MR465 - National Cohort study of mortality and cancer incidence in patients with cytogenetic and paediatric endocrine disorders

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:

The Institute of Cancer Research requires mortality, cancer incidence and demographic data for the purpose of a national cohort study of mortality and cancer incidence in patients with cytogenetic and paediatric endocrine disorders.

For more than 20 years, the Institute of Cancer Research, has been conducting a national cohort study in Britain of cancer incidence and cause-specific mortality risks in long-term follow-up of patients with cytogenetic disorders and paediatric endocrine disorders. Because modern treatments have led to greatly improved survival of patients with chronic diseases, the issue of long-term consequences of the diseases and their treatments has become an important one for advice to patients and (for children) to their parents. It is also important to clinicians deciding about treatment of diseases and the balance of benefit versus side-effects and complications, and to the Health Service, because of the costs accruing for continued follow-up and care of these patients and the planning required to take account of long-term consequences and to plan strategies, where possible, for their prevention and early detection. There is a great desire on the part of parents of children born with cytogenetic abnormalities and parents of children with endocrine diseases to know about their child’s prognosis. The conditions are ones where there is reason to be concerned about long-term mortality and cancer risks, and a deficiency of large-scale cohort information about this.

This is a very long-running study which began in the mid-1990s. The data was originally collected with appropriate national ethics agreement. There have been numerous changes in legislation since but at that time approval from an ethics committee was accepted as sufficient approval. After the Patient Information Advisory Group (PIAG) came into existence in 2001, this and other cohort studies run by the Institute of Cancer Research were given support under section 60 of the Health and Social Care Act 2001 (reference PIAG 3-07(j)2002). On PIAG’s advice, the ICR submitted a single application for s60 support for four cohort studies and this was approved.

The four cohort studies were (as named in the PIAG application):

1) A cohort study of cancer incidence and of mortality in 29,500 patients in the UK with insulin-treated diabetes

2) A cohort study of 48,000 patients with cytogenetic disorders from across Britain diagnosed up to 40 years ago…

3) A cohort study of patients with paediatric endocrine diseases

4) A national study of cancer in twins

For clarification, the data provided under this Agreement relates to cohorts 2 and 3 as described in the PIAG application. A single cohort was flagged under MR465 which encompasses both patients with cytogenetic abnormalities/disorders and patients with paediatric endocrine disorders. There is a large overlap between cytogenetic and paediatric endocrine disorders – several major paediatric endocrine conditions are due to cytogenetic abnormalities, so these individuals can be identified either via paediatric endocrine or cytogenetics records. For instance, Turner syndrome is one of the most common paediatric endocrine disorders, with abnormalities of oestrogen and growth hormone levels, and often of thyroid hormones. It is caused, however, by absence of an X chromosome, diagnosed by cytogenetics. The cohort included individuals identified from both sources, with the duplicates removed.

The cohort studies numbered 1 and 4 above are covered by the same section 251 support but are not in the scope of this Agreement.

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 this cohort is the largest worldwide. It includes 27,000 patients, diagnosed since as far back as records at the clinical centres were available – at earliest 1959 (i.e. almost 60 years ago). For the cytogenetic conditions it included patients from a base population of >55 million (Britain) and in several centres back to when cytogenetic diagnosis first became technically possible, worldwide. From this, approximately 27,000 patients from England, Wales and Scotland were selected for study based on the conditions of greatest priority to the study.

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. ICR has worked with leading paediatric endocrinologists and cytogenetics laboratories across Britain to assemble the cohort and with leading paediatric endocrinologists, geneticists and cytogeneticists (including the scientist who discovered several of the cytogenetic conditions) to interpret the results. However, no other organisations, apart from the ICR, will be involved in handling the data.

A cohort study, by definition, follows people with exposure information already collected (in this instance diagnostic information) to ascertain their subsequent risks of morbidity and/or mortality. ICR already holds the exposure (diagnostic) data (from laboratory and clinical sources) 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, their parents, and their health care.

ICR process data under Article 6 of EU GDPR the legal basis for the processing of personal data is that this is necessary to perform a task in the public interest and the exemption for the processing of special category personal data (Article 6(2)(e)).

Under Article 9 of EU GDPR is that the processing is necessary for scientific research purposes (Article 9 (2)(j)).

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.

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.

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, submitted on the risks of cancer incidence and cause-specific mortality in patients with these conditions, with separate papers for different underlying conditions (see below, for examples).

The research was initially funded by the Medical Research Council, as part of a programme of health-related peer reviewed research, funded by them, and 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. The extended follow-up will also enable analyses of less-common conditions that ICR was unable to publish in the previous round of analyses because of limited numbers of cancers and deaths, and for which there are currently no published analyses available for parents and clinicians on risks of cancer and mortality. It will also enable far longer-term risks to be assessed (up to 60 years follow-up) than has previously been possible.

ICR will publicise the results to patients, their parents, and society more widely by press releases and blogs, to professional standard, from the Institute͛'s very active communications department; from information sent to patient-centred charities and help groups and put on our website, and by talks given to patient and lay groups as well as to appropriate medical speciality (paediatric endocrinology and genetics) conferences, meetings and seminars.

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

Swerdlow et al., Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97:1204-10 [215 citations],

Swerdlow et al., Mortality in patients with Klinefelter͛s syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90:6516-22 [160 citations],

Schoemaker et al., Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93:4735-42 [160 citations],

Schoemaker et al., Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 2008;9:239-46 [112 citations],

Swerdlow et al., Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65:177-88 [169 citations],

Higgins et al. Mortality and cancer incidence in males with Y polysomy in Britain: a cohort study. Hum Genet 2007; 121:691-6 [21 citations],

Swerdlow et al., Mortality risks in patients with constitutional autosomal chromosome deletions in Britain: a cohort study. Hum Genet 2008; 123;215-24 [7 citations],

Swerdlow et al., Cancer risk in patients with chromosome deletions: a nationwide British cohort study. Br J Cancer 2008; 98:1929-33 9 [11 citations],

Swerdlow et al., Mortality and cancer incidence in women with extra X chromosomes: a cohort study in Britain. Hum Genet 2005; 118:255-60 [17 citations],

Swerdlow et al., Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr 1998; 133:51620 [62 citations],

Schoemaker et al., Mortality and Cancer Incidence in Carriers of Balanced Robertsonian Translocations: a National Cohort Study. Am J Epidemiol 2019; 18:500-508,

Schoemaker et al., Mortality and cancer incidence in carriers of constitutional t(11;22)(q23;q11) translocations: a prospective study. Int J Cancer. 2019; 145:1493-1498.

Further evidence is the use for these studies in constructing and assessing clinical practice guidelines (e.g. Gravholt et al., Clinical practice guidelines for the care of girls and women with Turner Syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;117:G1-G70. Leblicq et al., Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed? J Pediatr 2011; 158:492-498. Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. Onkopedia Guidelines. Klinefelter Syndrome and Cancer. DGHO; Berlin, Recommendations from the society for diagnosis and therapy of haematological and oncological diseases. Bondy et al., Care of girls and women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2006;92:10-25).

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

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:

The Institute of Cancer Research requires mortality, cancer incidence and demographic data for the purpose of a national cohort study of mortality and cancer incidence in patients with cytogenetic and paediatric endocrine disorders.

For more than 20 years, the Institute of Cancer Research, has been conducting a national cohort study in Britain of cancer incidence and cause-specific mortality risks in long-term follow-up of patients with cytogenetic disorders and paediatric endocrine disorders. Because modern treatments have led to greatly improved survival of patients with chronic diseases, the issue of long-term consequences of the diseases and their treatments has become an important one for advice to patients and (for children) to their parents. It is also important to clinicians deciding about treatment of diseases and the balance of benefit versus side-effects and complications, and to the Health Service, because of the costs accruing for continued follow-up and care of these patients and the planning required to take account of long-term consequences and to plan strategies, where possible, for their prevention and early detection. There is a great desire on the part of parents of children born with cytogenetic abnormalities and parents of children with endocrine diseases to know about their child’s prognosis. The conditions are ones where there is reason to be concerned about long-term mortality and cancer risks, and a deficiency of large-scale cohort information about this.

This is a very long-running study which began in the mid-1990s. The data was originally collected with appropriate national ethics agreement. There have been numerous changes in legislation since but at that time approval from an ethics committee was accepted as sufficient approval. After the Patient Information Advisory Group (PIAG) came into existence in 2001, this and other cohort studies run by the Institute of Cancer Research were given support under section 60 of the Health and Social Care Act 2001 (reference PIAG 3-07(j)2002). On PIAG’s advice, the ICR submitted a single application for s60 support for four cohort studies and this was approved.

The four cohort studies were (as named in the PIAG application):

1) A cohort study of cancer incidence and of mortality in 29,500 patients in the UK with insulin-treated diabetes

2) A cohort study of 48,000 patients with cytogenetic disorders from across Britain diagnosed up to 40 years ago…

3) A cohort study of patients with paediatric endocrine diseases

4) A national study of cancer in twins

For clarification, the data provided under this Agreement relates to cohorts 2 and 3 as described in the PIAG application. A single cohort was flagged under MR465 which encompasses both patients with cytogenetic abnormalities/disorders and patients with paediatric endocrine disorders. There is a large overlap between cytogenetic and paediatric endocrine disorders – several major paediatric endocrine conditions are due to cytogenetic abnormalities, so these individuals can be identified either via paediatric endocrine or cytogenetics records. For instance, Turner syndrome is one of the most common paediatric endocrine disorders, with abnormalities of oestrogen and growth hormone levels, and often of thyroid hormones. It is caused, however, by absence of an X chromosome, diagnosed by cytogenetics. The cohort included individuals identified from both sources, with the duplicates removed.

The cohort studies numbered 1 and 4 above are covered by the same section 251 support but are not in the scope of this Agreement.

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 this cohort is the largest worldwide. It includes 27,000 patients, diagnosed since as far back as records at the clinical centres were available – at earliest 1959 (i.e. almost 60 years ago). For the cytogenetic conditions it included patients from a base population of >55 million (Britain) and in several centres back to when cytogenetic diagnosis first became technically possible, worldwide. From this, approximately 27,000 patients from England, Wales and Scotland were selected for study based on the conditions of greatest priority to the study.

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. ICR has worked with leading paediatric endocrinologists and cytogenetics laboratories across Britain to assemble the cohort and with leading paediatric endocrinologists, geneticists and cytogeneticists (including the scientist who discovered several of the cytogenetic conditions) to interpret the results. However, no other organisations, apart from the ICR, will be involved in handling the data.

A cohort study, by definition, follows people with exposure information already collected (in this instance diagnostic information) to ascertain their subsequent risks of morbidity and/or mortality. ICR already holds the exposure (diagnostic) data (from laboratory and clinical sources) 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, their parents, and their health care.

ICR process data under Article 6 of EU GDPR the legal basis for the processing of personal data is that this is necessary to perform a task in the public interest and the exemption for the processing of special category personal data (Article 6(2)(e)).

Under Article 9 of EU GDPR is that the processing is necessary for scientific research purposes (Article 9 (2)(j)).

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.

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.

The planned outputs will include several published papers in high-profile peer-reviewed scientific journals, submitted over the next 2-3 years on the risks of cancer incidence and cause-specific mortality in patients with these conditions, with separate papers for different underlying conditions (see below, for examples). However, ICR are still awaiting release of cancer registration data from NHS Digital, which has been delayed for a year or more now, and is needed before sending papers for publication.

The research was initially funded by the Medical Research Council, as part of a programme of health-related peer reviewed research, funded by them, and 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. The extended follow-up will also enable analyses of less-common conditions that ICR was unable to publish in the previous round of analyses because of limited numbers of cancers and deaths, and for which there are currently no published analyses available for parents and clinicians on risks of cancer and mortality. It will also enable far longer-term risks to be assessed (up to 60 years follow-up) than has previously been possible.

ICR will publicise the results to patients, their parents, and society more widely by press releases and blogs, to professional standard, from the Institute͛'s very active communications department; from information sent to patient-centred charities and help groups and put on our website, and by talks given to patient and lay groups as well as to appropriate medical speciality (paediatric endocrinology and genetics) conferences, meetings and seminars.

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

Swerdlow et al., Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97:1204-10 [215 citations],

Swerdlow et al., Mortality in patients with Klinefelter͛s syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90:6516-22 [160 citations],

Schoemaker et al., Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93:4735-42 [160 citations],

Schoemaker et al., Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 2008;9:239-46 [112 citations],

Swerdlow et al., Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65:177-88 [169 citations],

Higgins et al. Mortality and cancer incidence in males with Y polysomy in Britain: a cohort study. Hum Genet 2007; 121:691-6 [21 citations],

Swerdlow et al., Mortality risks in patients with constitutional autosomal chromosome deletions in Britain: a cohort study. Hum Genet 2008; 123;215-24 [7 citations],

Swerdlow et al., Cancer risk in patients with chromosome deletions: a nationwide British cohort study. Br J Cancer 2008; 98:1929-33 9 [11 citations],

Swerdlow et al., Mortality and cancer incidence in women with extra X chromosomes: a cohort study in Britain. Hum Genet 2005; 118:255-60 [17 citations],

Swerdlow et al., Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr 1998; 133:51620 [62 citations],

Schoemaker et al., Mortality and Cancer Incidence in Carriers of Balanced Robertsonian Translocations: a National Cohort Study. Am J Epidemiol 2019; 18:500-508,

Schoemaker et al., Mortality and cancer incidence in carriers of constitutional t(11;22)(q23;q11) translocations: a prospective study. Int J Cancer. 2019; 145:1493-1498.

Further evidence is the use for these studies in constructing and assessing clinical practice guidelines (e.g. Gravholt et al., Clinical practice guidelines for the care of girls and women with Turner Syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;117:G1-G70. Leblicq et al., Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed? J Pediatr 2011; 158:492-498. Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. Onkopedia Guidelines. Klinefelter Syndrome and Cancer. DGHO; Berlin, Recommendations from the society for diagnosis and therapy of haematological and oncological diseases. Bondy et al., Care of girls and women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2006;92:10-25).

The Institute of Cancer Research requires mortality, cancer incidence and demographic data for the purpose of a national cohort study of mortality and cancer incidence in patients with cytogenetic and paediatric endocrine disorders.

For more than 20 years, the Institute of Cancer Research, has been conducting a national cohort study in Britain of cancer incidence and cause-specific mortality risks in long-term follow-up of patients with cytogenetic disorders and paediatric endocrine disorders. Because modern treatments have led to greatly improved survival of patients with chronic diseases, the issue of long-term consequences of the diseases and their treatments has become an important one for advice to patients and (for children) to their parents. It is also important to clinicians deciding about treatment of diseases and the balance of benefit versus side-effects and complications, and to the Health Service, because of the costs accruing for continued follow-up and care of these patients and the planning required to take account of long-term consequences and to plan strategies, where possible, for their prevention and early detection. There is a great desire on the part of parents of children born with cytogenetic abnormalities and parents of children with endocrine diseases to know about their child’s prognosis. The conditions are ones where there is reason to be concerned about long-term mortality and cancer risks, and a deficiency of large-scale cohort information about this.

This is a very long-running study which began in the mid-1990s. The data was originally collected with appropriate national ethics agreement. There have been numerous changes in legislation since but at that time approval from an ethics committee was accepted as sufficient approval. After the Patient Information Advisory Group (PIAG) came into existence in 2001, this and other cohort studies run by the Institute of Cancer Research were given support under section 60 of the Health and Social Care Act 2001 (reference PIAG 3-07(j)2002). On PIAG’s advice, the ICR submitted a single application for s60 support for four cohort studies and this was approved.

The four cohort studies were (as named in the PIAG application):

1) A cohort study of cancer incidence and of mortality in 29,500 patients in the UK with insulin-treated diabetes

2) A cohort study of 48,000 patients with cytogenetic disorders from across Britain diagnosed up to 40 years ago…

3) A cohort study of patients with paediatric endocrine diseases

4) A national study of cancer in twins

For clarification, the data provided under this Agreement relates to cohorts 2 and 3 as described in the PIAG application. A single cohort was flagged under MR465 which encompasses both patients with cytogenetic abnormalities/disorders and patients with paediatric endocrine disorders. There is a large overlap between cytogenetic and paediatric endocrine disorders – several major paediatric endocrine conditions are due to cytogenetic abnormalities, so these individuals can be identified either via paediatric endocrine or cytogenetics records. For instance, Turner syndrome is one of the most common paediatric endocrine disorders, with abnormalities of oestrogen and growth hormone levels, and often of thyroid hormones. It is caused, however, by absence of an X chromosome, diagnosed by cytogenetics. The cohort included individuals identified from both sources, with the duplicates removed.

The cohort studies numbered 1 and 4 above are covered by the same section 251 support but are not in the scope of this Agreement.

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 this cohort is the largest worldwide. It includes 27,000 patients, diagnosed since as far back as records at the clinical centres were available – at earliest 1959 (i.e. almost 60 years ago). For the cytogenetic conditions it included patients from a base population of >55 million (Britain) and in several centres back to when cytogenetic diagnosis first became technically possible, worldwide. From this, approximately 27,000 patients from England, Wales and Scotland were selected for study based on the conditions of greatest priority to the study.

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. ICR has worked with leading paediatric endocrinologists and cytogenetics laboratories across Britain to assemble the cohort and with leading paediatric endocrinologists, geneticists and cytogeneticists (including the scientist who discovered several of the cytogenetic conditions) to interpret the results. However, no other organisations, apart from the ICR, will be involved in handling the data.

A cohort study, by definition, follows people with exposure information already collected (in this instance diagnostic information) to ascertain their subsequent risks of morbidity and/or mortality. ICR already holds the exposure (diagnostic) data (from laboratory and clinical sources) 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, their parents, and their health care.

ICR process data under Article 6 of EU GDPR the legal basis for the processing of personal data is that this is necessary to perform a task in the public interest and the exemption for the processing of special category personal data (Article 6(2)(e)).

Under Article 9 of EU GDPR is that the processing is necessary for scientific research purposes (Article 9 (2)(j)).

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 planned outputs will include several published papers in high-profile peer-reviewed scientific journals, submitted over the next 2-3 years on the risks of cancer incidence and cause-specific mortality in patients with these conditions, with separate papers for different underlying conditions (see below, for examples). However, ICR are still awaiting release of cancer registration data from NHS Digital, which has been delayed for a year or more now, and is needed before sending papers for publication.

The research was initially funded by the Medical Research Council, as part of a programme of health-related peerreviewed research, funded by them, and 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. The extended follow-up will also enable analyses of less-common conditions that ICR was unable to publish in the previous round of analyses because of limited numbers of cancers and deaths, and for which there are currently no published analyses available for parents and clinicians on risks of cancer and mortality. It will also enable far longer-term risks to be assessed (up to 60 years follow-up) than has previously been possible.

ICR will publicise the results to patients, their parents, and society more widely by press releases and blogs, to professional standard, from the Institute͛s very active communications department; from information sent to patient-centred charities and help groups and put on our website, and by talks given to patient and lay groups as well as to appropriate medical speciality (paediatric endocrinology and genetics) conferences, meetings and seminars.

All results are summary statistical analyses and individuals cannot be identified from these results.

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

Swerdlow et al., Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97:1204-10 [215 citations],

Swerdlow et al., Mortality in patients with Klinefelter͛s syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90:6516-22 [160 citations],

Schoemaker et al., Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93:4735-42 [160 citations],

Schoemaker et al., Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 2008;9:239-46 [112 citations],

Swerdlow et al., Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65:177-88 [169 citations],

Hermon et al., Mortality and cancer incidence in persons with Down͛s syndrome, their parents and siblings. Ann Hum Genet 2001; 65:167-76 [55 citations],

Higgins et al. Mortality and cancer incidence in males with Y polysomy in Britain: a cohort study. Hum Genet 2007; 121:691-6 [21 citations],

Swerdlow et al., Mortality risks in patients with constitutional autosomal chromosome deletions in Britain: a cohort study. Hum Genet 2008; 123;215-24 [7 citations],

Swerdlow et al., Cancer risk in patients with chromosome deletions: a nationwide British cohort study. Br J Cancer 2008; 98:1929-33 9 [11 citations],

Swerdlow et al., Mortality and cancer incidence in women with extra X chromosomes: a cohort study in Britain. Hum Genet 2005; 118:255-60 [17 citations],

Swerdlow et al., Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr 1998; 133:51620 [62 citations],

Schoemaker et al., Mortality and Cancer Incidence in Carriers of Balanced Robertsonian Translocations: a National Cohort Study. Am J Epidemiol 2019; 18:500-508,

Schoemaker et al., Mortality and cancer incidence in carriers of constitutional t(11;22)(q23;q11) translocations: a prospective study. Int J Cancer. 2019; 145:1493-1498.

Further evidence is the use for these studies in constructing and assessing clinical practice guidelines (e.g. Gravholt et al., Clinical practice guidelines for the care of girls and women with Turner Syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;117:G1-G70. Leblicq et al., Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed? J Pediatr 2011; 158:492-498. Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. Onkopedia Guidelines. Klinefelter Syndrome and Cancer. DGHO; Berlin, Recommendations from the society for diagnosis and therapy of haematological and oncological diseases. Bondy et al., Care of girls and women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2006;92:10-25).

The Institute of Cancer Research requires mortality, cancer incidence and demographic data for the purpose of a national cohort study of mortality and cancer incidence in patients with cytogenetic and paediatric endocrine disorders.

For more than 20 years, the Institute of Cancer Research, has been conducting a national cohort study in Britain of cancer incidence and cause-specific mortality risks in long-term follow-up of patients with cytogenetic disorders and paediatric endocrine disorders. Because modern treatments have led to greatly improved survival of patients with chronic diseases, the issue of long-term consequences of the diseases and their treatments has become an important one for advice to patients and (for children) to their parents. It is also important to clinicians deciding about treatment of diseases and the balance of benefit versus side-effects and complications, and to the Health Service, because of the costs accruing for continued follow-up and care of these patients and the planning required to take account of long-term consequences and to plan strategies, where possible, for their prevention and early detection. There is a great desire on the part of parents of children born with cytogenetic abnormalities and parents of children with endocrine diseases to know about their child’s prognosis. The conditions are ones where there is reason to be concerned about long-term mortality and cancer risks, and a deficiency of large-scale cohort information about this.

This is a very long-running study which began in the mid-1990s. The data was originally collected with appropriate national ethics agreement. There have been numerous changes in legislation since but at that time approval from an ethics committee was accepted as sufficient approval. After the Patient Information Advisory Group (PIAG) came into existence in 2001, this and other cohort studies run by the Institute of Cancer Research were given support under section 60 of the Health and Social Care Act 2001 (reference PIAG 3-07(j)2002). On PIAG’s advice, the ICR submitted a single application for s60 support for four cohort studies and this was approved.

The four cohort studies were (as named in the PIAG application):

1) A cohort study of cancer incidence and of mortality in 29,500 patients in the UK with insulin-treated diabetes

2) A cohort study of 48,000 patients with cytogenetic disorders from across Britain diagnosed up to 40 years ago…

3) A cohort study of patients with paediatric endocrine diseases

4) A national study of cancer in twins

For clarification, the data provided under this Agreement relates to cohorts 2 and 3 as described in the PIAG application. A single cohort was flagged under MR465 which encompasses both patients with cytogenetic abnormalities/disorders and patients with paediatric endocrine disorders. There is a large overlap between cytogenetic and paediatric endocrine disorders – several major paediatric endocrine conditions are due to cytogenetic abnormalities, so these individuals can be identified either via paediatric endocrine or cytogenetics records. For instance, Turner syndrome is one of the most common paediatric endocrine disorders, with abnormalities of oestrogen and growth hormone levels, and often of thyroid hormones. It is caused, however, by absence of an X chromosome, diagnosed by cytogenetics. The cohort included individuals identified from both sources, with the duplicates removed.

The cohort studies numbered 1 and 4 above are covered by the same section 251 support but are not in the scope of this Agreement.

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 this cohort is the largest worldwide. It includes 27,000 patients, diagnosed since as far back as records at the clinical centres were available – at earliest 1959 (i.e. almost 60 years ago). For the cytogenetic conditions it included patients from a base population of >55 million (Britain) and in several centres back to when cytogenetic diagnosis first became technically possible, worldwide. From this, approximately 27,000 patients from England, Wales and Scotland were selected for study based on the conditions of greatest priority to the study.

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. ICR has worked with leading paediatric endocrinologists and cytogenetics laboratories across Britain to assemble the cohort and with leading paediatric endocrinologists, geneticists and cytogeneticists (including the scientist who discovered several of the cytogenetic conditions) to interpret the results. However, no other organisations, apart from the ICR, will be involved in handling the data.

A cohort study, by definition, follows people with exposure information already collected (in this instance diagnostic information) to ascertain their subsequent risks of morbidity and/or mortality. ICR already holds the exposure (diagnostic) data (from laboratory and clinical sources) 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, their parents, and their health care.

The planned outputs will include several published papers in high-profile peer-reviewed scientific journals, submitted over the next 2-3 years on the risks of cancer incidence and cause-specific mortality in patients with these conditions, with separate papers for different underlying conditions (see below, for examples).

The research was initially funded by the Medical Research Council, as part of a programme of health-related peer-reviewed research, funded by them, and 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. The extended follow-up will also enable analyses of less-common conditions that ICR was unable to publish in the previous round of analyses because of limited numbers of cancers and deaths, and for which there are currently no published analyses available for parents and clinicians on risks of cancer and mortality. It will also enable far longer-term risks to be assessed (up to 60 years follow-up) than has previously been possible.

ICR will publicise the results to patients, their parents, and society more widely by press releases and blogs, to professional standard, from the Institute’s very active communications department; from information sent to patient-centred charities and help groups and put on our website, and by talks given to patient and lay groups as well as to appropriate medical speciality (paediatric endocrinology and genetics) conferences, meetings and seminars.

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

Swerdlow et al., Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97:1204-10 [215 citations],

Swerdlow et al., Mortality in patients with Klinefelter’s syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90:6516-22 [160 citations],

Schoemaker et al., Mortality in women with Turner syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. 2008;93:4735-42 [160 citations],

Schoemaker et al., Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol. 2008;9:239-46 [112 citations],

Swerdlow et al., Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 2001; 65:177-88 [169 citations],

Hermon et al., Mortality and cancer incidence in persons with Down’s syndrome, their parents and siblings. Ann Hum Genet 2001; 65:167-76 [55 citations],

Higgins et al. Mortality and cancer incidence in males with Y polysomy in Britain: a cohort study. Hum Genet 2007; 121:691-6 [21 citations],

Swerdlow et al., Mortality risks in patients with constitutional autosomal chromosome deletions in Britain: a cohort study. Hum Genet 2008; 123;215-24 [7 citations],

Swerdlow et al., Cancer risk in patients with chromosome deletions: a nationwide British cohort study. Br J Cancer 2008; 98:1929-33 9 [11 citations],

Swerdlow et al., Mortality and cancer incidence in women with extra X chromosomes: a cohort study in Britain. Hum Genet 2005; 118:255-60 [17 citations],

Swerdlow et al., Mortality in patients with congenital adrenal hyperplasia: a cohort study. J Pediatr 1998; 133:516-20 [62 citations].

Further evidence is the use for these studies in constructing and assessing clinical practice guidelines (e.g. Gravholt et al., Clinical practice guidelines for the care of girls and women with Turner Syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;117:G1-G70. Leblicq et al., Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed? J Pediatr 2011; 158:492-498. Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. Onkopedia Guidelines. Klinefelter Syndrome and Cancer. DGHO; Berlin, Recommendations from the society for diagnosis and therapy of haematological and oncological diseases. Bondy et al., Care of girls and women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2006;92:10-25).