RAPid Testing fOR Covid-19 (RAPTOR-C19).

The University of Oxford is permitted to continue the processing and retention of data provided by NHS Digital under a previous iteration of this agreement.

RAPID COMMUNITY POINT-OF-CARE TESTING FOR COVID-19 (RAPTOR-C19) is a study being run by the University of Oxford.

The NHS urgently needs quick, accurate rapid diagnostic tests to diagnose people with coronavirus or to confirm that people do not have the infection. Point-of-care Tests (POCTs) can be used in community settings where there is no easy access to a specialist laboratory. They provide quick results that allow people to get immediate advice about self-isolation and treatment, potentially blocking further spread of infection in the community. Companies are quickly developing new rapid diagnostic tests, but we do not know how well they work. Some tests give a result like a pregnancy test by using a drop of blood from a finger prick. Others use saliva, or a swab to collect a sample from the nose or throat.

Companies check tests work in their laboratories, but usually tests do not work as well when used in the field with real patients. Accurate rapid diagnostic tests are important so that people are not falsely reassured when they are infected, and are not wrongly diagnosed when they are not really infected.

The University team manages a national surveillance system with a network of community settings including GP practices from all over England that report directly to the Department of Health and Social Care about a wide range of infections. These GP practices have been testing for coronavirus since January 2020 with samples sent for laboratory tests. In this study, practices in the network will quickly compare new POCTs for coronavirus with laboratory tests so we can see how good the new tests are in a coordinated and efficient way. National COVID-19 Test centres may also support the research project.

There are currently no rapid diagnostic tests that have been evaluated as fit-for-purpose in NHS primary care that aim to identify whether adults are currently, or have been, infected by COVID-19. The UK and wider world is in the midst of the 2019 novel coronavirus (SARS-CoV-2) pandemic. Accurate diagnosis of infection, identification of immunity and monitoring the clinical progression of infection are of paramount importance to our response, and for all of these diagnostics are central. Widespread population testing has proven difficult in western countries and has been limited by test availability, diagnostic test sensitivity, human resources and long turnaround times (up to 72 hours). This has limited our ability to

control the spread of infection and to develop effective clinical pathways to enable early social isolation of infected patients, early treatment for those most at risk and early return to work for those with resolved infection and potential immunity.

POCTs can be used in the community where there is no easy access to a specialist laboratory, in locations such as NHS general practices. POCTs provide quick results that allow people to get immediate advice about self-isolation and treatment, potentially blocking further spread of infection in the community. In-context evaluation of POCTs in the community is important as test accuracy can vary based on the prevalence of disease in the population tested. “In-context” in this case means “in the clinical environment that the test is to be used”, for example, RAPTOR is evaluating tests for use in general practice, in general practice. This is an important process as tests perform differently (either more or less accurate) when used in different settings/ environments/contexts.

The severity of the COVID-19 disease in the community is much lower than in hospital patients. Symptomatic acutely unwell hospitalised patient are likely to have higher viral loads that are easier to detect, and may be undergoing invasive procedures to collect samples from the lower respiratory tract, that have a higher yield. Testing only severe patients introduces spectrum bias, and biases the results to overestimate test performance. It is important to diagnose hospital patients, but from a public health point of view the most concerning patients are ambulatory outpatients, who may spread the virus much further in the community if falsely reassured. Evaluations of COVID-19 POCTs are therefore required in each clinical setting. Community based POCTs may lead to additional public health impacts such as reducing onward household transmission of COVID-19, improving surveillance of NHS and social care staff, accurate prevalence estimates, and understanding of COVID-19 transmission dynamics in the population.

RAPTOR-C19 will provide the community testbed to the COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR). It should be noted that CONDOR will not contain any NHS Digital data.

RAPID COMMUNITY POINT-OF-CARE TESTING FOR COVID-19 (RAPTOR-C19)

Aim - to assess the diagnostic accuracy of multiple current and emerging point-of-care tests (POCTs) for active or past COVID-19 infection in the community setting.

It is estimated that up to 10,000 patients will be recruited for the trial (approximately 1,500 patients per test).

Specific objectives - RAPTOR-C19 will incorporate a series of prospective observational parallel diagnostic accuracy studies of COVID-19 POCTs against laboratory and composite reference standards in patients with suspected current or past COVID-19 attending RCGP RSC general practices. Because the current reference tests are imperfect, the RAPTOR-C19 protocol allows “standard” and “enhanced” diagnostic accuracy studies for active and past infection:

• Standard diagnostic accuracy of POCTs for active COVID-19 infection with reference to Public Health England (PHE) reference standard virology testing.

• Standard diagnostic accuracy of POCTs for past COVID-19 infection with reference to PHE reference standard serology testing.

• Enhanced diagnostic accuracy of POCTs for active COVID-19 infection assessed against a composite reference standard using multiple tests data, linked Electronic Health Records (EHR) data, and patient reported outcomes data

• Enhanced diagnostic accuracy of POCTs for past COVID-19 infection assessed against a composite reference standard using multiple tests data, linked EHRs, and patient reported outcomes data

Composite reference standards - An assumption of standard diagnostic accuracy studies is that the reference standard is infallible. This constrains the performance of the index test to the performance of the reference standard and assumes every time the tests get different results the reference is correct and the index is incorrect. In reality, the reference standard is unlikely to be perfect, so we will undertake further analyses using composite reference standards. Composite reference standard 1 will be designed to minimise false negatives (FNs), and composite reference standard 2 will be designed minimise false positives (FPs).

For example, for POCTs for current infection:

1. A positive composite reference standard to minimise the impact of a FN PHE reference test result for current infection at visit one / increase sensitivity will also include:

i. paired PHE antibody testing suggesting active infection at visit one (positive Immunoglobulin G (IgM)) and past infection at visit two (positive Immunoglobulin G (IgG)), or

ii. EHRs showing a confirmed COVID-19 diagnosis (in another setting), such as a 111 contact, COVID-19 hospital related admission or death in the following 28 days, or

iii. a positive household contacts within 14 days identified via RCGP-RSC

2. A positive composite reference standard to minimise the impact of a FP PHE reference test result for current infection at visit one / increase specificity will also include:

i. at least two positive PHE reference tests for current infection, or

ii. paired PHE antibody testing suggesting active infection: visit one (positive for IgM) and visit two (positive IgG), or

iii. linked EHRs showing a 111 contact for COVID-19, COVID-19 hospital admission, or death

For POCTs for past infection:

1. A positive composite reference standard to minimise the impact of a FN PHE reference test result for past infection at visit one / increase sensitivity will also include:

i. positive visit two IgG positive PHE antibody tests, or

ii. linked EHRs showing a confirmed past COVID-19 diagnosis (in another setting), such as positive PHE test for active COVID-19 infection, a 111 contact for COVID-19, hospital COVID-19 related admission, or

iii. a previous household COVID-19 contact identified via RCGP-RSC

2. A positive composite reference standard to minimise the impact of a FP PHE reference test result for past infection at visit one / increase specificity will also include:

i. Paired PHE serology: visit one (positive IgG) and visit two (positive IgG), or

ii. linked EHRs showing a 111 contact for COVID-19, COVID-19 hospital admission

Linkage to the CHESS, SGSS, and the Civil Registration of Deaths datasets will allow clinical information about SARS-CoV-2 to be captured from outside of the primary care setting prior to and following the date of RAPTOR point of care test evaluation. These data will allow the RAPTOR team to construct a composite reference standard to identify occasions where the laboratory SARS-CoV-2 test used as the primary reference standard is likely to have been a false negative or false positive. Civil Registration of Deaths is required as CHESS only captures COVID death in hospital and there is the need to identify any COVID mortality (in hospital and in the community) within 28 days of recruitment to use in the composite reference standard.

Organisations Involved

The University of Oxford are the sole data controller for this request.

Public Health England (PHE)

For the purposes of the RAPTOR trial PHE do not hold any data controllership responsibilities. However members of the statistical team are based at PHE working under the direction of the data controller and are therefore listed as data processors.

Royal College of General Practitioners (RCGP)

For the purpose of the RAPTOR trial RCGP are not a data controller. The RCGP are joint data controllers for the RCGP RSC collected data which is being linked to the cohort data. The RCGP play no role in determining the means by which or the purpose for which the data will be processed for the RAPTOR trial.

University of Surrey

The RCGP Research Surveillance Centre (RCGP RSC) was based at the University of Surrey, but is in the process of transferring to Oxford. Data being shared for the RAPTOR trial will be sent to Surrey so that the data they hold on the RCGP RSC for the consented cohort can be linked to the RAPTOR cohort. The RCGP RSC is a growing network of over 1200 GP surgeries based in England. University of Surrey are data processors

The University of Surrey acts as Data Processor on behalf of the Data Controller for the RAPTOR trial (Oxford). An existing secure network at the University of Oxford is progressively housing the RCGP RSC data. This data collection is known as (ORCHID secure). This process is underway and due to be completed by early 2021, at which stage all these data will all be held on the Oxford secure network. Further information relating to ORCHID can be found here: JPH - The Oxford Royal College of General Practitioners Clinical Informatics Digital Hub: Protocol to Develop Extended COVID-19 Surveillance and Trial Platforms | de Lusignan | JMIR Public Health and Surveillance

University of Surrey currently host the RCGP RSC Database for which the trial participants data will also be linked with. The RCGP RSC dataset includes individual patient level up-to-date primary and secondary care data which can be easily queried. Primary care/general practice data is rich in terms of diagnosis and information about the process of care. For example, the database contains the following variables for each patient (where present):

• Detailed demographic and risk factor data.

• COVID-19 appointments: including information on whether or not a virology swab was taken and the outcome of the swab

• Non-COVID-19 appointments.

• Detailed data for the 32 conditions monitored by RCGP RSC on behalf of PHE

• Vaccination status: date of vaccination, type of vaccination

• Co-morbid conditions

• Medication which may be associated with better or adverse outcomes.

• Test results

• Referrals made

• A & E visits

• Inpatient appointments, including critical care

• Outpatient appointments

• Mortality data (if applicable).

The RAPTOR-C19 study (IRAS ref 284320) was approved by the North West - Liverpool Central Research Ethics Committee (ref 20/NW/0282) on June 10th 2020. Participants give individual patient consent for RAPTOR-C19 to access their medical records data.

Note that current funding for the study is until June 2021, but the end date could be later than this depending on whether test continue to require evaluation and further funding is secured.

The University of Oxford is permitted to continue the processing and retention of data provided by NHS Digital under a previous iteration of this agreement.

Participants who have consented to the RAPTOR Trial will have their data initially linked with the primary care data which is already held as part of the Royal College of General Practitioners (RCGP RSC) Research and Surveillance Network database.

• The University of Surrey, on behalf of the University of Oxford for the RAPTOR trial, will provide NHS Digital with a list of NHS numbers and date of births along with a unique Study ID for the RAPTOR cohort. A specific University of Surrey IT team within the IT department will share the identifiers with NHS D not the research team.

• NHS Digital will send back to University of Surrey the linked cohort data.

• University of Surrey will store the data on the secure network researchers will then analyse a pseudonymised data to produce outputs for the RAPTOR Study.

The data is controlled and processed by a group of staff who are all based at the University of Surrey; all are mandated to complete information governance training. The group is made up of analysts, academic fellows, Structure Language Query (SQL) developers, RCGP RSC practice liaison officers, a project manager and a head of department. The team work from secure workstations or secure laptops with encrypted drives within the group’s secure network. These same processes are replicated in Oxford.

The general practices in the RCGP RSC take virology swabs and serology samples to know if someone has a COVID-19 or a range of other infections, including influenza. These results are being passed back to the patients GP for their clinical care. However, a pseudonymised copy will go to the RCGP RSC. The COVID-19 status will be shared with the RAPTOR trial team (who also pseudonymise NHS number to allow this linkage).

All record level data will be held and stored within England and Wales.

Specific outputs for this trial are:

• RAPTOR-C19 will publish the results of each POCT evaluation in open-access journals, the protocol on the study website (https://www.condor-platform.org/condor_workstreams/raptor) and registries, and summary reports which can be made publicly available through e.g. the websites of the study and of the NIHR Community Healthcare MIC (https://www.community.healthcare.mic.nihr.ac.uk/). RAPTOR-C19 will work with patient and public representatives to ensure that such reports are communicated in an appropriate manner for a lay audience. The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising from the study. Authors will acknowledge that the study was funded by UKRI-MRC and any other funding that is secured. Authorship will be determined in accordance with the ICMJE guidelines and other contributors will be acknowledged. All outputs are expected to be submitted by the end of Q2 in 2023.

Findings from this trial will contribute to the main outputs of the RCGP RSC.

The NIHR Community Healthcare MedTech and In vitro Diagnostics Co-operative and CONDOR have PPI groups feeding into the RAPTOR-C19 study. They have contributed to the development of the RAPTOR-C19 protocol, have commented on the relevance and acceptability of research questions and methods, they have assisted in the development of patient facing materials, and continue to advise on the public dissemination of results.

For RAPTOR-C19 linked data allows the development of an enhanced reference standard to overcome imperfections in laboratory tests for COVID-19, thereby providing more accurate estimates of diagnostic accuracy. It also allows validation and enhancement of sociodemographic and comorbidity data for RAPTOR-C19 participants.

University of Oxford have used linked hospital data to construct the enhanced reference standard for RAPTOR-C19 participant as outlined above. The linked data has been less helpful with regards to confirming sociodemographic data as this is well recorded in the RAPTOR-C19 data collection tool.