Pre-participation screening: Clinical outcomes of a large UK cohort

The UK National Screening Committee (UK NSC) does not recommend a national sponsored screening program for cardiac disease in young asymptomatic individuals with no relevant family history. In the most recent UK NSC review the authors highlight the low incidence of sudden cardiac death (SCD) in young adults and raised concerns regarding the performance of the proposed screening tools and in particular the 12-lead ECG. The 12-lead ECG is a representation of the heart's electrical activity recorded from electrodes on the body surface.

The true incidence of sudden cardiac death (SCD) in children and young adults is widely debated. Accurate calculation of the incidence requires a precise numerator (number of deaths per year) and an exact denominator (number of participants per year) in the population studied. The reported incidence of SCD in young adults (age 14-35 years) varies widely depending on the group studied and the methodology used and has been reported as low as 1:300,000. In the absence of systematic registries, collection methods using retrospective review of media reports, electronic databases and insurance claims in these early studies, are limited by ascertainment and selection bias which underestimate calculations of incidence. Gauging the effect of preventative strategies such as preparticipation cardiovascular screening (PPS) is limited by unreliable estimates of SCD incidence.

Cardiac Risk in the Young (CRY) has provided a voluntary cardiac screening program to children and young individuals since 1996. In this time CRY have screened in excess of 150,000 individuals for conditions associated with SCD. This has formed the largest database of its kind with a well-defined denominator. Up till now research on screening outcomes has primarily focussed on individuals that were flagged as positive by the screening and proceeded to further evaluation. As such they have been able to define the positive predictive value as well as the false discovery rate of the screening programme and in particular the 12-lead ECG. For the first time, this project will explore outcomes in the entire population and in particular individuals whose screening tests were considered normal and were reassured that they did not have any cardiac condition predisposing them to sudden cardiac death. These individuals comprise >90% of the screened population.

The organisation requests mortality data for approximately 120,000 consecutive individuals screened over a decade, from 2007 till 2018. These individuals were screened across England, Wales, Scotland and Northern Ireland. Individuals were aged between 14 and 34 years of age at the time of data acquisition. Outcomes will not be compared to an un-screened population and for that reason no control group exists.

The following steps have been taken to minimise the data requested:

1. The data request only relates to those individuals in the cohort. Data outcomes from individuals who have undergone cardiac evaluation by other screening providers (not Cardiac Risk in the Young) will not be included.

2. There is no requirement for data which was stored prior to the screening period of the cohort. For this reason, data stored earlier than 2007 is not requested.

3. This study aims to ascertain the prevalence of conditions which are associated with sudden cardiac death. For that reason, the ICD-10 codes have been filtered to reflect these conditions only.

4. This study aims to ascertain the frequency of cardiac interventions which are performed in order to reduce the individual's risk of sudden cardiac death. The OPCS4 codes have been filtered to include these procedures only.

5. This study aims to ascertain the incidence of sudden cardiac death. The timing and location of an individual's collapse/sudden cardiac arrest prior to death can disguise the cause of death. The clinical experience from a dedicated sudden arrhythmic death syndrome service has highlighted this fact. Examples include: Cardiac rarest with resuscitation and survival to hospital admission but died with hypoxic brain injury (stated as cause of death), drowning where circumstances are not clear or appear unusual (without struggle), road traffic accident where circumstances indicate the driver may have collapsed before the trauma related impact (no brake marks, or driver found dead at the hand-wheel of a car that is stationary). Indeed, familial evaluation of such cases has, from experience and others, identified familial forms of the Long QT syndrome, Brugada syndrome and catecholaminergic polymorphic tachycardia which are then attributed to the cause of death retrospectively. These outcomes reflected in the available medical literature. For this reason, the request for all-cause mortality to evaluate the possible number of additional cardiac deaths which manifest atypically and are then incorrectly coded.

From these datasets the aim is to identify any individual with: A) sudden cardiac death, B) Sudden Cardiac Arrest (SCA) and C) a diagnosis of a cardiac condition associated with sudden cardiac death. The data will be securely returned to the storage location in the pseudonymised form for outcome analysis.

Pilot data from a cohort of 5,000 individuals from the same research group supported by CRY looking at the outcomes of a specific ECG index (early repolarisation) indicates that through this process the study will be able to obtain outcomes in excess of 95% of the individuals screened.

This study will be the most comprehensive study on cardiac screening of children and young individuals yet and will be able to define the: 1. The exact incidence of sudden cardiac death in a screened population of young individuals and compare it to reported rates in the UK, 2. Assess the sensitivity, specificity, positive and negative predictive value of cardiac screening overall as well as the individual tests used (12-lead ECG and health questionnaire) of identifying individuals with conditions predisposing to sudden cardiac death, 3. Assess the effectiveness of screening in terms of detecting different conditions predisposing to sudden cardiac death.

This study has the potential to define the future approach to PPS not only in the UK, but worldwide. Accurate assessment of SCD incidence, as well as insight into the true performance of commonly used screening tools, will guide the outcome of PPS policies including that of the UK NSC. As a result, the Primary Investigator (PI) and the organisation, believes the processing of such data is justified on legal grounds - GDPR Article 6(1)(e). Data processing is also necessary for reasons of substantial public interest under Article 9(2)(j).

This project has the potential to form the basis for a number of other projects including 1. Comparison of mortality rates in a screened compared to a well-defined non-screened population, 2. Assessment of true screening costs, 3. Assess the predictive value of identifying cardiac disease of different ECG indices.

Study Rationale

A government sponsored screening program, mandated by Italian law, has demonstrated a fall in rates of sudden cardiac death by 89%. Currently no equivalent UK state sponsored program exists. Concerns in part relate to the perceived low incidence of sudden cardiac death (SCD) and sudden cardiac arrest (SCA) in young individuals. This study will provide the most reliable estimate for the incidence rate for SCD and SCA in the literature. Only once a reliable estimate of SCD and SCA is calculated, can the screening community gauge the need for preventative strategies such as cardiac screening.

Primary Objectives

1. To define the incidence of sudden cardiac death in a screened population of children and young individuals.

2. To assess the value of cardiac screening overall, individual tests used (12-lead ECG and health questionnaire), as well as specific indices of these tests (specific questions or ECG indices) of identifying individuals with conditions predisposing to sudden cardiac death or sudden cardiac arrest.

3. Assess the effectiveness of screening of detecting different conditions predisposing to sudden cardiac death.

Primary aim:

• The primary aim is to estimate the incidence of sudden cardiac death and sudden cardiac arrest in a population of individuals who had previously undergone assessment with pre-participation screening over a ten-year period.

Secondary aims:

•

To assess the value of cardiac screening overall, individual tests used (12-lead ECG and health questionnaire), as well as specific indices of these tests (specific questions or ECG indices) of identifying individuals with conditions predisposing to sudden cardiac death or adverse outcomes (sudden cardiac death, sudden cardiac arrest).

• Assess the effectiveness of screening of detecting different conditions predisposing to sudden cardiac death.

The following organisations are involved:

• St George’s, University of London

Role: Sole data controller and sole data processor

Organisation Type: Academic

• Cardiac Risk in the Young

Role: Source of funding for study. Owners of source data.

Organisation Type: Charity

The Principal Investigator is substantively employed at St Georges, University of London but holds an honorary contract at Cardiac Risk in the Young (CRY), so they can access the identifiers from the database. However, no linkage of the NHS Digital data disseminated under this agreement is permitted to the identifiers held at CRY. St George’s, University of London are not permitted to re-identify any members in the cohort.

There are no other organisations/commissioners involved in this or wider anticipated projects.

The research output will be submitted to peer-reviewed cardiology and/or general medical journals in the form of an original research article. It is expected that the work will be accepted for publication in a high-impact cardiology-specific journal, such as Circulation, the Journal of the American College of Cardiology (JACC) or the European Heart Journal (EHJ). These journals are widely read amongst the clinical and academic cardiology community worldwide. Articles published in these journals therefore frequently inform clinical practice are often cited in national and international guideline documents.

CRY hold 6 monthly ‘Heart Group Meetings’. The meetings are advertised on the CRY website. The Primary Investigator presented the study to 80 attendees which included individuals within the study cohort. Feedback was positive and there were no concerns about the methodology expressed. Further clarity has been sought by sending emails to the cohort requesting their feedback, this process has begun and was confirmed in a call with the applicant on 13/09/2019, at each screening event questionnaires are given out, each event is attended by approx. 200 people

Only aggregated data, with small numbers suppressed in line with HES analysis guidance, will be included in any research output. No patient level data will be included. It is expected that the research article will be submitted for peer review within 3 months of receipt of the data from NHS digital.

In addition to the written outputs, the research data will be submitted for oral presentation at national and international cardiology conferences such as the British Cardiac Society annual conference, British Heart Rhythm Congress, European Heart Rhythm Association conference and Heart Rhythm Congress in the USA. Similarly to the journal listed above, these conferences serve to dissipate cutting edge clinical research findings to leading clinical and academic cardiologists. Through this network of academic research presentations the findings, if significant, will lead to changes in national and international guidance on the assessment and management of young adults at apparent risk of sudden cardiac death or undergoing pre- participation ECG screening in the context of elite or amateur sport. Such guideline documents are widely circulated and advertised within clinical service. They inform the basis of clinical practice of cardiologists, sports physicians and general practitioners looking after such individuals. Summaries of the research findings will also be published by Cardiac Risk in the Young including on their website, via twitter and at the annual CRY International Conference on Sports Cardiology.

The UK National Screening Committee (UK NSC) does not recommend a national sponsored screening program for cardiac disease in young asymptomatic individuals with no relevant family history. In the most recent UK NSC review the authors highlight the low incidence of sudden cardiac death (SCD) in young adults and raised concerns regarding the performance of the proposed screening tools and in particular the 12-lead ECG. The 12-lead ECG is a representation of the heart's electrical activity recorded from electrodes on the body surface.

The true incidence of sudden cardiac death (SCD) in children and young adults is widely debated. Accurate calculation of the incidence requires a precise numerator (number of deaths per year) and an exact denominator (number of participants per year) in the population studied. The reported incidence of SCD in young adults (age 14-35 years) varies widely depending on the group studied and the methodology used and has been reported as low as 1:300,000. In the absence of systematic registries, collection methods using retrospective review of media reports, electronic databases and insurance claims in these early studies, are limited by ascertainment and selection bias which underestimate calculations of incidence. Gauging the effect of preventative strategies such as preparticipation cardiovascular screening (PPS) is limited by unreliable estimates of SCD incidence.

Cardiac Risk in the Young (CRY) has provided a voluntary cardiac screening program to children and young individuals since 1996. In this time CRY have screened in excess of 150,000 individuals for conditions associated with SCD. This has formed the largest database of its kind with a well-defined denominator. Up till now research on screening outcomes has primarily focussed on individuals that were flagged as positive by the screening and proceeded to further evaluation. As such they have been able to define the positive predictive value as well as the false discovery rate of the screening programme and in particular the 12-lead ECG. For the first time, this project will explore outcomes in the entire population and in particular individuals whose screening tests were considered normal and were reassured that they did not have any cardiac condition predisposing them to sudden cardiac death. These individuals comprise >90% of the screened population.

The organisation requests mortality data for approximately 120,000 consecutive individuals screened over a decade, from 2007 till 2018. These individuals were screened across England, Wales, Scotland and Northern Ireland. Individuals were aged between 14 and 34 years of age at the time of data acquisition. Outcomes will not be compared to an un-screened population and for that reason no control group exists.

The following steps have been taken to minimise the data requested:

1. The data request only relates to those individuals in the cohort. Data outcomes from individuals who have undergone cardiac evaluation by other screening providers (not Cardiac Risk in the Young) will not be included.

2. There is no requirement for data which was stored prior to the screening period of the cohort. For this reason, data stored earlier than 2007 is not requested.

3. This study aims to ascertain the prevalence of conditions which are associated with sudden cardiac death. For that reason, the ICD-10 codes have been filtered to reflect these conditions only.

4. This study aims to ascertain the frequency of cardiac interventions which are performed in order to reduce the individuals risk of sudden cardiac death. The OPCS4 codes have been filtered to include these procedures only.

5. This study aims to ascertain the incidence of sudden cardiac death. The timing and location of an individual's collapse/sudden cardiac arrest prior to death can disguise the cause of death. The clinical experience from a dedicated sudden arrhythmic death syndrome service has highlighted this fact. Examples include: Cardiac rarest with resuscitation and survival to hospital admission but died with hypoxic brain injury (stated as cause of death), drowning where circumstances are not clear or appear unusual (without struggle), road traffic accident where circumstances indicate the driver may have collapsed before the trauma related impact (no brake marks, or driver found dead at the hand-wheel of a car that is stationary). Indeed, familial evaluation of such cases has, from experience and others, identified familial forms of the Long QT syndrome, Brugada syndrome and catecholaminergic polymorphic tachycardia which are then attributed to the cause of death retrospectively. These outcomes reflected in the available medical literature. For this reason the request for all-cause mortality to evaluate the possible number of additional cardiac deaths which manifest atypically and are then incorrectly coded.

From these datasets the aim is to identify any individual with: A) sudden cardiac death, B) Sudden Cardiac Arrest (SCA) and C) a diagnosis of a cardiac condition associated with sudden cardiac death. The data will be securely returned to the storage location in the pseudonymised form for outcome analysis.

Pilot data from a cohort of 5,000 individuals from the same research group supported by CRY looking at the outcomes of a specific ECG index (early repolarisation) indicates that through this process the study will be able to obtain outcomes in excess of 95% of the individuals screened.

This study will be the most comprehensive study on cardiac screening of children and young individuals yet and will be able to define the: 1. The exact incidence of sudden cardiac death in a screened population of young individuals and compare it to reported rates in the UK, 2. Assess the sensitivity, specificity, positive and negative predictive value of cardiac screening overall as well as the individual tests used (12-lead ECG and health questionnaire) of identifying individuals with conditions predisposing to sudden cardiac death, 3. Assess the effectiveness of screening in terms of detecting different conditions predisposing to sudden cardiac death.

This study has the potential to define the future approach to PPS not only in the UK, but worldwide. Accurate assessment of SCD incidence, as well as insight into the true performance of commonly used screening tools, will guide the outcome of PPS policies including that of the UK NSC. As a result, the Primary Investigator (PI) and the organisation, believes the processing of such data is justified on legal grounds - GDPR Article 6(1)(e). Data processing is also necessary for reasons of substantial public interest under Article 9(2)(j).

This project has the potential to form the basis for a number of other projects including 1. Comparison of mortality rates in a screened compared to a well-defined non-screened population, 2. Assessment of true screening costs, 3. Assess the predictive value of identifying cardiac disease of different ECG indices.

Study Rationale

A government sponsored screening program, mandated by Italian law, has demonstrated a fall in rates of sudden cardiac death by 89%. Currently no equivalent UK state sponsored program exists. Concerns in part relate to the perceived low incidence of sudden cardiac death (SCD) and sudden cardiac arrest (SCA) in young individuals. The organisation this study will provide the most reliable estimate for the incidence rate for SCD and SCA in the literature. Only once a reliable estimate of SCD and SCA is calculated, can the screening community gauge the need for preventative strategies such as cardiac screening.

Primary Objectives

1. To define the incidence of sudden cardiac death in a screened population of children and young individuals.

2. To assess the value of cardiac screening overall, individual tests used (12-lead ECG and health questionnaire), as well as specific indices of these tests (specific questions or ECG indices) of identifying individuals with conditions predisposing to sudden cardiac death or sudden cardiac arrest.

3. Assess the effectiveness of screening of detecting different conditions predisposing to sudden cardiac death.

Primary aim:

• The primary aim is to estimate the incidence of sudden cardiac death and sudden cardiac arrest in a population of individuals who had previously undergone assessment with pre-participation screening over a ten-year period.

Secondary aims:

•

To assess the value of cardiac screening overall, individual tests used (12-lead ECG and health questionnaire), as well as specific indices of these tests (specific questions or ECG indices) of identifying individuals with conditions predisposing to sudden cardiac death or adverse outcomes (sudden cardiac death, sudden cardiac arrest).

• Assess the effectiveness of screening of detecting different conditions predisposing to sudden cardiac death.

The following organisations are involved:

• St George’s, University of London

Role: Sole data controller and sole data processor

Organisation Type: Academic

• Cardiac Risk in the Young

Role: Source of funding for study. Owners of source data.

Organisation Type: Charity

The Principal Investigator is substantively employed at St Georges, University of London but holds an honorary contract at Cardiac Risk in the Young (CRY), so they can access the identifiers from the database. However, no linkage of the NHS Digital data disseminated under this agreement is permitted to the identifiers held at CRY. St George’s, University of London are not permitted to re-identify any members in the cohort.

There are no other organisations/commissioners involved in this or wider anticipated projects.

The research output will be submitted to peer-reviewed cardiology and/or general medical journals in the form of an original research article. It is expected that the work will be accepted for publication in a high-impact cardiology-specific journal, such as Circulation, the Journal of the American College of Cardiology (JACC) or the European Heart Journal (EHJ). These journals are widely read amongst the clinical and academic cardiology community worldwide. Articles published in these journals therefore frequently inform clinical practice are often cited in national and international guideline documents.

CRY hold 6 monthly ‘Heart Group Meetings’. The meetings are advertised on the CRY website. The Primary Investigator presented the study to 80 attendees which included individuals within the study cohort. Feedback was positive and there were no concerns about the methodology expressed. Further clarity has been sought by sending emails to the cohort requesting their feedback, this process has begun and was confirmed in a call with the applicant on 13/09/2019, at each screening event questionnaires are given out, each event is attended by approx. 200 people

Only aggregated data, with small numbers suppressed in line with HES guidance, will be included in any research output. No patient level data will be included. It is expected that the research article will be submitted for peer review within 3 months of receipt of the data from NHS digital.

In addition to the written outputs, the research data will be submitted for oral presentation at national and international cardiology conferences such as the British Cardiac Society annual conference, British Heart Rhythm Congress, European Heart Rhythm Association conference and Heart Rhythm Congress in the USA. Similarly to the journal listed above, these conferences serve to dissipate cutting edge clinical research findings to leading clinical and academic cardiologists. Through this network of academic research presentations the findings, if significant, will lead to changes in national and international guidance on the assessment and management of young adults at apparent risk of sudden cardiac death or undergoing pre- participation ECG screening in the context of elite or amateur sport. Such guideline documents are widely circulated and advertised within clinical service. They inform the basis of clinical practice of cardiologists, sports physicians and general practitioners looking after such individuals. Summaries of the research findings will also be published by Cardiac Risk in the Young including on their website, via twitter and at the annual CRY International Conference on Sports Cardiology.

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