The Healthcare Evaluation of Absolute Risk Testing Study: A Multi-centre, Single Arm, Pragmatic Study in Primary Care Setting
Phase: NA
Conditions: Cardiovascular Diseases
Sponsor: Genomics PLC

STUDY PROTOCOL
The Healthcare Evaluation of Absolute Risk Testing Study:
A multi-centre, single arm, pragmatic study in primary care setting
The HEART Study
GEN2020-02
Version 2.0 06 December 2021
NCT05294419

 
 
 
 
 
 
 
STUDY PROTOCOL 
 
 
The Healthcare Evaluation of Absolute Risk Testing Study: 
A multi-centre, single arm, pragmatic study in primary care setting 
 
 
 
The HEART Study 
GEN2020-02 
 
 
 
Version 2.0  06 December 2021       
 
 
 
Previous Versions 
Protocol Version 1.0, Date 24 July 2021 
 
 
 
 
 
This protocol has regard for the HRA guidance and order of content. 
 
 

 
 
GEN2020-02 HEART Study Protocol 
 
 
 
 
 
 
 
 
 
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Version 2.0 06 December 2021      
 
 
Protocol Version: 
 
2.0  
06 December 2021 
      
IRAS (Integrated Research Application System) Number: 
 
285420 
SPONSORS Number: 
GEN-2020- 02 
 
FUNDERS Number: 
Genomics plc, GEN-2020- 02 
NECS, NECS-6419 
CPMS Portfolio Number: 
 
46497 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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KEY STUDY CONTACTS 
Chief Investigator 
Professor Ahmet Fuat 
Carmel Medical Practice 
Nunnery Lane 
Darlington Co.Durham DL3 8SQ  
Tel: 01325 520794  
Email: ahmetfuat@nhs.net 
Sponsor 
Genomics plc 
King Charles House 
Park End Street 
Oxford 
OX1 1JD  
Tel: 01865 981 600 
Clinical Operations, Director 
  
 
Adverse Event reporting 
eCRF  
Device deficiency notification 
eCRF  
<<
 
DNA extract laboratory, Blood 
LGC Biosearch Technologies 
Unit 1-2 Trident Industrial Estate 
Hoddesdon 
Herts  
EN11 0WZ 
DNA extract laboratory, Saliva 
UK Biocentre 
Units 2 and 3 Java Park 
Bradbourne Drive 
Tilbrook 
Milton Keynes 
MK7 8AT 
Genotyping Laboratory 
Thermo Fisher Scientific 
3380 Central Expressway  
CA 95051  
USA 
Funders 
Genomics plc (see address above)  
and 
NHS North of England Commissioning Support (NECS) 
John Snow House  
Durham 
DH1 3YG 

 
 
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TABLE OF CONTENTS 
Table of Contents 
PROTOCOL SIGNATURE PAGE 
2 
INVESTIGATOR STATEMENT 
4 
KEY STUDY CONTACTS 
5 
TABLE OF FIGURES AND TABLES 
10 
LIST OF ABBREVIATIONS 
11 
STUDY SUMMARY 
13 
ROLE OF STUDY SPONSOR AND FUNDER 
15 
ROLES AND RESPONSIBILITIES 
15 
PROTOCOL CONTRIBUTORS 
15 
1. 
BACKGROUND 
16 
1.1. 
Cardiovascular Disease 
16 
1.2. 
The Integrated Risk Tool for Cardiovascular Disease (CVD IRT) 
17 
1.3. 
Management of QRISK®2 and CVD IRT report for participant discussion 
17 
2. 
RATIONALE 
18 
2.1. 
Assessment and management of risk 
18 
3. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
19 
3.1. 
Primary objective 
19 
3.2. 
Secondary and exploratory objectives 
19 
3.3. 
Outcome measures 
19 
3.4. 
Primary endpoint 
19 
3.5. 
Secondary and exploratory endpoints 
19 
3.6. 
Summary of Objectives and Outcomes 
20 
4. 
DESIGN 
22 
4.1. 
Quantitative Design 
23 
4.2. 
Qualitative Design 
23 
5. 
STUDY SETTING 
23 
5.1. 
COVID-19 Restrictions 
23 

 
 
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6. 
ELIGIBILITY CRITERIA 
24 
6.1. 
Participant Eligibility Criteria 
24 
6.1.1. 
Inclusion criteria 
24 
6.2. 
HCP Eligibility Criteria 
24 
6.3. 
PCC Eligibility Criteria 
25 
7. 
STUDY PROCEDURES 
25 
7.1. 
Patient Participants 
25 
7.1.2. 
Participant identification 
28 
7.1.3. 
Participant Screening 
28 
7.1.4. 
Participant Payment 
29 
7.1.5. 
Participant Consent 
29 
7.1.6. 
Additional participant consent provisions for collection of saliva samples and interviews
 
29 
7.1.7. 
Participant Study assessments, per visit 
30 
7.1.7.1. 
Visit 1, Baseline 
30 
7.1.7.2. 
Saliva Samples 
32 
7.1.8. 
Visit 2, Receiving CVD IRT results and study participant management 
32 
7.1.9. 
Visit 3, Online questionnaire 
33 
7.1.10. 
Visit 4, Phone interview 
33 
7.2. 
HCP participation 
34 
7.3. 
PCC participation 
35 
7.4. 
End of study 
35 
7.5. 
Storage, analysis and destruction of clinical samples 
36 
7.5.4. 
Future research 
37 
7.6. 
Qualitative assessments 
38 
7.6.3.1. 
HCP 
39 
7.6.3.2. 
PCCs 
39 
8. 
CONCOMITANT MEDICATIONS 
40 
9. 
SAFETY MONITORING 
40 
9.1. 
Definitions 
40 
9.2. 
Adverse Event Recording 
43 
9.3. 
Device Deficiency Recording 
44 
9.4. 
Recording and Reporting Responsibilities 
44 
9.5. 
Reporting urgent safety measures 
45 
10. 
STATISTICS AND DATA ANALYSIS 
45 

 
 
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10.1. 
Sample size justification 
45 
10.2. 
Planned recruitment rate 
46 
10.3. 
Description of Methods of Analysis 
46 
10.3.1. 
Operational analysis 
46 
10.3.2. 
Feedback analysis 
46 
11. 
DATA MANAGEMENT 
47 
11.1. 
Data collection tools and source document identification 
47 
11.2. 
Data handling and record keeping 
47 
11.3. 
Access to Data 
47 
12. 
MONITORING, AUDIT AND INSPECTION 
48 
12.1. 
Internal audits 
49 
12.2. 
External inspections 
49 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
49 
13.1. 
Research Ethics Committee (REC) Review and Reports 
49 
13.2. 
Research Ethics Committee (REC) Review and Reports 
49 
13.3. 
Peer review 
49 
13.4. 
Public and Patient Involvement 
49 
13.5. 
Indemnity 
50 
13.6. 
Post study care 
50 
14. 
DISSEMINATION AND PUBLICATION 
50 
14.1. 
Data sharing 
50 
14.2. 
Publication Plan 
50 
14.3. 
Authorship eligibility guidelines and any intended use of professional writers 
50 
15. 
REFERENCES 
51 
16. 
PROTOCOL AMENDMENT HISTORY 
52 
 
 
 
 
 

 
 
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TABLE OF FIGURES AND TABLES 
 
Figure 1: Schematic of study activities.. 
24 
Figure 2: CONSORT diagram for patient participants. 
25 
Figure 3: Patient Participant Flow Diagram. . 
27 
Figure 4: Transport and processing of study samples. 
33 
 
 
Table 1: Summary of protocol contributors. 
13 
Table 2: Summary of Objectives, Outcome Measures and timepoints. 
19 
Table 3: Schedule of assessments; patient participant, HCP and PCC. 
23 
Table 4: Definitions of AEs and device deficiency. 
37 
Table 5:Severity Classification 
37 
Table 6: Definitions of relationship to device or procedure 
38 
Table 7: Event outcomes. 
38 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
BAME 
Black, Asian and Minority Ethnic 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CVD 
Cardiovascular Disease 
DNA 
Deoxyribonucleic Acid 
EMIS 
EMIS Health (formerly Egton Medical Information Systems)  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GP 
General Practice 
DMP 
Data Management Plan 
HCP 
Healthcare Professional 
IB 
Investigator Brochure 
IFU 
Instructions For Use 
ICF 
Informed Consent Form 
ID 
Identifier 
IRT 
Integrated Risk Tool 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
IVD 
In Vitro Diagnostic 
LPLV 
Last Participant Last Visit 
MI 
Myocardial Infarction 
NECS 
NHS North of England Commissioning Support 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 
NIHR 
National Institute for Health Research 

 
 
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PCC 
Primary Care Commissioner 
PI 
Principal Investigator 
PIC 
Patient Identification Centre 
PIS 
Patient Information Sheet 
PRS 
Polygenic Risk Score 
QALY 
Quality-Adjusted Life Years 
QC 
Quality Control 
QRISK 
A clinical risk assessment tool for CVD used by GPs in the UK 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SMF 
Study Master File 
SNP 
Single Nucleotide Polymorphism 
SOP 
Standard Operating Procedure 
TIA 
Transient Ischaemic Attack 
USADE 
Unanticipated Serious Adverse Device Effect 
YLL 
Years of Life Lost 
 
 
 

 
 
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STUDY SUMMARY 
 
Study Title 
Healthcare Evaluation of Absolute Risk Testing: A multi-centre, single arm, 
pragmatic study in primary care setting 
Short title 
The HEART Study 
Clinical Phase 
 Performance evaluation to assess clinical utility 
In Vitro Device 
Cardiovascular disease (CVD) Integrated Risk Tool (IRT) 
A risk assessment tool combining patient clinical and genetic information 
to provide a score of the risk of developing cardiovascular events (heart 
attack or stroke) within the next 10 years.  
Study Design 
Multi-centre, prospective, single arm, interventional, pragmatic study. 
Study Participants 
Inclusion 
Aged 45-64 years, 
either biological sex, 
any ancestry or background, 
eligible for National Health Service (NHS) Health Check using QRISK®2 
assessment. 
 
Exclusion 
Those excluded from NHS Health Checks, 
Currently prescribed and taking HMG-CoA reductase inhibitors (lipid-
lowering preventive treatments or statins) for any indication. 
Planned Size of 
Sample (if applicable) 
1000 participants will be recruited across 10-12  general practitioner (GP) 
practices in the North of England where they will provide blood samples 
and answer questionnaires.  A subset of 100 participants will consent to 
and provide saliva samples.  
Additionally 20-30 participants who have answered the questionnaire will 
be invited to take part in an interview. 
 
Duration for 
participants (if 
applicable) 
Estimated 5-12 weeks per participant, with a questionnaire up to 2 weeks 
later. 
 
A subgroup of 20-30 participants will be invited for an interview within      
2 months of the questionnaire. 
Planned Study Period 
(Recruitment) 
5-7 months 
 
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Study Aim 
The aim of this study is to describe the operational acceptability and 
impact of predictive genetic testing for CVD risk within a primary health 
care setting.  
Primary Objective 
  
To demonstrate that an IRT (combining genetic and non-genetic risk 
factors) for CVD can be incorporated into routine primary care. 
Secondary Objectives 1. To explore and assess the impact of the CVD IRT on clinical decision-
making. 
2. To assess the magnitude of the change in risk score between QRISK®2 
and CVD IRT. 
3. To explore and assess to what extent healthcare providers (HCPs) and 
primary care commissioners (PCCs) perceive the CVD IRT as 
operationally efficient and enhancing the service that they provide. 
4. To explore and assess to what extent HCPs and PCCs perceive the CVD 
IRT as clinically relevant.  
5. To explore and assess to what extent participants perceive the 
information received through the CVD IRT as informative for health 
and wellness. 
6. To explore and assess the impact of the CVD IRT on patient 
engagement.  
7. To identify and explore effective ways to communicate risk and 
genetics information about CVD IRT to patients, HCP and PCCs.  
8. To evaluate the performance of saliva as compared to blood for use in 
the CVD IRT. 
9. To monitor the study for any potential safety concerns. 
 
 
 
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1. 
BACKGROUND 
Every individual has a unique set of genes (or genome), and variation in the genome can affect an 
individual’s risk of developing disease.  Sometimes, diseases are caused by rare changes (mutations) 
in one particular part of the genome. For example, 55%–72% of women who inherit a harmful BRCA1 
variant and 45%–69% of women who inherit a harmful BRCA2 variant will develop breast cancer by 
70–80 years of age1.  
More frequently, common diseases such as cardiovascular disease (CVD) do not stem from rare high-
risk variants, but rather are known to be influenced by many tiny changes, called single nucleotide 
polymorphisms (SNPs), across many different parts of the genome2. These variations (often hundreds 
of thousands or more) have small effects individually, but together, these variants can be powerful 
in understanding and measuring the genetic risk of developing certain diseases. Summing these 
effects together results in a Polygenic Risk Score (PRS), a single numerical score which provides a 
summary of an individual’s propensity to develop that disease based on their genetics3.  
This PRS can be combined with clinical risk factors to create an Integrated Risk Tool (IRT), which can 
give a more accurate picture of an individual’s overall risk of developing a health condition in the 
future4,5. 
Importantly, genetic risk factors do not change over time, and so can be measured much earlier 
(before any symptoms of a disease develops) in a person’s lifetime. This means that genetic risk 
factors are potentially very powerful tools for preventative healthcare.  Preventing disease is a 
fundamental challenge for public health. Not only do we need to know how to treat, but also who 
and when to treat. Timing matters, as interventions often need to be initiated early. Improved 
prevention lies at the heart of the NHS 10-year plan6. 
Identifying rare mutations such as the BRCA1 and 2 variants usually requires reading entire blocks of 
the genome (an expensive process known as sequencing); however, the many common variants 
which affect risk of common diseases can be measured with genotyping chips, which measure a 
predetermined set of about 1 million of the 3 billion positions in the human genome7. This technology 
opens the prospect of offering cost-effective genetic analysis in primary care. 
1.1. 
Cardiovascular Disease 
In addition to being a burden to affected individuals, CVD events are a major operational and 
financial burden for the NHS. Research by Danese et al8 estimates that myocardial infarction (MI) has 
an initial mean cost for the NHS per patient of £4,275 and thereafter a yearly cost of £922. The costs 
of managing co- or multi-morbid patients with CVD is higher due to the increased complexity of care.   
● CVD is a leading cause of morbidity, mortality, and expenditure. It accounts for a quarter of all 
deaths in the UK (170,000 deaths a year), and £9 billion in healthcare cost9. 
● Each percentage of reduction in cardiovascular events in England and Wales would result in 
3,500 fewer deaths, 98,000 more Quality-Adjusted Life Years (QALY), and gains of £265M over 
10 years10. 
● The Global Burden of Disease Study identified ischaemic heart disease as the leading cause of 
Years of Life Lost (YLLs) in the UK in 2016 for both sexes11. 
Given this burden, the NHS Long Term Plan6 has identified CVD prevention as a national clinical 
priority, with an ambition to prevent 150,000 heart attacks and strokes over the next 10 years by 
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improving the detection and management of high blood pressure, high cholesterol, and atrial 
fibrillation. The Long Term Plan also commits to the commissioning of a new national CVD prevention 
audit for primary care. The audit is aimed at improving the earlier identification of patients with CVD. 
HMG-CoA reductase inhibitors (lipid-lowering preventive treatments or statins) and other low cost 
management strategies (including support for lifestyle changes) are already well established 
strategies for the reduction of CVD incidence12.  Improving the identification of individuals at 
increased risk is a key opportunity for the targeted delivery of these low-cost and accepted 
preventive interventions within the NHS. 
The current widely used risk calculation tool used by healthcare practitioners is QRISK®, a calculator 
which combines a range of non-genetic risk factors, to measure ten-year CVD risk in patients13.   The 
latest version of QRISK® is QRISK®3; however, QRISK®214 is still widespread due to the embedding of 
the calculator in primary care patient administration systems such as EMIS and SystmOne. QRISK®2 
remains the version officially recommended by National Institute for Health and Care Excellence 
(NICE) guidelines12. Under current NICE guidelines, patients identified by QRISK®2 of having a ten-
year risk greater than 10% are at-risk and considered for intervention by GPs.  
1.2. 
The Integrated Risk Tool for Cardiovascular Disease (CVD IRT) 
The CVD IRT is a system-supported algorithm that combines an individual’s PRS with their QRISK®2 
score to calculate the integrated risk of developing CVD over the next 10 years, including events such 
as angina, myocardial infarction (MI), stroke, or transient ischaemic attack (TIA). Research performed 
by Genomics plc has demonstrated that IRTs combining disease-specific PRSs with existing clinical 
CVD risk assessment tools can significantly improve risk prediction4,5, and that when it comes to the 
risk of developing heart disease, genetics are as important to measure as factors such as blood 
pressure.  
Using UK Biobank data, of younger middle-aged individuals that are currently invisible to the system 
under QRISK®2, 6.4% would be flagged at high risk (≥10%) by the use of the CVD IRT of developing 
CVD within the next ten years.  Extrapolated to the UK population, this represents 27,250 patients 
presenting as CVD cases within a ten-year period4.   
This CVD IRT has been validated for use in 45-64 year old individuals of all biological sexes of any 
ancestry, who do not have pre-existing cardiovascular disease and do not currently take statins5.  
1.3. 
      Management of QRISK®2 and CVD IRT report for participant discussion 
Although the CVD IRT makes use of sophisticated techniques including genetic analysis and the 
application of complex algorithms, the system is simple for the HCP and patient to use and 
understand. The CVD IRT requires the patient to provide a blood sample that is sent for genetic 
analysis and the HCP to complete a QRISK®2 assessment for the patient.  
When the PRS is combined with the QRISK®2 score to generate the IRT score, the GP will receive a 
report to share with the patient and to inform treatment options as per NICE guidelines.  Current 
NICE guidance recommends intervention if the ten-year risk of CVD is greater than 10%. Both 
QRISK®2 and CVD IRT produce estimates of 10-year CVD risk, therefore, where the QRISK®2 and / or 
the CVD IRT score exceeds 10%, NICE guidance is recommended to be followed.   
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The CVD IRT report will be available up to 12 weeks after the sample is taken. If QRISK®2 indicates 
intervention is needed within this timeframe, the physician's discretion should be used. 
2. 
RATIONALE 
The aim of this study is to demonstrate the integration and use of CVD IRT in an environment as close 
to real-world as possible. 
This study will recruit participants of both biological sexes and any ancestry or background who 
require and are eligible for a CVD risk assessment15 as part of the NHS Health Check. Those aged 45-
64 years are most likely to benefit from CVD IRT and will be included in the study, as they are more 
likely to be asymptomatic but also derive most benefit from preventative measures. 
The study will be conducted in GP surgeries as the CVD IRT will have its greatest impact if 
incorporated into primary care practice for early identification of patients at highest risk. 
Training and guidance on the interpretation of the CVD IRT report will be provided before study 
recruitment commences. The training will comprise an understanding of the CVD IRT, indications and 
contraindications for use and review of potential risks. For this study a training session will be 
delivered either in person or via video conferencing. 
2.1. 
Assessment and management of risk 
The CVD risk assessment tool currently available within primary care is QRISK®. This online tool allows 
HCPs to enter patient information (including some blood results) to generate a percentage risk of 
the patient developing CVD over the next 10 years. For the IRT, as well as generating a QRISK®2 score, 
the patient provides an additional blood sample for genetic analysis (PRS). In either scenario, the 
patient will need to provide blood samples and clinical data. 
Regardless of which risk assessment score is used, the patient may experience anxiety in awaiting 
the report and receiving the report. A person’s inability to influence genetics may cause additional 
distress compared to the QRISK®2 score. However, in a summary of 30 studies, predispositional 
genetic testing had no significant impact on psychological outcomes, little effect on behaviour, and 
did not change perceived risk15. With this in mind, it is assessed that the risk to benefit ratio of the 
study is acceptable, exposing the participant to limited risk similar to a QRISK®2 score. 
Training of staff on understanding the influence of genetics on an individual’s risk and how to 
interpret and present the genetic data will aim to alleviate patient anxiety.  
The qualitative aspect of the study to the participant, HCP and PCCs is considered extremely low risk. 
 
 
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3. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
The aim of this study is to describe the operational acceptability and impact of predictive genetic 
testing for CVD risk within a primary health care setting.  
3.1. 
Primary objective 
The primary objective of this study is to demonstrate that an IRT combining genetic and non-genetic 
risk factors) for CVD can be incorporated into routine primary care. 
3.2. 
Secondary and exploratory objectives 
The secondary objectives are described as follows: 
1. To explore and assess the impact of the CVD IRT on clinical decision-making. 
2. To assess the magnitude of the change in risk score between QRISK®2 and CVD IRT. 
3. To explore and assess to what extent HCPs and PCCs perceive the CVD IRT as operationally 
efficient and enhancing the service that they provide. 
4. To explore and assess to what extent HCPs and PCCs perceive the CVD IRT as clinically 
relevant.  
5. To explore and assess to what extent participants perceive the information received 
through the CVD IRT as informative for health and wellness. 
6. To explore and assess the impact of the CVD IRT on patient engagement.  
7. To identify and explore effective ways to communicate risk and genetics information about 
CVD IRT to patients, HCP and PCCs.  
8. To evaluate the performance of saliva as compared to blood for use in the CVD IRT. 
9. To monitor the study for any potential safety concerns. 
The exploratory objectives are described as follows: 
1. To explore and assess the perception of healthcare providers and commissioners on the 
usefulness of CVD IRT.   
2. To collect further insights from the study which may aid in the development of clinical 
decision tools and products based on PRS for disease risk prediction. 
3.3. 
Outcome measures 
Outcome measures will be a combination of operational data such as report return rates and 
qualitative and quantitative data gathered from questionnaires, interviews and focus groups. 
3.4. 
Primary endpoint 
The primary endpoint will be measured both by operational success (report return rates), and 
feedback from HCPs and patients.  
3.5. 
Secondary and exploratory endpoints 
The secondary endpoints will be measured as follows: 
1. Changes in patient treatment based on risk scores at Visit 2.  
2. Comparison of QRISK®2 and CVD IRT scores. 
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1. To explore and assess the 
impact of the CVD IRT on 
clinical decision-making. 
Changes in patient 
treatment based on risk 
scores 
● Visit 2 
2. To assess the magnitude of the 
change in risk score between 
QRISK®2 and CVD IRT 
QRISK®2 and CVD IRT 
scores to be compared 
● 
Visit 2 
3. To explore and assess to what 
extent HCPs and PCCs perceive 
the CVD IRT as operationally 
efficient and enhancing the 
service that they provide 
HCP feedback via 
● 
questionnaires 
● 
focus group(s) 
 
● 
Visit 2  
● 
As close to or just after LPLV2 
● 
As close to or just after V4 
      
PCC feedback via 
● focus group 
 
● 
As close to or just after HCP focus 
group(s) 
4. To explore and assess to what 
extent HCPs and PCCs perceive 
the CVD IRT as clinically 
relevant 
HCP feedback via 
● 
questionnaires 
● 
focus group(s) 
 
● 
Visit 2  
● 
As close to or just after LPLV2 
● 
As close to or just after V4 
           
PCC feedback via 
● 
focus group 
 
● 
As close to  or just after HCP focus 
group(s)      
 
5. To explore and assess to what 
extent participants perceive the 
information received through 
the CVD IRT as informative for 
health and wellness 
Participant feedback via 
● 
questionnaires 
● 
interviews 
 
● 
Visit 3 
● 
Visit 4 
6. To explore and assess the 
impact of the CVD IRT on 
patient engagement 
Participant feedback via 
● 
questionnaires 
● 
interviews 
 
● 
Visit 1 
● 
Visit 3 
● 
Visit 4 
7. To identify and explore 
effective ways to communicate 
risk and genetics information 
about CVD IRT to patients, HCP 
and PCCs 
Participant feedback via 
● 
questionnaires 
● 
interviews 
 
● 
Visit 3 
● 
Visit 4 
HCP feedback via 
● 
questionnaires 
● 
focus group 
 
● 
Visit 2  
● 
As close to or just after LPLV2 
● 
As close to or just after V4 
      
PCC feedback via 
● 
focus group 
 
● 
As close to or just after HCP focus 
group(s) 
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4.1. 
Quantitative Design 
The study will collect approximately 2000 blood samples (one sample for analysis and a second for 
back-up) from 1000 participants to undertake genomic testing to provide a CVD IRT score to each 
participant.  
Of the 1000 participants, 100 participants at 1 or 2 selected site(s) will also provide saliva samples. 
These samples do not contribute to the CVD IRT score, but will be used to assess the potential use of 
saliva as DNA source for genomic analysis for PRS.   
4.2. 
Qualitative Design 
Qualitative data in the form of questionnaires and interviews will be collected from the participants. 
In addition, the study will gather qualitative data (questionnaires and focus groups) from the HCPs 
undertaking the clinical study, as well as a focus group with PCCs. The content and timing of the 
questionnaires, interviews and focus are provided in Figure 1. 
5. 
STUDY SETTING 
This multi-centre study to be conducted at 10-12 GP practices plans to recruit approximately 1000 
participants, divided to around 50-100 patients per site.  
The GP practices are responsible for participant identification, informed consent, biosample 
collection and collection of study data, and discussing results and care plans with participants. The 
sites are also responsible for supporting the qualitative research team with distributing 
questionnaires, arranging interviews and participating in focus groups. 
The study sites should already be participating in the NHS Health Check programme, using QRISK®2 
as part of the Health Check to assess patient risk of developing CVD. 
To be included in the study, GP practices must: 
● have access to the internet and hardware that they can use to interact with the study 
solution (i.e. a computer that can run the Chrome web-browser); 
● use EMIS or SystmOne to calculate the QRISK®2 score; 
 
To boost recruitment, recruiting centres may use Participant Identification Centres (PIC)s with the 
prior agreement of the sponsor. A limit of 2 PICs per recruitment centre will be applied. 
 A list of participating sites and PICs will be held in the Study Master File (SMF). 
5.1. 
COVID-19 Restrictions 
Any patient contact for the purposes of the study must comply with COVID-19 restrictions applicable 
at the time of study recruitment. This includes careful adherence to guidance around blood and saliva 
sampling. Based on restrictions, it is anticipated that COVID-19 positive patients will not be attending 
the surgery and therefore additional exclusion criteria based on COVID-19 have not been included in 
the study design. 
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6. 
ELIGIBILITY CRITERIA 
The study includes patients who are due an NHS Health Check, the inclusion and exclusion criteria 
are outlined in the following section (6.1). 
The study also includes interviews and focus groups with HCPs and PCCs. For clarity, these groups of 
contributors are described in sections 6.2 and 6.3 respectively.   
6.1. 
Participant Eligibility Criteria 
The study will aim to recruit an estimated 1000 participants as defined by the inclusion and exclusion 
criteria.  
6.1.1. 
Inclusion criteria 
Participants must meet the following criteria to be eligible for this study: 
1. 
Able and willing to provide written informed consent and to comply with the study protocol  
2. 
Either male or female (biological sex) 
3. 
Aged 45-64 years (inclusive) 
4. 
Any ancestry or background 
5. 
Eligible for NHS Health Check using QRISK®2 assessment 
6.1.2. 
Exclusion criteria 
Participants who meet any of the following exclusion criteria will not be eligible for this study.  
1. 
Those excluded from NHS Health Checks; Currently prescribed and taking HMG-CoA 
reductase inhibitors (lipid-lowering preventive treatments or statins) for any indication. 
6.2. 
HCP Eligibility Criteria 
6.2.1. 
Online Questionnaire 
All HCPs (physician or nurse) having received study training who are listed on the site delegation log, 
and have interacted with study participants, will be asked to complete the online questionnaire. 
6.2.2. 
Focus Group(s) 
Physicians for the focus group will be drawn from those who completed the online questionnaire 
and will be selected using standard qualitative research sampling techniques. 
Depending on the number of online questionnaire responses, a focus group for nurses may also be 
conducted, with participants selected using standard qualitative research sampling techniques. 
Multiple physician and nurse focus groups may be undertaken if scheduling of only one focus group 
for physicians and nurses, respectively, is challenging.      
 
 
 
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Interview consent 
        X 
 
 
      
 
Participant Interview 7 
 
 
 
X 
 
HCP Questionnaire 
  
X  
  
  
X8 
HCP Focus Group(s) 
 
 
 
 
X9 
NHS PCC Focus Group  
 
 
 
 
X10 
1. 
Signed, written informed consent obtained prior to any study specific procedure. Separate consent required for saliva samples. 
2. 
2x2.5ml samples for genetic analysis, the second sample as back-up in case of failure at any stage of processing. 
3. 
A subset of participants (~100) at selected sites (1-3 sites depending on recruitment) will provide a 2ml saliva sample. 
4. 
The QRISK®2 score will be available some days after Visit 1.The IRT score will be available up to 12 weeks after the sample collection.  
5. 
Related adverse events (ADEs) are to be collected from the provision of written informed consent up to the completion of the online 
questionnaire. 
6. 
Following the questionnaire and up till study end, only SADEs self-reported by the participants will be collected. 
7. 
A subset of participants (20-30) who expressed an interest in participating in an interview will be invited for a 30 minute phone 
interview. Separate consent will be collected for the interview from all participants when approx. ⅓ enrolment completed      
8. 
HCP questionnaires will take place at each site after at least ⅔ of that site’s participants or at least ⅔ of the total study participants 
(whichever is first for each site) have completed Visit 2. 
9. 
The HCP focus groups will take place after the HCP questionnaires have been completed but may take place before all of the site’s 
participants have received their study results.      
10. The PCC focus group may be scheduled at any time after the HCP questionnaires have been issued.       
 
Table 3: Schedule of assessments; patient participant, HCP and PCC. 
 
The following figure demonstrates the timing of participant activities in relation to HCP and PCC 
activities. The HCP and PCC focus groups will be undertaken towards the end of the study aiming to 
finish no later than the end of the patient interviews        
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Figure 1. Schematic of study activities. The last study activity will be either the last participant interview, last 
HCP focus group or the PCC focus group, whichever comes last. (V - visit, LPLV - Last Participant Last Visit) 
      
7.1.1. 
Participant Recruitment 
The following figure demonstrates planned participant recruitment and anticipated attrition. 
 
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Figure 2: CONSORT diagram for patient participants. If identified participants decide not to proceed in the 
study, they will have the opportunity to continue with a CVD risk assessment as per standard practice 
(QRISK®2). If during the study, it is not possible to provide the participant with the CVD IRT score, they will 
receive the QRISK®2 score and continue with standard recommended treatment based on the QRISK®2 score 
received. 
7.1.2. 
Participant identification 
Potential participants will be identified primarily by searching the clinic database for patients due an 
NHS Health Check. Additionally, opportunistic recruitment during routine consultations may also 
take place, if they require an NHS Health Check.  
7.1.3. 
Participant Screening 
Identified potential participants who are eligible for an NHS Health Check and QRISK®2 evaluation 
will be considered for participation in the study,  unless the investigator considers the potential 
participant unsuitable for the study.  
The study invitation letter will be provided with a copy of the patient information sheet (PIS) and 
consent form (on surgery headed paper). Study sites participating in the saliva sub-study will provide 
the PIS and consent form for the saliva sample as well.  
A screening log of those identified by search will be maintained, documenting when invites are sent, 
if they are not invited or if they fail to respond. For ease, this can be documented on a print out of 
the search results, or a separate screening log can be maintained. The screening log, in whichever 
format used, will be filed in the Investigator Site File (ISF).  
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7.1.4. 
Participant Payment  
Participants may be reimbursed for reasonable travel expenses, but no other payments will be made. 
7.1.5. 
Participant Consent  
The Principal Investigator (PI) will retain overall responsibility for the conduct of research at their 
site, including the taking of written informed consent of participants at their site. They will ensure 
that any person delegated responsibility to participate in the informed consent process is duly 
authorised, trained and competent to participate according to the ethically approved protocol, 
principles of Good Clinical Practice (GCP) and Declaration of Helsinki. 
Physicians or practice nurses will take consent, as per delegation log. 
Written informed consent will be obtained from the participant after they have been given adequate 
time and opportunity to discuss any study related questions with the health care team. Consent is 
anticipated to be provided during an appointment (in person) with the health care team, but may 
also be provided remotely, via telephone or video conference,  and written consent will be obtained 
before any other study procedures (data and biosample collection) commence.  
The staff member recording consent will be responsible for assessing the capacity of the interested 
participant to provide informed consent.  
Patients will be informed that if they decline to participate in the study (without having to give a 
reason), that decision will not compromise their ongoing health care.  
The sponsor will keep anonymised genetic data to support future research. If the participant does 
not wish to allow the sponsor to keep genetic data for future research, they will not be able to 
participate in the study. 
The participant will remain free to withdraw at any time from the study without having to give a 
reason and without prejudicing their further management and will be provided with a contact point 
where they may obtain further information about the study. Where a participant is required to re-
consent or new information is required to be provided to a participant it is the responsibility of the 
PI to ensure this is done in a timely manner.  
The original signed consent form will be provided to the participant, and copies filed in the 
investigator site file (ISF) and participant medical notes if required by local practice. 
7.1.6.  Additional participant consent provisions for collection of saliva samples and 
interviews 
Around 100 participants (at 1-2 sites) of the 1000 participant population will be asked to provide 
saliva samples for a subanalysis of the study, looking at the capability of using DNA extracted from 
saliva samples for genetic analysis. A separate information sheet and consent form will be provided 
for the provision of saliva samples. 
Participants asked to provide saliva samples can decline to do so and still participate in the main 
study. 
Around 20-30 participants will be invited for an interview after one  third of participants have been 
recruited. The participants will be selected by the qualitative researcher from data provided  by the 
sponsor on participants who have provided consent to take part in the interview as described in 
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7.1.6.1.      The researcher will notify the relevant site clinical study team to identify and pass on 
contact details to the qualitative researcher. 
7.1.7. 
Participant Study assessments, per visit 
A participant’s journey will include 3 visits, and potentially up to 4 visits, as demonstrated in Figure 
2. 
 
 
Figure 3: Patient Participant Flow Diagram. Only patient participant visits are outlined in the schedule above.      
The HCP questionnaires and focus groups (HCP and PCC) will be conducted in parallel with the participant 
Interviews where necessary.       
 
7.1.7.1.     Visit 1, Baseline 
Before (remotely) or During Visit 1, the participant will have the opportunity to further review the 
information sheet and have any questions answered before signing a consent form. The participant 
should only sign and date the consent form if they wish to participate in the study. If for any reason 
they are unwilling or unable to sign the consent form, they cannot participate in the study. 
After approximately ⅓ of participants are enrolled,  subsequent participants will be asked if they are 
willing to consent for selection to take part in an interview, consisting of a 30 minute telephone 
interview about the study,  approximately 1-2 months after receiving their results.  If the participant 
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agrees to take part they are asked to sign the interview consent form at Visit 1. Information to be 
collected at Visit 1 after written informed consent has been obtained will comprise: 
● date of visit 
● date of consent 
● confirmation of eligibility 
● date of blood sample 
● age at time of sample 
● biological sex 
● self identified ethnicity 
● educational level 
● date of consent for saliva sample (if applicable) 
● date of saliva sample (if applicable) 
● QRISK®2 score (when available) 
● questionnaire (4 questions to participants). 
Since the study requires the participant to receive an online questionnaire, the site will require the 
participant’s email address. This will be documented in the enrolment log. 
Study eligibility will be confirmed by a member of the study team (as per delegation log) using 
participant medical notes and questioning the participant, and eligibility will be documented in the 
Case Report Form (CRF), but no details of the medical history will be collected for the purposes of 
the study. 
When eligibility has been confirmed, the participant will be added to The HEART Application using 
their age and biological sex. The study staff will be trained on the use of The HEART Application and 
receive instruction for use (IFU), electronic Case Report Form (eCRF) and sample handling and 
posting and their site responsibilities. The system will generate a participant ID, which is used to 
identify the participant in all study documentation and added to the enrolment log, participant 
medical notes, sample shipping logs, adverse and serious adverse device event in the  eCRF. 
Since all participants are attending for a CVD risk assessment, they will be providing a blood sample 
as part of the process. The study requires blood to be taken using a butterfly and vacutainer holder, 
which will allow all blood samples (standard care and study) to be obtained via a single venepuncture. 
The study samples will be prepared as described in the ‘Sample Handling and Shipping Instructions 
Manual’. To ensure tracking, the samples will be labelled with a barcode and its human readable 
form (a six-digit number (XX-YYY-Z). The six-digit number is entered into The HEART Application. 
Spare labels are provided. 
Before the participant leaves Visit 1, they will be asked to complete a short questionnaire (4 
questions) on paper, with their participant ID and date of visit completed on the questionnaire. 
Participants hand the completed form to the study staff before they leave. Study staff enters 
questionnaire answers to the participants data in the eCRF. 
When the QRISK®2 score is available, this will be added to The HEART Application as it is required to 
calculate the CVD IRT. 
QRISK®2 score will be provided to the participant at the same time as the CVD IRT to simplify the 
process for the participant (unless physician intervention based on the QRISK 2 is needed before the 
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CVD IRT is available), so as not to receive two separate scores for the risk of developing CVD at 
different times. 
In the event that a CVD IRT score cannot be provided to the participant, a replacement sample will 
not be sought and the participant’s QRISK*2 score will be used to determine the standard of care. 
This may be due to loss of sample in transit to the laboratory or under the quality controls for sample 
processing, the sample integrity does not yield adequate DNA or the PRS score cannot be generated.  
7.1.7.2. 
Saliva Samples  
If the participant is attending a clinic recruiting for the saliva subanalysis, they will be asked to provide 
a saliva sample. They will be given the opportunity to review a separate information sheet and sign 
a separate consent form. They may decline the substudy while still participating in the main study. 
They will provide a 2ml sample, which will be labelled and packaged according to the instructions, 
and sent to a separate laboratory for DNA extraction.  
There is a small possibility that saliva samples go missing in transit to the laboratory, despite 
processes in place to mitigate the risk. If this is the case, there will be no impact to the participant 
and they will not be asked to provide a replacement sample.  
Saliva samples are for research purposes only.  The CVD IRT will be based on blood samples not saliva 
samples.  
7.1.8.     Visit 2, Receiving CVD IRT results and study participant management  
Approximately 5-12 weeks after the blood sample collection, the CVD IRT result will be available. The 
study staff will be notified of its availability by email and will be able to download the CVD IRT report 
from The HEART Application. Study personnel will be trained on the content of the report and best 
practice on sharing genetic information. Only those trained and listed on the delegation log will be 
permitted to share the CVD IRT results with the participants. 
Current NICE guidance recommends intervention if the ten-year risk of CVD is greater than 10%. Both 
QRISK®2 and CVD IRT produce estimates of 10-year CVD risk, therefore, where the QRISK®2 and / or 
the IRT score exceeds 10%, NICE guidance is recommended to be followed.  
The IRT report will be available up to 12 weeks after the sample is taken.  If QRISK®2 indicates 
intervention is needed within this timeframe, the physician's discretion should be used. 
The HCP will determine the best method of sharing the results (QRISK®2 and CVD IRT) as per standard 
practice. Participants may be contacted by phone or videoconference or may be asked to attend the 
clinic in person. 
At Visit 2 the following data will be collected: 
● date of visit 
● the method of sharing results, e.g., phone, videoconference or clinic visit 
● who shared results, e.g., GP or nurse 
● whether QRISK®2 score required change in treatment (e.g., statin, life style, both or none 
influenced the change) 
● any change in treatment (e.g. statin) 
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● if the participant’s CVD IRT score was higher than their QRISK score, whether the CVD IRT 
score influenced (or informed on) a change in treatment (e.g. statin. lifestyle, both or none)  
● what treatment was changed       
● the participant will be asked about any potential adverse events since the previous visit. 
The report is intended for HCP use to share results, but if requested by the participant a copy can be 
provided. The participant should be reminded of the online questionnaire and its importance to the 
study which will be sent to their email address in around 0-14 days’ time. The study staff should also 
ensure that the participant's personal email address is available and correct on the enrolment log, 
for the above purposes and for participation in Interviews, if required by NECS . 
7.1.9.     Visit 3, Online questionnaire 
Each participant will be emailed a link to a questionnaire by the study team. The individualised link 
for the questionnaire can be copied from The HEART Application, which will be available when the 
report is available for download. It is essential that the link copied from the correct participant ID is 
sent to the correct participant.  
Responses are anonymous and each questionnaire should take around 20 minutes to complete. 
If the questionnaire is not completed within 2 weeks, the participant will be reminded of the 
questionnaire either by re-sending the link by email or by phone contact from the clinical study team. 
If the questionnaire is still not completed, a further reminder can be sent. One  reminder will be the 
maximum number of reminders allowed per participant. The questionnaire link will be disabled no 
earlier than 4 weeks after the link was first sent, therefore, each participant is allowed at least 4      
weeks to complete the online questionnaire. 
The following information will be collected: 
● date questionnaire link sent to the participant 
● dates of reminders, if applicable 
● date of completion  
● anonymised questionnaire responses. 
7.1.10.     Visit 4, Phone interview 
     To participate in an interview, the participant must have signed the relevant focus group consent 
form at visit 1 and completed the online questionnaire at Visit 3. The participant will be informed 
that they may not be selected as only a small number of interviewees are required. If they are 
selected, they will be contacted by the study team conducting the Interview to arrange a suitable 
time. If they are not selected, there will be no further communication. 
If a participant is selected for a phone interview, they will be contacted by the qualitative research 
team.  
Consent procedures will be followed as described in section 7.1.5. 
With consent, their details will be passed to the qualitative research team to arrange a convenient 
time for the interview. A discussion guide will be used for the interview. 
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The following information will be collected: 
● consent date 
● interview date 
● audio recording, transcribed 
If the interviewee does not attend the interview, a single attempt will be made to reschedule. Non-
attendees will be replaced as required until approx 20- 30 participants are interviewed 
7.1.11. 
Withdrawal criteria  
Participants may be withdrawn from the study at any time for any reason.   
Reasons for withdrawal from the study may include, but are not limited to, the following: 
● Participant’s withdrawal of consent at any time. 
● Investigator or Sponsor determines it is in the best interest of the patient. 
Participants who wish to withdraw from the study can inform the investigator or study team at any 
time during the study. Participants who withdraw and who have had specimen samples taken for 
genetic analysis will not receive their results but their results will be used in the study analyses. A 
participant that wishes to withdraw before receiving the CVD IRT score will continue to receive their 
QRISK®2 score as per standard practice.  
Reasonable effort will be made to obtain information about participants who withdraw from the 
study, and the primary reason for withdrawal/discontinuation documented.  
The CRF will collect: 
● date of withdrawal 
● reason for withdrawal if the participant is willing to share. 
As described in section 9.2, if a participant has an ongoing serious adverse device effect (SADE) or 
unanticipated SADE (USADE) at their final visit, follow-up to resolution should be attempted. 
Patients who withdraw from the study will not be replaced. 
7.2. 
HCP participation 
7.2.1. 
Screening 
The Sponsor representative will work with qualitative researchers to identify HCPs that are eligible 
to complete the questionnaire (see section 6.2.1). 
7.2.2. 
Consent 
The online questionnaire includes a preamble to inform the HCP that by completing the 
questionnaire they are providing consent for the use of their data and responses. 
The focus group will require separate and written consent prior to focus group participation. 
7.2.3. 
Schedule   
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There will be two questionnaires for HCPs to complete - 
1) At Visit 2 - When the CVD IRT report has been received and discussion with the participant 
has taken place, the HCP will be required to complete a focused questionnaire in the eDC. 
2) When at least ⅔ of the site’s participants or at least ⅔ of the total study participants 
(whichever is first for each site) have completed Visit 2, the clinical study team will be 
provided with a link to an online questionnaire, designed specifically for the physicians and 
nurses who have participated in the clinical study. The questionnaire will take approximately 
20 minutes to complete.  
The HCPs will be reminded to complete the questionnaire a maximum of two times. 
When no more questionnaire responses are anticipated, focus groups will be arranged 
selecting HCPs from those that have completed the questionnaire. 
The timeline of the focus groups will be towards the end of participant participation at site, and the 
completion of the HCP questionnaires. It is intended that focus groups may be conducted in parallel 
with the participant Interviews . It is anticipated that the interviews will be conducted as close to or 
just after all participants have completed Visit 2.                  
7.3. 
PCC participation 
7.3.1. 
Screening 
The qualitative researcher will identify approximately five PCCs from the North East England Clinical 
Commissioning Groups (CCGs). 
7.3.2. 
Consent 
The focus group will require written consent prior to focus group participation. 
7.3.3. 
Schedule 
The PCC focus group will be conducted at any time after the HCP questionnaires have been sent 
out and maybe conducted in parallel with the participant interviews and HCP focus groups.          .  
7.4. 
End of study 
The end of the study is taken as the date of the last participant, last interview (Visit 4). Focus groups 
with HCPs and PCCs may      take place before or after the end of the study     . 
The end of the study for an individual participant is defined as the date when the participant has 
completed the online questionnaire, OR for a participant being interviewed as soon as that interview 
has taken place, unless they have been withdrawn from the study earlier.  
The end of the study for an individual GP practice is defined as the date that the last participant has 
completed Visit 2, the HCPs have completed the online HCP questionnaire OR for a practice 
participating in the HCP focus group, as soon as that focus group meeting has taken place.   
When recruitment is complete, the function to add new participants will be removed from all sites.  
The HEART application will be kept live until the final reminder for the questionnaire has been 
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submitted, to allow access to the questionnaire link. Access will be removed on a site by site basis as 
each site completed study activities. 
The final activity of the study is either the final participant Interview, the final HCP focus group of the 
PCC focus group, whichever comes last.      
7.5. 
Storage, analysis and destruction of clinical samples  
A ‘Sample Handling and Shipping Instructions Manual’ will be provided for sites to instruct on the 
samples required and how to package for delivery. No sample processing will take place at site and 
no blood or saliva samples will be stored at site and all samples will be packaged on the day of 
collection and sent for analysis within 24 hours. No patient identifiable information will be provided 
with the samples; only the participant ID and sample number/barcode linked to the samples. 
Samples will be tracked and monitored through to destruction.  
7.5.1. 
Biosample processing  
Biosample processing and the generation of the genetic data will take place in contracted research 
laboratories following laboratory standard operating procedures (SOPs) and Sponsor’s instructions.  
Anonymised samples collected from consenting participants will be transported to separate UK 
laboratories (one for blood, one for saliva) where DNA will be extracted from the samples. Blood and 
saliva DNA, only sufficient for analysis and no more, will be transported to a single genotyping 
laboratory in the US for genetic analysis. The resulting DNA sequences (electronic files) will be 
returned to Genomics plc in the UK. 
Anonymisation of samples will be maintained throughout sample processing.  
7.5.2. 
Genetic data analysis 
Blood samples 
On receipt of the individual genetic results, analysis of genetic data will take place at Genomics plc. 
Individual level CVD IRT reports will be generated for each participant and returned to the GP 
practice.  
Saliva samples 
DNA extracted from the saliva samples will be used for exploratory purposes only to understand 
whether DNA extracted from saliva can provide comparable results. 
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Figure 4: Transport and processing of study samples.  
 
7.5.3. 
Sample destruction 
The DNA will be extracted from one of the blood samples and the saliva sample at the respective 
DNA extraction laboratories. The second blood sample will be stored in case of quality failure with 
the initial blood sample. 
The DNA will be stored at the extraction lab, with only sufficient DNA for analysis sent to the 
Genotyping laboratory in the US. Excess DNA will be stored at the UK DNA extraction laboratories in 
case replacement samples are required. At the end of the study, any and all unused DNA and 
remaining blood and saliva samples will be destroyed when genetic analysis for the study is 
complete, on the sponsor’s instructions. 
The DNA sequence (now electronic data) will be sent to Genomics plc to calculate the PRS, and to 
determine the CVD IRT score. 
7.5.4. 
Future research 
The anonymised genetic data (electronic only) will be kept for future research, and this will be clearly 
set out in the participant consent forms. If the participant does not agree to their genetic data being 
kept for future work, they will not be able to participate in the study. 
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7.6. 
Qualitative assessments  
The study uses questionnaires, interviews and focus groups as qualitative assessments. 
7.6.1. 
Questionnaires 
Visit 1 (baseline): Participants will be asked to complete a paper questionnaire consisting of four 
questions. Participants will complete after the study procedures have been completed and just 
prior to leaving the GP Surgery. The study staff will enter the data into the eCRF and keep the 
questionnaires filed in the site file as source data. 
Visit 2: HCPs will be asked to complete a focused questionnaire via the eDC. 
Visit 3: An online questionnaire (using SurveyMonkey) will be sent to study participants and HCPs to 
complete. The questionnaires, different for participants and HCPs, are mixed qualitative and 
quantitative questionnaires designed to capture their understanding and perception of the CVD IRT 
as well as its usefulness and impact. 
All participants who completed Visit 2 will be requested to complete an online mixed quantitative 
and qualitative questionnaire. A link will be emailed by the site staff to the patients’ personal email 
address up to 14 days after the receiving test results, and patients will be reminded once to complete 
the questionnaire.  If there is no response after 4  weeks, the questionnaire will be closed to the 
participant. The target minimum response rate is 20%. 
All HCPs involved in the study will be emailed a link to the HCPs’ work email address after at least ⅔ 
of that site’s participants or at least ⅔ of the total study participants (whichever is first for each site) 
have completed visit 2. HCPs will be reminded to complete the questionnaire no more than twice. 
HCPs are expected to respond to the questionnaire within three weeks of issue. The target response 
rate is 50%.  
7.6.2. 
Interviews 
From the questionnaire respondents, a sample of participants will be selected by NECS for semi-
structured individual telephone interviews (which will be recorded) lasting approximately 30 minutes 
in length.  
The interview process will take place 1-2 months after a participant has completed their survey      
Participants  who consent to participate in these interviews will be selected to represent a purposive 
sample from a variety of practices and areas within the study. A total of 20-30 participants  will be 
interviewed (the final number will be dependent upon total interview recruitment figure) via 
telephone with the aim of undertaking up to  2 months after test results are returned.  
Interview topics will be structured around the relevant outcome measurements of the key study 
objectives.  Detailed interview questions will be developed and guided by the data received from 
online questionnaires and agreed with the Sponsor before the interviews take place.   
For example, patients may be asked about: 
● Study process - Level of satisfaction in experience 
● Study report results - Level of satisfaction in outcome 
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● Communication – Before and during the testing and results process 
The interviews will be recorded. The content will be analysed using thematic analysis. These findings 
will present anonymised patients’ perspectives and experiences and will be triangulated with the 
online questionnaire and quantitative data collection. 
NECS  will provide  anonymised typed transcripts from the recordings of the interviews and thematic 
analysis will be provided to Genomics plc Audio recordings will be destroyed once transcriptions have 
been analysed. 
7.6.3. 
Focus Groups 
7.6.3.1.   HCP 
The HCP focus groups will follow the completion by HCPs of the online questionnaire.  HCPs will be 
asked to provide and sign consent for the release of typed anonymised transcripts from the 
recordings of the focus groups to  NECS and thematic analysis provided to Genomics plc.  
NECS will run an online focus group(s) of around 15 HCPs from a number of practices.  The number 
is dependent upon the total recruitment figure and will be run until saturation is reached).  The focus 
groups will last 45 - 60 minutes in length and be held online (e.g. Zoom/Teams) after the majority or 
all of the HCP questionnaires have been returned.  There may be an option to incorporate this into 
a weekly practice meeting for HCP convenience. Dependent on recruitment, and subject to 
responses, a separate focus group(s) may be organised for nurses involved in the study.  
Interview topics will be structured around the relevant outcome measurements of the key study 
objectives.  Detailed interview questions will be developed and guided by the data received from 
online questionnaires and patient interviews, and agreed with the Sponsor before the interviews 
take place.   
For example, HCPs may be asked about: 
● 
Set-up - Incorporating the test into practice systems and initial approach to patients  
● 
Communication – Exchanges with patients and Genomics plc  
● 
Results - Level of satisfaction and perception of the process of obtaining and 
communicating results to patients 
● 
Implementation - Consideration of genetics as a risk factor in primary care 
● 
Usefulness - Value of genetics as a risk factor for cardiovascular disease 
The focus groups will be recorded.  The content will be analysed using thematic analysis. These 
findings will present HCPs anonymised perspectives and experiences and will be triangulated with 
the online questionnaire and quantitative data collection. 
7.6.3.2.    PCCs 
Primary Care Commissioners (PCCs) (<5) will be recruited from Northeast England Clinical 
Commissioning Groups (CCGs) to understand their views on potential implementation.  They will be 
invited to a separate focus group 45-60 minutes in length. The session will take place in parallel with      
the HCP focus groups.       
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Attending PCCs will be asked to provide and sign consent for the release of typed anonymised 
transcripts from the recordings of the focus groups.  
Interview topics will be structured around the relevant outcome measurements of the key study 
objectives.  Detailed interview questions will be developed and guided by the data received from 
online questionnaires, patient interviews and HCP focus groups, and agreed with the Sponsor before 
the interviews take place.   
For example, Primary Care Commissioners may be asked about: 
● Acceptability of the test in the current primary care setting 
● Implementation of genetics as a risk factor in primary care 
● Usefulness of genetics as a risk factor. 
Audio recordings will be analysed using thematic analysis. These findings will present PCCs’ 
anonymised perspectives and experiences. 
8. 
 CONCOMITANT MEDICATIONS 
No data on participant concomitant medications will be collected for this study. 
Participants who are required to start statin treatment based on the CVD risk assessment score 
provided at visit 2 will be able to do so.  
9. 
SAFETY MONITORING 
9.1. 
Definitions 
9.1.1. 
Adverse Events and Device Deficiency 
The adverse event and device deficiency definitions are aligned to those in the international 
standard ISO 20916: 2019 for in vitro diagnostic medical devices, allowing for CVD IRT being a risk 
assessment tool rather than a diagnostic tool.  
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, inappropriate patient management 
decision, unintended disease or injury, or untoward clinical signs, whether 
or not related to the IVD or study procedures. 
Serious Adverse 
Event (SAE) 
AE that led to any of the following 
a) death 
b) serious deterioration in the health of the participant as defined by 
one or more of the following 
i) 
a life-threatening illness or injury, or 
ii) 
a permanent impairment of a body structure or a body function 
including chronic diseases, or 
iii) 
in-patient of prolonged hospitalisation, or 
iv) 
medical or surgical intervention to prevent life-threatening 
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illness or injury or permanent impairment to a body structure or 
a body function 
c) foetal distress, foetal death or a congenital abnormality or birth 
defect including physical or mental impairment 
Adverse Device 
Effect (ADE) 
AE related to the use of an IVD. 
Serious Adverse 
Device Effect (SADE) 
ADE that has resulted in any of the consequences characteristic of a SAE 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
SADE which by its nature, incidence, severity or outcome has not been 
identified in this protocol. 
Device deficiency 
A device deficiency is an inadequacy of a medical device related to its 
identity, quality, durability, reliability, usability, safety, or performance, 
such as malfunction, misuse or use error or inaccurate results and 
inadequate labelling. 
Table 4: Definitions of AEs and device deficiency.  
 
The following should not be considered an AE: a condition requiring a pre-planned procedure unless the 
condition worsened since screening or a pre-existing condition found as a result of screening, unless the 
condition has worsened since enrolment.  
 
9.1.2. 
Adverse Event Severity Classification  
An AE can be classified as severe and not deemed a SAE. Similarly, a SAE is not automatically severe 
in nature. 
Severity will be defined according to the following criteria:  
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or perform normal daily activity 
Table 5:Severity Classification 
 
9.1.3. 
Adverse Event Relationship Classification   
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Each Adverse Event will be assigned a relationship to the study tool or study procedures. 
Relationships will be assessed as follows: 
Not related 
Relationship to the device or procedures can be excluded when there is no 
temporal relationship, the event is not known for the type of device or 
procedure, is implausible and other more reasonable explanations are 
available. 
Unlikely 
The relationship with the use of the device or procedures seems not 
relevant and/or the event can be reasonably caused by another cause. 
Possible 
The relationship with the use of the device or procedures is weak but cannot 
be ruled out. 
Probable 
The relationship with the use of the device or procedures cannot be 
reasonably explained by another cause. 
Causal relationship 
The event is associated with the device or procedures when there is a 
temporal relationship, the event is known for the type of device or 
procedure, and no other reasonable explanation is available. 
Table 6: Definitions of relationship to device or procedure 
  
9.1.4. 
Adverse Event Outcome Classification  
Outcome of the event will be defined according to the following:  
Resolved: 
The event was fully resolved at the end of the study. 
Resolved with 
sequelae: 
The event has resolved, but retained pathological conditions resulting 
from the results and presentation.  
Continuing: 
The event is ongoing at the end of the study.  
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Death: 
This event is determined to be the cause of death. 
Table 7: Event outcomes. 
9.2. 
Adverse Event Recording  
Adverse event monitoring outlined in this protocol is reflective of the risk/benefit ratio of 
participating in the study to the patient. Intervention is minimal; an additional blood sample and 
saliva sample for a subgroup, the participant will receive a second CVD risk score in addition to the 
standard CVD QRISK®2 score, followed by an online questionnaire (and possible interview). All these 
activities are considered low risk. 
To this end, the study will only collect adverse events considered related to study procedures or the 
risk assessment tool (CVD IRT). In addition, since all participants will provide a blood sample as part 
of standard practice (for QRISK®2), the study is requesting that study blood samples be collected 
using the same venepuncture. Therefore, mild events such as the following which are common when 
giving blood samples will not be collected for the study safety database: 
● Pain 
● Feeling faint 
● Bruising 
● Minor bleeding 
● Haematoma 
● Site infection 
However, adverse events due to the process of blood sampling that are not common or are severe 
in nature will be collected. The WHO Best Practices for Injections and Related Procedures Toolkit can 
be referred to minimise adverse events16.  
From point of consent to collection of results at visit 2, all AEs considered related to the risk 
assessment tool or study procedures will be collected during visit 2 by the clinical team. At visit 3, 
the online questionnaire will be reviewed by the qualitative research team to identify related AEs 
and reported to the clinical team for documentation. 
Similarly, during interviews, the qualitative research team (interviewer) will again identify related 
adverse events, but in this instance only those meeting the criteria of ‘serious’ will be collected. All 
SADEs will be forwarded to the clinical team for documentation. 
Throughout the study, the participant will be invited to contact the study team at any time to discuss 
any concerns and issues raised by the study, and any related AEs identified will be collected as 
described above. Up to the point of online questionnaires, self-reported related adverse events will 
be collected and after the online questionnaires, self-reported related adverse events meeting the 
criteria of ‘serious’ will be collected until study end. Related SAEs should be followed to resolution if 
possible. 
All adverse events must be recorded in the eCRF as soon as possible. 
9.2.1. 
Anticipated Adverse Events 
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Low numbers of adverse events are thought to occur in this clinical study. However, it is possible that 
providing participants with a risk score for their likelihood of developing CVD in the next 10 years, 
may cause anxiety to the participant, both in anticipating the score and after receiving the score. In 
addition, the genetic component may cause additional concerns, due to the immovable nature of 
the genetic component. As such, the following events and those with similar meaning that are mild 
in nature, are anticipated for CVD IRT. 
● Anxiety 
● Nervousness 
● Distress 
● Unease 
 
However, adverse events of this type, but that are considered moderate or severe, will not be 
considered anticipated for the purposes of this clinical study for patients that previously did not 
experience such events.  
For participants who already experience mild anxiety for example, an increase to moderate anxiety 
would be considered anticipated. Similarly, an increase from moderate to severe anxiety would be 
considered anticipated.   
The sponsor (or delegate) has the final responsibility of assigning whether AEs are anticipated. 
9.3. 
Device Deficiency Recording 
All device deficiencies, such as failure to log on, inability to create new participants or error messages 
will be documented and reported to <<
>>.  
Adverse events that resulted from a device deficiency (which would by definition be related to the 
CVD IRT) will be recorded as outlined in section 9.2.  
9.4. 
Recording and Reporting Responsibilities 
9.4.1. 
Investigator Responsibilities  
The investigator and study team are responsible for collecting AEs as described in section 9.2 using 
the eCRFs (AE log and SAE page ) within 24 hours of learning of the event. The investigator is 
responsible for reviewing all AEs and SAEs. 
AEs will also be recorded in the participant medical notes. 
The investigator is responsible for assigning seriousness and relationship to the risk assessment tool 
or study procedures and document this in the eCRF.  If this is not available immediately, the initial 
report using the paper backup should be submitted to 
and follow-
up information reported as soon as possible, in a timely manner. 
9.4.2. 
Qualitative Researcher Responsibilities 
ADEs and SADEs identified by the qualitative research team will be collected and shared with the 
clinical study team at site immediately upon identification to then be entered into the eCRF  The 
qualitative research team will review questionnaires on a regular basis to ensure appropriate and 
timely reporting.  
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9.4.3. 
Chief Investigator (CI) Responsibilities 
The CI has clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
9.4.4. 
Sponsor Responsibilities 
● Central data collection and verification of AEs, ADEs, SAEs, SADEs and USADEs according to the 
study protocol onto a database.  
● Expedited reporting of USADEs to REC within required timelines. 
● Notifying Investigators of SAEs/SADEs and USADEs that occur within the trial. 
● Update Reference Safety Information for the trial annually and share with investigators. 
9.5. 
 Reporting urgent safety measures  
If any urgent safety measures are required during the clinical study to protect participants against 
immediate hazard to their health or safety, the investigator shall immediately inform the sponsor so 
as to inform the REC within set timelines, 3 working days. 
9.5.1. 
Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
The sponsor will be notified immediately of any case where the above definition applies during the 
trial conduct phase. 
The sponsor of a clinical study will notify the REC, as appropriate. 
10. 
STATISTICS AND DATA ANALYSIS 
10.1. 
Sample size justification 
The aim of this study is to demonstrate that predictive genetic testing can be incorporated into 
primary health care.  
This study is adding genetic testing to a tool that is already available; QRISK®2 predicts the likelihood 
of developing CVD over the next 10 years by assessing clinical data. It is intended that the addition 
of a genetic component to the test should not complicate the process, maintaining ease of use.   
To this end, it is planned to select sites of different size, capacity and resource to test assimilation of 
the genetic component into their varying processes. Additionally, the addition of the genetic 
component should not hinder the number of assessments normally undertaken, therefore high 
throughput is essential.  
Also of interest to the study is a diverse population. The study will aim to recruit an equal number of 
male and female, even numbers across the 5 year age brackets (e.g., 45-49 years), and also aim to 
include 10-15% black, asian and minority ethnic (BAME) participants.    
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It is considered that 10-12 sites from areas of varying affluence and deprivation, and recruiting a high 
number of participants reflective of normal practice (50-100) will serve to answer the study 
objectives. It is planned to recruit around 1000 participants from 10-12  sites. 
This number will also be sufficient to answer the secondary and exploratory objectives. 
100 saliva samples are required to demonstrate comparability of risk scores with those achieved with 
blood derived DNA. 
10.2. 
Planned recruitment rate 
It is planned that each of the 10 to 12  sites recruit between 5 and 10 participants per week. Based 
on this, and allowing for staggered site initiations, it is anticipated that recruitment will take between 
5 and 7 months.  
10.3. 
Description of Methods of Analysis 
Analysis will be undertaken as outlined in the Statistical Analysis Plan (SAP).  
10.3.1. 
Operational analysis 
Analysis of the primary objective includes a calculation of the return rate of reports. In addition, an 
in depth analysis of the operational process of returning reports to the surgery will be undertaken. 
A comparative analysis will be undertaken to explore incidences of reclassification between a 
patient’s QRISK®2 score and their combined risk score. 
The analysis will explore and assess the impact of the CVD IRT on clinical decision making where the 
addition of genetic information shows an increase in risk. 
A comparative analysis will be undertaken of PRS derived from DNA extracted from blood and saliva. 
Further analysis may be undertaken, guided by the interpretation and understanding of study 
results. 
10.3.2. 
Feedback analysis 
Feedback from the Visit 1 Participant and Visit 2 HCP  questionnaires entered into the eCRF will be 
analysed by Genomics plc as set out in the statistical analysis plan. 
SurveyMonkey will be used to gather online mixed quantitative and qualitative data from an online 
questionnaire. This will be a formal sample of participants (both HCPs and patients). Tables and 
charts as well as basic statistics are created by SurveyMonkey for closed questions. Charts include 
bar, line and pie charts, and trend lines can be included where appropriate. Basic statistics vary 
depending on question type, but will include minimum, maximum, mean, median and standard 
deviation. Responses will be filtered to compare results from different responders. 
In addition to the questionnaire data thematic analysis will be conducted on participant one to one 
interviews and HCP and PCC focus group discussions. 
Descriptive statistics will be used to initially assess the data, with consideration to using further 
statistical tests depending on the initial finding, if further analysis is required. Presentation of the 
results will be charts and graphs. 
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11. 
DATA MANAGEMENT  
A Data Management Plan (DMP) will describe how data will be acquired and how it will be handled, 
stored, checked for consistency and made available for final analysis. 
11.1. 
Data collection tools and source document identification 
Data will be collected electronically via the CVD IRT, as well as via CRFs by Genomics plc. 
The anonymised online survey data (managed by NECS) for both study participants and HCPs will be 
downloaded and presented as part of the thematic analysis. The patient interviews will be audio 
recorded by NECS for their evaluation. Thematic analysis will be made and will be shared with 
Genomics plc. Audio recordings of any interviews conducted as part of the qualitative feedback will 
be destroyed once transcripts have been analysed by the qualitative researchers.  
The HCP and PCC Focus Groups will have audio recordings made and transcribed by NECS. Written 
copies of the transcripts will be used for thematic analysis. Audio recordings of the focus groups will 
be destroyed once transcripts have been analysed by the qualitative researchers. 
11.2. 
Data handling and record keeping  
The personal details and consent form will only be accessible to appropriate staff members at the 
GP practice and, if requested, by monitors from the study Sponsor for monitoring, or for audit 
purposes. 
Each biosample will be assigned a unique identifier, and only the GP practice will hold the source 
data       to link back the sample identifier to the participant.  
The Sponsor will implement and ensure that GP practices implement appropriate measures to ensure 
that all personal data is collected, stored, used, and otherwise processed according to all applicable 
data protection laws including the UK GDPR, the UK Data Protection Act 2018, and any successor 
legislation.  
All clinical study findings and documents will be regarded as the Sponsor’s confidential information. 
Study documents (protocols and other material) will be stored appropriately to ensure their 
confidentiality. The Chief Investigator and members of their research team (including the REC) must 
not use or disclose such information without prior written approval from the Sponsor, except to the 
extent necessary to obtain informed consent from subjects who wish to participate in the study or 
to comply with regulatory requirements. 
Genetic information extracted by contract research laboratories will be handled and held by those 
laboratories strictly in accordance with the Sponsor’s instructions, before being transferred to the 
Sponsor using secure and encrypted methods. The contract research laboratories will be directed to 
destroy all of the study samples, DNA and the genetic data in their possession once they have 
completed the contracted services. 
11.3. 
Access to Data 
Study data stored and used by the Sponsor will be encrypted and access will be limited to authorised 
and authenticated users. The Sponsor’s information security practices have been independently 
certified to meet international standards (ISO 27001: 2013). 
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Direct access to study data will be granted to authorised representatives from the Sponsor, host 
institution and the regulatory authorities to permit study-trial-related monitoring, audits and 
inspections. 
11.4 
Archiving 
Anonymised data generated as part of this study, including both genetic and other study data, will 
be retained indefinitely and may be used for future research and validation purposes and product 
development.  
Records and documents pertaining to the conduct of this study, including participant generated 
information, ePRO data, ICFs, laboratory test results, and the study report, must be retained by the 
Principal Investigator for at least 10 years after completion or discontinuation of the study, or for the 
length of time required by relevant national or local health authorities, whichever is longer. After 
that period of time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or moving 
them to another location. 
NECS will keep questionnaire responses and transcripts of interviews and focus groups as per NECS 
processes,      for a minimum of 10 years, and only be destroyed with agreement from the sponsor.  
12. 
MONITORING, AUDIT AND INSPECTION 
Study monitoring will be undertaken according to the Study Monitoring Plan (SMP) which will at a 
minimum include the following: 
● The anticipated frequency and scheduling for monitoring. 
● Mode of monitoring, remote or in-person. 
● Identification of source data. 
● Percentage of source data verification 
● Protocol deviation reporting and capture 
● Safety reporting requirements and timelines 
● Device deficiency reporting requirements and timelines. 
The investigator is not permitted to deviate from this protocol, except when a deviation is necessary 
to protect a participant’s rights, safety and well-being, or the scientific integrity of the clinical 
performance study. Accidental protocol deviations can happen at any time. Any deviation from the 
protocol will be reported by the study site to the Sponsor, which will keep a record of these 
deviations, and as appropriate, reported to the Chief Investigator and Sponsor immediately. 
Deviations from the protocol which are found to frequently recur are not acceptable and will require 
immediate action that could potentially be classified as a serious breach. These will be mitigated in 
the first instance by re-training and increased monitoring, but if persistent, the site can be excluded 
from the study as a last resort. 
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12.1. 
Internal audits 
Internal audit procedures are in place and will be applied to The HEART Study. 
12.2. 
External inspections 
Genomics plc will comply with the requirements of external inspections. 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Research Ethics Committee (REC) Review and Reports 
This study will be conducted in accordance with ethical principles set out in the Declaration of 
Helsinki and principles of GCP.  
Before the start of the study, a favourable opinion will be sought from the UK Health Departments 
Research Ethics Service (NHS REC) and HRA for the study protocol, informed consent forms and other 
relevant documents e.g. invitation letters, advertisements if to be used. Substantial amendments 
that require review by NHS REC will not be implemented until review is complete and amendment 
approved. 
REC will be notified of the end of the study, whether premature or as planned, as per REC 
requirements. 
Within one year after the end of the study, the Sponsor will submit a final report with the results, 
including any publications/abstracts, to the REC.All correspondence with the REC will be retained in 
the Study Master File 
13.2. 
Research Ethics Committee (REC) Review and Reports 
The CVD IRT is a device for performance evaluation under Directive 98/79/EC (EU IVDD). 
The protocol and study conduct will follow the applicable clauses of the UK Medical Device 
Regulations 2002, giving effect to Directive 98/79/EC (EU IVDD) and ISO 20916, and any relevant 
amendments. 
13.3. 
Peer review 
The study design process has involved pre-study scoping focus sessions with healthcare professionals 
to ensure the feasibility and acceptability of the study design. Six GPs, two nurses, and four practice 
managers from a range of practices and locations in the North East of England were consulted. 
In addition, this protocol has been reviewed by the following clinical peers: 
Two independent reviewers, 
 and 
 reviewed the protocol 
before its finalisation. 
13.4. 
Public and Patient Involvement 
At the protocol design stage, a focus group involving three patient representatives, identified via the 
NIHR CRN, provided input into the study design and patient facing material.  
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13.5. 
Indemnity 
The Sponsor will hold appropriate insurance to cover all of its legal responsibilities and liabilities as 
study sponsor and will indemnify the participating sites against liabilities and claims arising from the 
trial, except for claims that arise from their malpractice and/or negligence. 
The sponsor's policies and procedures will address the costs of treatment of study participants in the 
event of study-related injuries in accordance with the applicable regulatory requirement(s).If study 
participants receive compensation, the method and manner of compensation will comply with 
applicable regulatory requirement(s).  
13.6. 
Post study care 
Post-study care will be assured by the HCPs who enrolled the participants into the study. Any changes 
to patient treatment or management will be instituted at the decision of the treating doctor or health 
care professional. If changes in medication are instituted, these will be at the cost of the participant 
and prescribing physician.  
14. 
DISSEMINATION AND PUBLICATION  
14.1. 
Data sharing 
The output of the study will be analysed, tabulated and presented in a Final Clinical Study Report 
(held on file at Genomics plc). 
ummary data will be presented as per public registry guidelines. 
14.2. 
Publication Plan 
The results generated by this study will be owned by Genomics plc. The right to publish the findings 
of this study in the scientific literature will belong to, and will only be granted by, Genomics plc.  
The output of the study will be analysed, tabulated and presented in a Final Clinical Study Report 
(held on file at Genomics plc).  
It is anticipated that a study summary report will be made available to all participating practices.  
Participating patients who are interested in the results will be directed to the public registry for a 
summary of the study.  
Publications in peer-reviewed journals will be authored by a combination of the CI, NECS 
stakeholders, and the Genomics plc research team. NECS will be acknowledged as a partial funder of 
the study and a contributor to the protocol. 
No participants will be identified by any of the reports or publications resulting from this research.  
14.3. 
Authorship eligibility guidelines and any intended use of professional writers 
Authorship of the final report will reflect the contribution of investigators at the design and analysis 
stages.  
In the case a scientific publication is agreed, the standard guidelines of the International Committee 
of Medical Journal Editors will be followed.      
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15. 
REFERENCES  
 
1. 
National Cancer Institute. BRCA Gene Mutations: Cancer Risk and Genetic Testing. Available at: 
https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. Accessed 
May 21, 2021. 
2. 
Timpson NJ, Greenwood CMT, Soranzo N, Lawson DJ, Richards JB.  Genetic architecture: the 
shape of the genetic contribution to human traits and disease. Nature Reviews Genetics 2018, 
19: 110–124. https://www.nature.com/articles/nrg.2017.101  
3. 
Lewis CM, Vassos E. Polygenic risk scores: from research tools to clinical instruments. Genome 
Medicine 2020, 12:44. https://doi.org/10.1186/s13073-020-00742-5 
4. 
Riveros-Mckay F, Weale ME, Moore R et al. An Integrated Polygenic Tool Substantially 
Enhances Coronary Artery Disease Prediction. Circulation: Genomic and Precision Medicine 
2021. https://doi.org/10.1161/CIRCGEN.120.003304 
5. 
Weale ME, Riveros-Mckay F, Selzam S, et al. Validation of an Integrated Risk Tool, Including 
Polygenic Risk Score, for Atherosclerotic Cardiovascular Disease in Multiple Ethnicities and 
Ancestries [published online ahead of print, 2021 Mar 3]. Am J Cardiol. 2021;S0002-
9149(21)00207-1. doi:10.1016/j.amjcard.2021.02.032 
6. 
NHS England. (2019). The NHS Long Term Plan. 
https://www.longtermplan.nhs.uk/publication/nhs-long-term-plan/ 
7. 
The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases 
of seven common diseases and 3,000 shared controls. Nature 2007, 447: 661-678. 
doi:10.1038/nature05911 
8. 
Danese MD, Gleeson M, Kutikova L, Griffiths RI, et al. Estimating the economic burden of 
cardiovascular events in patients receiving lipid-modifying therapy in the UK. BMJ Open 2016, 
6:e011805. doi:10.1136/bmjopen-2016-011805British Heart Foundation. (2021). UK Factsheet. 
https://www.bhf.org.uk/what-we-do/our-research/heart-statistics 
9. 
British Heart Foundation. (2021). UK Factsheet. https://www.bhf.org.uk/what-we-do/our-
research/heart-statistics 
10. Barton, P. (2011). Effectiveness and cost effectiveness of cardiovascular disease prevention in 
whole populations: modelling study. the BMJ, 343. doi: https://doi.org/10.1136/bmj.d4044 
11. The Global Burden of Disease Study 2016. http://ghdx.healthdata.org/gbd-2016 
12. NICE Clinical Guideline. (2014, July). Cardiovascular disease: risk assessment and reduction, 
including lipid modification. 
13. QRISK. www.qrisk.org 
14. QRISK2. https://qrisk.org/2017/ 
15. Heshka JT, Palleschi C, Howley H, Wilson B, Wells PS. A systematic review of perceived risks, 
psychological and behavioural  impacts of genetic testing. Genet Med. 2008 Jan;10(1):19-32. 
doi: 10.1097/GIM.0b013e31815f524f. PMID: 18197053. 
16. WHO Best Practices for Injections and Related Procedures Toolkit. Geneva: World Health 
Organization; 2010 Mar. 3, Best practice in phlebotomy and blood collection. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK138496/ 
 
 
 
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16. 
PROTOCOL AMENDMENT HISTORY 
Any substantial amendments will be submitted to the REC and HRA for review. No changes will be 
implemented at any site until any required approvals for amendments have been obtained.  
 
Protocol 
Version  
Section  
Summary of changes  
1.0 to 2.0 
 
1.3 
7.1.9 
Clarification of title to ‘management of report for participant 
discussions’ 
Clarification of NICE guidance for use when both QRISK and CVD 
IRT are available and one risk calculation exceeds 10% 
3.5 
Endpoint relating to saliva added to reflect the list of objectives  
3.6 
Amendment of timepoints when endpoint will be collected for 
Participant interview, HCP and PCC focus groups 
6.1.2 
Matching of synopsis and protocol exclusion criteria.  
6.2.2 
Clarification on scheduling of the focus groups for singular to 
multiple, if needed  
7.1 
Clarification for collection of participant interview consent at 
visit 1  for participant convenience. 
Acknowledgement of the HCP questionnaire at visit 3, following 
the results discussion with participants. 
Clarification to the footnotes to acknowledge the change in 
timing for the participant interviews, HCP and PCC 
questionnaires 
7.1  
Figure 1  
Redrawn to align with the changes in the timings of the 
participant interviews, HCP and PCC questionnaires 
7.2  
Figure 2  
Redrawn to incorporate  the participant questionnaire at Visit 1. 
7.1.3 
Clarification on participant screening for eligibility to the 
HeathCheck and QRISK evaluation before invitation to the study 
7.1.7 
Figure 3  
Redrawn to update the timing of the questionnaire at Visit 3  
 
7.1.6 
7.1.7.1 
Additional wording explaining the timing for when the 
recruitment for participant interviews will take place 
 
7.1.7.1 
Re-wording of paragraph for when a sample does not provide a 
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CVD IRT score  
7.1.8 
Clarification to the data collected at Visit 2  
7.1.10 
The consent to participate in an interview is moved to Visit 1. 
The paragraph relating to consent at visit 4 has been removed 
and instruction that not all participants would be interviewed  
7.2 
7.3 
7.4 
Additional information on when the questionnaires would be 
administered to HCPS added and the timings of the  
Change in HCP and PCC interview timings to occur as close 
together as possible 
7.6 
10.0 
11.0 
Clarification to the transfer of thematic results to Genomics and 
not transcripts. 
 
10.0 
Additional wording on the impact of  the participants QRISK and 
CVD IRT score where the genetic information shows an 
increased risk. 
 
 
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