic aetiology; appropriate clinical action for monozygotic twins needs consideration. This information about risks of cancers in twins is hoped to be helpful in-patient education and cancer risk counselling. The next set of publications are planned after 2028 when further follow-up has accrued.

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

Expected output

[2 paragraphs unchanged] The However it is planned that future outputs will include published papers in high-profile peer-reviewed scientific journals, submitted over the next 3 years, and subsequently further papers with longer follow-up over the next 20 years in high-profile peer-reviewed scientific journals on the risks of site-specific cancer incidence and cause-specific mortality in twins. [52 words unchanged] enable far longer-term risks to be assessed than has previously been possible. [1 paragraph unchanged]

Benefits reported

Not stated in the previous version; added here.

The next set of publications are planned for 5 years from now when the follow-up has accrued.

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

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

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling The Institute of Cancer Research to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). The following provides background information on the purpose of the original study: [17 paragraphs unchanged]

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. The study data, including data provided by NHS Digital under previous agreements, are currently held by The Institute of Cancer Research. The following provides background on the processing activities undertaken prior to this Agreement: [5 paragraphs unchanged]

Expected output

This Agreement permits the secure retention of the data only and no other processing. No new outputs will be produced under this Data Sharing Agreement. [2 paragraphs unchanged]

Expected measurable benefits

[6 paragraphs unchanged] Previous outputs from this study have been widely used, as evidenced by the citation rates of the papers (in square brackets below): Swerdlow et al., Lancet 1997;350:1729-8 [204] Swerdlow et al., J Natl Cancer Inst. 2002;94:1238-46 [47] Swerdlow et al., Int J Cancer. 1996; 67:472-8 [27] Swerdlow et al., Br J Cancer. 1999;80:1098-102 [65]

Benefits reported

Stated in the previous version and removed here.

Previous outputs from this study have been widely used, as evidenced by the very high citation rates of the papers (in square brackets below):

Swerdlow et al., Lancet 1997;350:1729-8 [204]

Swerdlow et al., J Natl Cancer Inst. 2002;94:1238-46 [47]

Swerdlow et al., Int J Cancer. 1996; 67:472-8 [27]

Swerdlow et al., Br J Cancer. 1999;80:1098-102 [65]