MR1033 - CROSS-SECTIONAL MULTI-CENTRE STUDY OF UK ADULTS WITH CONGENITAL ADRENAL HYPERPLASIA

This agreement is from joint data controllers The University of Sheffield and The Society for Endocrinology.

Nearly 20 years ago the Society for Endocrinology conducted an audit of UK adults with CAH which revealed the lack of a consensus on the treatment and monitoring of adults with CAH.

CAH was subsequently identified as an area that required further research to inform the day to day management of conditions. As most centres have a relatively low number of patients with CAH, a collaborative multi-centre study was needed to enable investigation of a large cohort to extend previous studies.

Now that steroid treatment has been widely available for nearly 60 years and people with CAH now survive into adulthood, the investigators are collecting information on causes of morbidity and mortality.

The justification for the Society of Endocrinology processing is Article 6 1(f): Legitimate interest and Article 92(j) processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes

The data is being processed as a legitimate interest with the added provision that participants must consent to having their data collected and processed in order to take part. Purpose, necessity and balance has been considered in the Legitimate Interest Assessment.

Purpose:

Most of the current literature on Congenital Adrenal Hyperplasia (CAH) is centred on CAH in childhood and the studies published on adults have generated some conflicting data. Now that an increasing number of patients are surviving into adulthood, further research is needed to collate information on morbidity and mortality to see how co-morbidities and different treatment modalities might influence outcomes. Processing cause of death and cancer registration data this data might uncover information that could help inform the day to day management of conditions. Improving day to day management might help to prolong life and enable earlier detection/better surveillance of certain morbidities/causes of mortality. If not able to process the data as requested the study would not be able to collect accurate and complete cause of death or cancer information for CAH patients. Day to day management of conditions would remain the same and their healthcare would not be improved.

Necessity:

Retrieval and processing of the data allows the reporting of number of deaths in the cohort, number of deaths in each cause subgroup, the distribution of age at death, number of cancers reported in the study cohort and frequency of cancer subtypes. Linking this data with other data collected in this study allows the investigators to fulfil the ultimate interest; to see how co-morbidities and different treatment modalities might influence outcomes and to determine how day to day management of CAH patients can be improved. The data that has been requested is needed to achieve the aim. Obtaining data from NHS Digital (as opposed to the hospitals directly) is the best way to ensure accurate and complete data. Obtaining data directly from patients or their families would be an unnecessary burden to them, would likely result in recall bias when questioned on past events and would increase the likelihood of collecting poor quality data.

Balance:

Participants have consented to the use of their data to achieve the study aims. They will therefore not be surprised that their data be used in the ways described. The study has a participant information explaining the use of data to participants. Use was also explained during the consent process and participants are able to contact a member of the local research team at any time. There are a number of safeguards in place to maintain security of the data. These include adherence to system level security policies, encryption of data during data transfer, password protection of data files, timely and absolute destruction of data no longer needed, appropriate training of staff involved in data handling and processing, third party data security evaluation and GDPR compliance checks. Participants are free to withdraw at any time.

The justification for the University of Sheffield processing is Article 61(e)processing is necessary for the performance of a task in the public interest. The University of Sheffield is a public authority. The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”.

Also, Article 92(j) processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes.

The Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) was formed in 2003 to study the health status of Congenital Adrenal Hyperplasia (CAH) patients in adulthood.

As data is being requested as part of an approved clinical research study, participants are asked to provide consent for the collection and processing of this data. The data is being processed in the interest of patients with CAH, their families and their healthcare providers. Research helps understanding of the causes, prevention and treatment of disease and improve health care provision. The data requested is necessary to achieve the aim of the research and obtaining this from NHS Digital is considered to be the least intrusive option. Individuals are research participants and all have consented for their data to be collected and processed. As this is a research study, participants are able to withdraw at any point without giving a reason.

CAH affects 1:14,200 live births. It is the result of a genetic defect in one of the enzymes (in most cases 21-hydroxylase) required for cortisol biosynthesis, leading to reduced levels of cortisol and aldosterone, increased ACTH concentrations and consequently increased adrenal androgen production. The severity of the symptoms experienced by affected individuals varies depending on the mutation and the genetic background of the individual. The ability to tailor CAH therapy on an individual basis, as determined by the severity of the underlying defect and an understanding of the likely natural history of the disease, is a key goal in clinical management.

Study aim: To obtain and share data that will inform on practice nationally and internationally.

Now that more patients with CAH survive into adulthood the study wishes to obtain information on the causes of morbidity and mortality. Requesting fact and cause of death and cancer registration data over an extended period of time is therefore helping to achieve this aim.

The main study commenced in 2004 and data collection from sites ceased in 2014. Ethical Approval continues to be extended on an annual basis to obtain data over a longer period of time.

There is no relationship between the project under this agreement and any wider project, collaboration or associated work or follow up. The data is to be used to provide morbidity and mortality statistics for the current cohort of patients in this study only.

The data subjects are approximately 143 adults, male and female, with all forms of CAH, recruited from UK sites. Recruitment of new subjects ceased >5 years ago.

The purpose of the project under this agreement is to help inform the day to day management of patients with CAH. Whilst this study was able to collect lots of data directly from the patients and their hospitals, NHS Digital is able to provide more up to date and accurate data regarding cause of death and cancer registration. In order to be able to report on any trend in cause of death or number/type of cancer registrations in these patients specifically, the data needs to be collected over a longer period of time to increase the chance of gaining more information. For example, up until 2018 there were only 4 deaths recorded for this small cohort which is now 143 patients.

The study must be able to link the cause of death/cancer data to the information already held for the patients (age, sex, other morbidities, medication use etc.) and therefore receive the study ID with the NHS Digital data. In order to be inclusive and reduce any selection bias, data is requested for all participants providing consent for this purpose. Requesting data from NHS Digital is less intrusive than contacting the individual hospitals/patients. From past experience the data received from sites is often incomplete and inaccurate.

The data requested is the minimum required to meet the purpose, this has been minimised down to the cohort of 143 people treated in England and the minimum fields required regarding cause of death and cancer registration.

The Society for Endocrinology provided the following fields (as required by NHS digital): NHS number, forename, surname, date of birth and sex. These identifiers are held by NHS Digital and the cohort recruitment was completed in 2013.

NHS Digital return an identifiable report to the Society for Endocrinology.

Data includes: Event type, Event date, Latest posting location, Death district or cancer registration number, Death sub district or cancer anniversary year, Register number or cancer site, Entry number or cancer type, Cancer behaviour, Cause of death.

Record level data is stored securely at the Society for Endocrinology, on a server within a locked room. The office itself is also secure

• Only identifiable data necessary for the analysis is made visible to the statistician in Sheffield they do not receive identifiers such as names, addresses, place of death etc.

Each individual is given a study ID instead of sharing NHS number, forename and surname.

Date of Birth, Date of Death, Cause of death and cancer registrations are provided to Sheffield who undertake the analyses.

• The statistician pools the data in to aggregated tabular form with small numbers suppressed inline with the HES Analysis Guide, for publication in peer-reviewed journals, presentation at national and international meetings. A lay summary of the information is provided to participants and patient support groups.

The purpose of collecting this data is to learn about the causes of morbidity and mortality in CAH patients. Requesting fact and cause of death and cancer registration data over an extended period of time is therefore helping to achieve this aim.

The data is stored in its raw form at the Society for Endocrinology. Data includes Event type, Event date, Latest posting location, Death district or cancer registration number, Death sub district or cancer anniversary year, Register number or cancer site, Entry number or cancer type, Cancer behaviour and Cause of death. The patients identifiers are replaced with a study ID and the following fields are shared with the statistician at Sheffield University: Patient ID, date of death, date of birth, cause of death and cancer information. The statistician uses this data to provide aggregated tables with small numbers suppressed to show number of deaths in the cohort, number of deaths in each cause subgroup, the distribution of age at death, number of cancers reported in the study cohort and frequency of cancer sub types.

The study only link the cause of death/cancer data to the information already held for the patients (age, sex, other morbidities, medication use etc.). Linkage is made via a unique study ID.

Only the participating site, the central study coordination office, including the study statistician based at The University of Sheffield have access to identifiable information about participants.

Every attempt is made to mitigate risk of identification by use of participant IDs when collecting, recording, storing and analysing data.

Date of Birth, Date of Death, Cause of death and cancer registrations are provided to The University of Sheffield as these are necessary for the study to analyse the data. Any published study results will always be anonymous.

Recruitment and data collection for this study ended a long time ago. At that time, a number of high quality manuscripts were published and patients were informed of the main study outcomes. They were also informed that the study planned to collect a further 2 years of data from NHS Digital, to gain a better understanding of mortality and cancer related morbidity. There is a fair processing notice for this study on the website and a page describing the study outputs so far. Patients are expecting a further data collection and the study team will notify them should enough data be gained to submit another manuscript for publication. This study will close completely early next year.

There will be no requirement/attempt to re-identify individuals beyond the study.

The study team confirm that data processing is only carried out by substantive employees of the University of Sheffield or Society for Endocrinology.

Data is stored on a secure server within the Society for Endocrinology. This server is in a locked room and access to data is restricted to named individuals only.

Data is sent to the University of Sheffield, either as a password protected document via email or on an encrypted USB stick by recorded post.

As a result of data processing the study expects to obtain useful information on the causes of morbidity and mortality in patients with CAH. This information (along with other study results) needs to be disseminated to help inform the day to day management of conditions. Improving day to day management is expected to prolong life and enable earlier detection/better surveillance of certain morbidities/causes of mortality.

The intention is publication in peer-reviewed journals, presentation at national and international meetings (to include The Society for Endocrinology BES annual conference) and a summary of the results (using lay terminology) will be available on the Society for Endocrinology’s website.

The data disseminated will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

The aim is to disseminate the results to key stakeholders including participants, the public, and health care professionals responsible for caring for CAH patients.

The results will be available to all Society members including scientists, nurses, clinicians and patient groups. If strong enough evidence is found for a change in current care strategies, the Society for Endocrinology will release a Clinical Guideline or Position Statement. This will be shared with NHS Trusts and policy decision makers.

The dissemination strategy will facilitate engagement with the scientific and policy-making communities and will ensure that knowledge developed by the research can benefit these communities.

Dissemination channels

Channels include a peer reviewed journal, the Society’s public facing website and member website. The Society has a number of social media channels and these will be utilised if appropriate.

The study group confirm that dissemination of the results will be done proactively to ensure all interested groups are engaged.

Communication channels

The Society will provide a link to any significant results in the member newsletters. If strong evidence is found the Press Office will engage with the media.

A talk will be given by the study Chief Investigator at The Society for Endocrinology’s annual conference.

Exploitation of results/outputs

The Society for Endocrinology will ensure the data is made available in an open access journal. If this research leads to further research questions a steering group will be convened to discuss a new application to the HRA and REC. Under current approvals the main study data will need to be archived with access and use restricted until destruction.

The data provided by this agreement will be destroyed when the agreement expires, as per NHS Digital policy.

The final study manuscript describing mortality will be published in 2021 after a further 2 years of data collection.

Due to its comparative rarity, no one UK centre could observe sufficient numbers of patients to enable analysis of potential influences on mortality and morbidity of pre-existing co-morbidities and different treatment modalities.

CAH is relatively rare (though one of the most common of the inherited diseases) and therefore the study results will not be of interest to the majority of the general public. Ensuring data is disseminated to all involved in the care of these patients, the patients themselves and their families, and the scientific community interested in researching CAH will help achieve the study aim of improving healthcare provision and informing day to day management of the condition. Improving day to day management might help to prolong life and enable earlier detection/better surveillance of certain morbidities/causes of mortality.

The data is being processed as a legitimate interest with the added provision that participants must consent to having their data collected and processed in order to take part. Purpose, necessity and balance has been considered in the Legitimate Interest Assessment.

The data received from NHS Digital will provide information on the number of deaths in the cohort, number of deaths in each cause subgroup, the distribution of age at death, number of cancers reported in the study cohort and frequency of cancer sub types. This data will be reviewed alongside wider project information on morbidity and different treatment modalities. The NHS Digital information is only a small part of the wider project aim which is to improve healthcare provision for CAH patients in general.

This project has been running for a number of years and this agreement is for a renewal to collect longer term data on death and cancer. All other data collection ceased some time ago. This means that there have already been a number of dissemination events and publications and the benefits of the study are already apparent. A comprehensive list describing all yielded benefits to date is provided below. Management of CAH conditions has already been improved and longer term data regarding death and cancer might impact on future care advice. The final manuscript is expected to be published in 2021 and this will be disseminated to the policy makers. The Society for Endocrinology publishes its own Clinical Guidance and will create a new guideline should the results show one is needed.

The impact of the CaHASE study was acknowledged in an independent review published in the Journal of Clinical Endocrinology & Metabolism (December 2011) and presented at Endo 2011. The review identified the results of CaHASE published in November 2010 as one of the eleven most significant papers published in the field of adrenal endocrinology that year (Carey. 2011. Adrenal disease update 2011. JCEM, 96:3583–3591).

The significance of CaHASE is highlighted by the number of publications, invited talks and presentations at conferences and patient support events and the reported improvement in patient services (listed below). The project has been invited to join the Euro-DSD registry and as a direct result of the project, the Society is preparing clinical guidance on the management of the adult patient with congenital adrenal hyperplasia. No NHS Digital has or will flow to the Euro-DSD registry.

International Impact

Leverage funding - Data from CaHASE was used to support a successful bid for 4,200,000 Euros of EU funding and the establishment of a spin out campaign using higher level results not including NHS Digital data.

Establishment of the CAH-specific arm, i-CAH (www.i-cah.org) of an international registry for disorders of sexual development.

Development of guidelines for Adults with CAH are being developed by the Society for endocrinology.

• 2015 Professor Arlt, Symposium talk, 2nd Endocrinology and Global exchange (EDGE) meeting for paediatric endocrinology, Berlin, Germany

• 2014 Abstract presented at ECE 2014

• 2014 Abstract presented at ENDO 2014

• 2014 Professor Arlt, Symposium talk, 53rd Annual Meeting of the European Society of Paediatric Endocrinology (ESPE), Dublin, Ireland

• 2013 Poster ENDO 2013 (selected for featured poster session)

• 2013 Professor Ross, Chair of CaHASE invited speaker at ICE/ECE 2013 Nurse Session,

• 2013 Poster ECE 2013

• 2012 Oral ENDO 2012

• 2012 Professor Ross, Chair of CaHASE invited speaker at ICE/ECE 2012, Florence

• 2012 Poster ICE/ECE 2012, Florence

• 2012 Oral genetics ICE/ECE 2012, Florence

• 2011 Dr Mooij presented novel mutation analysis results at ESPE, Glasgow

• 2010 CaHASE published results in American Journal– JCEM

• 2010 Professor Ross, Chair of CaHASE invited speaker at ICE, Japan

• 2009 Dr Krone presented genetic results at LWPES/ESPE, New York, USA

• 2009 Professor Arlt , Oral communication at Endo, Washington, USA

• 2009 Dr Krone presented genetic results at Endo, Washington, USA

National impact

• 2014 Editorial submitted to Clinical Endocrinology

• 2014 Manuscript in JCEM

• 2014 Poster at SfE BES 2014

• 2013 Professor Ross, Chair of CaHASE, invited speaker at BSPED 2013

• 2013 Poster at SfE BES 2013

• 2012 Oral SfE BES 2012

• 2012 Poster SfE BES genetics

• 2011 Dr Steve Ball. Annual North East Endocrine Research and Audit meeting

• 2011 Dr Steve Ball Northern Paediatric Endocrine group meeting

• 2010 Professor Ross, Chair of CaHASE, invited speaker at SfE BES 2010

• 2009 Dr Doherty presented fertility aspects at SfE BES

• 2009 Dr Thang Han presented bone and body composition aspects at SfE BES

• 2009 Dr Krone presented quality of life aspects at SfE BES

Interaction with Patient support groups.

• 2011 Professor Ross invited speaker at UK patient support group annual meeting, Manchester

• 2008 Article in patient support group (living with CAH) newsletter

• 2007 Professor Ross invited speaker at UK patient support group annual meeting, Stevenage

• 2006 Professor Ross invited speaker at USA patient support group (CARES)

Effect on clinical practice at participating centres,

Centres report finding patients lost to follow up and improved transition from paediatric to adult endocrine care. Specifically;

• Oxford - identified patients lost to follow-up and set up a designated CAH clinic in 2007-2008 after having comments from CAH patients that they would like consistency of care. This clinic is held jointly with a consultant in Clinical Genetics. They have managed to bring back the majority of patients who had been lost to follow-up and also to expand further the number of patients they see. Based on data of the last 8 months, their DNA (did not attend) rate is down to 3% from approximately 20% before the set up of the clinic

• Edinburgh - presented the CaHASE data locally, resulting in increased collaboration with local paediatric team to improve transitional care. They report wider effects to include most of the rest of Scotland.

• Spin out company - underpinned formation of Diurnal LTD spin out from Sheffield http://www.diurnal.co.uk/

Publications

Full papers

1. Han TS, Conway GS, Willis DS, Krone NP, Rees DA, Stimson RH, Arlt W, Walker BR, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Relationship between final height and health outcomes in adults with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2014; 99:E1547-E1555. doi: 10.1210/jc.2014-1486

2. Han TS, Walker BR, Arlt W, Ross RJ 2013. Treatment and health outcomes in adult patients with congenital adrenal hyperplasia; perspectives from the UK CaHASE study investigators. Nat Rev Endocrinol. 2014;10(2):115-24

3. Ross RJ. CaHASE: a Specialist Society Led Academic Collaboration to improve the management of CAH. Clin Endocrinol (Oxf). 2014;81(3):334-5.

4. Han TS, Krone N, Willis DS, Conway GS, Hahner S, Rees DA, Stimson RH, Walker BR, Arlt W, Ross RJ; United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) 2013. Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Eur J Endocrinol. 2013 May 3;168(6):887-93. doi: 10.1530/EJE-13-0128. Print 2013 June

5. Krone N, Rose IT, Willis DS, Hodson J, Wild SH, Doherty EJ, Hahner S, Parajes S, Stimson RH, Han TS, Carroll PV, Conway GS, Walker BR, MacDonald F, Ross RJ, Arlt W; United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. J Clin Endocrinol Metab. 2013 Feb;98(2):E346-54. doi: 10.1210/jc.2012-3343. Epub 2013 Jan 21.

6. Han TS, Stimson RH, Rees DA, Krone N, Willis DS, Conway GS, Arlt W, Walker BR, Ross RJ; United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) 2013. Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2013 Feb;78(2):197-203. doi: 10.1111/cen.12045.

7. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ; United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) 2010 Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010 Nov;95(11):5110-21. doi: 10.1210/jc.2010-0917. Epub 2010 Aug 18.

Abstracts presented at meetings

1. Han TS, Krone N, Willis DS, Conway GS, Hahner S, Rees DA, Stimson RH, Walker BR, Arlt W, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Quality of Life in Adults With Congenital Adrenal Hyperplasia Relates to Glucocorticoid Treatment, Adiposity and Insulin Resistance: United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). ENDO 2013 P 5428.

2. Han TS, Krone N, Willis DS, Conway GS, Hahner S, Rees DA, Stimson RH, Walker BR, Arlt W, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Impaired quality of life in CAH adults is associated with adiposity and insulin resistance. ECE 2013 Poster

3. Ross RJM. Management of CAH in Adults. ECE 2013 Oral

4. Han TS, Krone N, Willis DS, Conway GS, Rees DA, Stimson RH, Walker BR, Arlt W, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Quality of life relates to glucocorticoid treatment regimen, and adiposity and insulin resistance in adults with congenital adrenal hyperplasia: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). SfE BES 2013 poster

5. Han TS, Stimson RH, Rees A, Krone N, Willis DS, Wild SH, Conway GS, Arlt W, Walker BR, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) 2012. Glucocorticoid dose in adults with CAH; association with clinical and biochemical variables – analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. ENDO 2012 Oral.

6. Han TS, Stimson RH, Rees A, Krone N, Willis DS, Wild SH, Conway GS, Arlt W, Walker BR, Ross RJ and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) 2012. Relationship of current glucocorticoid dose with metabolic outcomes in CAH – analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort ICE/ECE 2012; P 53.

7. Ross RJ. CAH and adulthood. Invited talk at ICE/ECE 2012.

8. Krone N, Rose IT, Crosby C, Willis DS, Wild SH, Doherty EJ, Hahner S, Parajes S, Han TS, Carrol PV, Conway GS, Walker BR, MacDonald F, Ross RJ, Arlt W and the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) 2012 (submitted) Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency – analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. BES 2012; P306.

9. Christiaan F. Mooij, Silvia Parajes, Ian T. Rose, Angela Taylor, Taner Bayraktaroglu, John Wass, John Connell, David Ray, Wiebke Arlt, Nils Krone (2011) In vitro analysis of five CYP11B1 gene mutations detected in patients with classic and nonclassic 11β-hydroxylase deficiency. 50th Annual ESPE Meeting