Study Title. Date and version number: 08/07/2015 Version 1.4. Dr Katie Harron. Dr Sam Oddie. Dr Berit Muller Pebody. Dr Bo Fu

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1 Study Title Monitoring bloodstream infection in neonatal units in England and Wales and evaluation of the generalisability of the PREVAIL trial (PREVenting infection using Antibiotic Impregnated long Lines) Date and version number: 08/07/2015 Version 1.4 Dr Katie Harron Dr Sam Oddie Dr Berit Muller Pebody Dr Bo Fu for the PREVAIL Trial team and Professor Neena Modi for the UK Neonatal Collaborative and Neonatal Data Analysis Unit 1

2 BACKGROUND Improved infection control strategies across the NHS have led to falling rates of blood stream infection (BSI) in paediatric intensive care units over the past decade.[1, 2] However, there has been no systematic national surveillance of rates of BSI in neonatal units, nor evidence on how rates vary between units and over time. A major contributory factor is that no single data source holds the information required for deriving risk-adjusted rates of BSI in neonatal units. For paediatric intensive care, linkage between national audit data including information on admission and risk factors (PICANet) and national laboratory surveillance data collated by Public Health England has provided risk-adjusted monitoring of BSI.[2, 3] We now have a unique opportunity to provide similar enhanced surveillance in neonatal units, using routinely-recorded data held in the National Neonatal Research Database (NNRD) by the Neonatal Data Analysis Unit at Imperial College London, linked to national laboratory surveillance data on BSI held by Public Health England.[4, 5] Such a dataset would provide risk-adjusted trends of BSI in neonatal units across the NHS, which could be used to support service evaluation and to determine benefits of new interventions and practices to improve care in neonatal units. This protocol relates to i) the creation of the linked dataset ( NNRD-BSI ) for monitoring BSI in neonatal units across England and Wales; and ii) the evaluation of trends in risk-adjusted rates of BSI in neonatal units to help determine the generalisability of a large trial in neonatal intensive care units (PREVAIL: PREVenting infection using Antibiotic Impregnated long Lines). The linked NNRD-BSI dataset will be created and held securely at Public Health England. An anonymised copy of NNRD-BSI will be provided to the PREVAIL investigators at UCL to support the PREVAIL generalisability study. A copy of the linked NNRD-BSI data will also be provided to the Neonatal Data Analysis Unit to enable validation of which babies had a positive blood culture; the copy provided to the Neonatal Data Analysis Unit will retain the unique Badger ID, extracted from the NNRD and submitted to PHE by the Neonatal Data Analysis Unit. The study will establish processes for further linkage between NNRD and infection surveillance data, which can be used to monitor implementation of changes in practice once the trial results are known. The PREVAIL Generalisability Study forms an integral component of interpreting results from the National Institute of Health Research funded PREVAIL trial (Research Ethics Reference 14/LO/1965), the aim of which is to determine the effectiveness of antibiotic-impregnated peripherally-inserted central catheters (PICCs) for reducing the risk of BSI compared with standard PICCs in very preterm babies). The PREVAIL Generalisability Study will help inform decisions on implementation of antibiotic-impregnated PICCs, by evaluating how the benefits of introducing different PICCs varies between neonatal units with different baseline rates of BSI. AIM 1) To create a linked dataset for monitoring BSI in neonatal units in England and Wales 2) To provide risk-adjusted trends in BSI in neonatal units in England and Wales, in order to determine the generalisability of the PREVAIL trial 2

3 METHODS Data sources Neonatal units in England and Wales will be informed about the proposed use of their data (collected between 2010 and 2018) in the creation of NNRD-BSI and to support the PREVAIL Generalisability Study. Neonatal units will be given the opportunity to participate in this study (see letter, Appendix 1). NNRD: The NNRD contains patient data entered onto the Badger.net system (used by all neonatal units in England and Wales) and released with NHS Trust approval (Caldicott Guardian and Lead Neonatal Clinician) to the Neonatal Data Analysis Unit at Imperial College London. The NNRD is approved by the National Research Ethics Service (10/H0803/151) and the Confidentiality Advisory Group of the Health Research Authority in respect of the inclusion of patient identifiable data without explicit patient consent (ECC-05(f)/2010). Contributing neonatal units are known as the UK Neonatal Collaborative. Data held in NNRD and items that will be extracted for inclusion in NNRD-BSI are shown in Appendix 2. These comprise NNUEpisodes data on admission details, antenatal details, demographics and birth information, diagnoses and procedures, discharge details, general admission, baby and discharge information, and labour and delivery; NNUAdHoc data on diagnoses and procedures, and infection cultures; and NNUDaily data on daily dependency items (fluids and feeding, respiratory support and infections). Daily use of PICCs will be identified within the daily dependency data. Identifiable data extracted for linkage purposes will be infant NHS number, Badger ID, date of birth, sex, and mother s postcode. Data will be extracted from NNRD at the Neonatal Data Analysis Unit and transmitted securely to Public Health England (see attached data flow diagram for specific details, Appendix 3). Second Generation Surveillance System (SGSS): All positive isolates from blood culture captured by the national laboratory surveillance system coordinated by Public Health England will be extracted from SGSS, including specimen date, organism type and laboratory. Identifiable data required for linkage will also be extracted (infant NHS number, hospital number, postcode, date of birth, sex). Stage 1: Linkage between NNRD and SGSS Babies acquiring a BSI in neonatal units will be identified through linkage between the NNRD and SGSS, for data between 2010 and BSIs occurring during or immediately following an admission will be identified through comparison of specimen dates (SSGSS data) with admission and discharge dates (NNRD data). NHS number will be the primary unique identifier for linkage between datasets. Badger ID will also be used where available As NHS number and Badger ID are incomplete within SGSS, additional partial identifiers (date of birth, sex, mother s postcode) will also be used within advanced linkage algorithms (probabilistic linkage)[6]. This process will create probabilistic match weights according to agreement on these partial identifiers, which will be used to classify record pairs as links or non-links. 3

4 Where available, infection culture sample dates, hospital performing culture and organism type in NNRD will be used to help validate the linkage, although these variables may not be complete for all records. For PREVAIL babies, primary outcome data from the trial will also be used to validate the linkage, by comparing babies as having a BSI in PREVAIL with those in the linked data. The full NNRD-BSI data will be held at Public Health England. An anonymised copy of the NNRD-BSI data will be created by removing infant NHS number from the linked data. Full date of birth will be changed to month and year of birth only. All other dates (e.g. admission date, discharge date, specimen date) will be changed to number of days since birth. Microbiology specimen information from SGSS (organism identity and resistance data) will be retained in NNRD-BSI. A copy of the anonymised NNRD-BSI data will be transferred to the PREVAIL team at UCL. A copy of the anonymised NNRD-BSI retaining the Badger ID will be provided back to the Neonatal Data Analysis Unit at Imperial College London. The study will establish processes for further linkage between NNRD and infection surveillance data, which can be used to monitor implementation of changes in practice once the trial results are known. Stage 2: Analysis The anonymised NNRD-BSI data will be used to provide risk-adjusted trends in BSI for neonatal units in England and Wales, in order to help inform decisions on implementation of antibioticimpregnated PICCs after the PREVAIL trial. Trends in BSI rates over time and between units will be modelled to evaluate quality of care and changing practices in neonatal units. The baseline rate of BSI will be estimated for babies in both trial and non-trial neonatal units using Poisson regression and adjusting for clinical risk-factors such as length of stay. Information on the number of PICCs required in neonatal units will be used to estimate the number of BSI avoided in relation to the number of babies requiring PICCs. This will help determine the additional benefit of antibiotic PICCs over and above any ongoing improvements in infection control across the NHS. These analyses will be useful for informing NHS purchasing decisions on the most effective strategies for preventing BSI. DATA GOVERNANCE An exemption under Section 251 of the NHS Act 2006 (previously Section 60 of the Health and Social Care Act 2001) allows Public Health England to receive patient-identifiable data from other organisations without patient consent in order to monitor infectious disease. Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002 provides a basis for accessing and sharing identifiable data with NNRD. Specific permission for linkage of personal identifiers between SGSS data and NNRD has been given by PHE (Appendix 4). All identifiable data will be held on an encrypted drive with restricted access for research staff with permission on a secure PC in an electronic pass protected area within the Healthcare Associated Infection & Antimicrobial Resistance Department at Health Protection Services, Colindale (Public Health England). The Colindale site is a secure site with no unauthorised access and 24hr site-security ( Safe Haven ). 4

5 Oversight of the NNRD-BSI data will be detailed in a data sharing agreement between the PREVAIL team at UCL, the Neonatal Data Analysis Units and Public Health England (Appendix 5). The study sponsor is UCL. APPENDICES 1) Letter of invitation to Neonatal Units 2) NNRD data items to be extracted for inclusion in NNRD-BSI 3) System flow-diagram for transfer of data between NNRD and PHE 4) Public Health England permission for accessing and linking identifiable data with the Neonatal Data Analysis Unit 5) Data Sharing Agreement between the PREVAIL team at UCL, the Neonatal Data Analysis Unit and Public Health England REFERENCES 1. Harron K, Wade A, Muller-Pebody B, Goldstein H, Parslow R, Gray J, Hartley JC, Mok Q, Gilbert R (2013) Risk-adjusted monitoring of blood-stream infection in paediatric intensive care: a data linkage study. Intens Care Med 39(6): Harron K, Goldstein H, Wade A, Muller-Pebody B, Parslow R, Gilbert R (2013) Linkage, evaluation and analysis of national electronic healthcare data: application to providing enhanced blood-stream infection surveillance in paediatric intensive care. PLoS One 8(12):e Wilson J, Elgohari S, Livermore DM, Cookson B, Johnson A, Lamagni T, Chronias A, Sheridan E (2011) Trends among pathogens reported as causing bacteraemia in England, Clin Microbiol Infect 17(3): Neonatal Data Analysis Unit, (2013) NDAU 2013 Report.www1.imperial.ac.uk/departmentofmedicine/divisions/infectiousdiseases/paediatric s/neonatalmedicine/ndau/reports_1/ 5. Herzog T, Scheuren F, Winkler W, Data quality and record linkage techniques 2007, New York: Springer Verlag. 6. Department of Health, (2007) Saving Lives: reducing infection, delivering clean and safe care, Department of Health, London ublications/publicationspolicyandguidance/dh_ Bion J, Richardson A, Hibbert P, Beer J, Abrusci T, McCutcheon M, Cassidy J, Eddleston J, Gunning K, Bellingan G, Patten M, Harrison D, The Matching Michigan Collaboration Writing Committee (2012) Matching Michigan : a 2-year stepped interventional programme to minimise central venous catheter-blood stream infections in intensive care units in England. BMJ Qual Saf 22(2):