WP2 - Task 1: Pilot report - Norway | UNITED4Surveillance

UNITED4Surveillance Grant Agreement Number 101102070 WP2 Outbreak detection – Task 1: Improving Laboratory Based-Reporting Milestone 37: Pilot report Norway Requirement mapping for data export and integration Exploring potential improvements to the laboratory-based surveillance for Shiga toxin-producing Escherichia coli (STEC) in Norway Authors Norwegian Institute of Public Health: Naseer, Umaer; Aasand, Nina Therese; Brandal, Lin T.; Cyr, Pascale Reneé; Hungnes, Olav; Rohringer, Andreas. Oslo, 12.3.2025 Disclaimer Copyright message This document was produced under the terms and conditions of Grant Agreement No. 101102070 for the European Commission. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or HaDEA. Neither the European Union nor the granting authority can be held responsible for them. © UNITED4Surveillance Consortium, 2025 This deliverable contains original unpublished work except where clearly indicated otherwise. Acknowledgement of previously published material and of the work of others has been made through appropriate citation, quotation or both. Reproduction is authorized provided the source is acknowledged. UNITED4Surveillance Grant Agreement Number 101102070 TABLE OF CONTENT EXECUTIVE SUMMARY ........................................................................................ 3 BACKGROUND .................................................................................................... 4 LEGAL FRAMEWORK FOR LABORATORY DATA COLLECTION ............................... 5 REPORTING OF SHIGA TOXIN PRODUCING ESCHERICHIA COLI (STEC) IN NORWAY .................................................................................................................... 5 STEC REPORTING TO MSIS .................................................................................... 5 STEC REPORTING TO THE MSIS REGISTRY (MSIS) ........................................................ 6 STEC REPORTING TO THE MSIS LABORATORY DATABASE (MSIS-LAB) ................................. 6 STEC SUBMISSION TO THE NATIONAL REFERENCE LABORATORY (NRL) ................................. 6 STEC LABORATORY DATA MODEL ....................................................................... 7 AIM OF THE PILOT.............................................................................................. 8 OBJECTIVES ....................................................................................................... 8 ACTIVITIES TO ACHIEVE SET OBJECTIVES ..................................................................... 9 MAPPING STEC DATA REPORTED TO THE MSIS LABORATORY DATABASE ........... 9 CHALLENGES TO THE CURRENT LEGAL FRAMEWORK FOR SHARING LABORATORY DATA .......................................................................................................... 10 CHALLENGES TO CURRENT TECHNICAL FRAMEWORK FOR SHARING LABORATORY DATA .......................................................................................................... 11 UNITED4Surveillance Grant Agreement Number 101102070 EXECUTIVE SUMMARY This document outlines the gaps and needs towards development of an integrated real-time surveillance system for infectious diseases. The Norwegian Institute of Public Health’s (NIPH) pilot focuses on the gaps in reporting practices of Shiga toxin-producing Escherichia coli (STEC) to the MSIS-laboratory database (MSIS-lab) and an assessment of legal and technical needs for sharing of microbial next-generation sequence (NGS) data to allow for the development and implementation of a national integrated surveillance system. STEC is a notifiable disease in Norway, and epidemiological and microbiological data (save NGS data) is shared with NIPH through The Norwegian Surveillance System for Communicable Diseases (MSIS) by clinicians, medical microbiological laboratories (MMLs) and the national reference laboratory (NRL). Reported and generated microbiological data is stored in databases at NRL and MSIS-lab. Currently, microbiological NGS data is not shared between MMLs, NRL and the MSIS-lab. Mapping of STEC reporting practices of MMLs to MSIS-lab revealed that most laboratories report results using codes of the Norwegian Laboratory Code System (NLK). However, laboratories differ in their adherence to the kind-of-property standards set for the NLK codes, and laboratories are more inclined to use comment fields to describe their findings. This practice poses significant challenges for interpretation and categorisation of the reported findings. NIPH have distributed recommendations to the MMLs for harmonized reporting. The current legal framework for sharing laboratory data to MSIS does not include provisions for sharing NGS data. NGS data and accompanied metadata are considered a special category of personal data for potential presence of human DNA and is therefore subjected to the General Data Protection Regulation (GDPR), Article 5. Since the COVID-19 pandemic, various initiatives at NIPH have sought clarification from the Ministry of Health and Care Services (HOD) regarding sharing of NGS data. Most recent communication with HOD (September 2023) suggests that a formal legal basis for sharing NGS data along with de-identified personal data with national and international organizations will be included in a revision of the Communicable Diseases Act. Current reporting practices of microbiological data to and from NIPH is supported by the in-place ITinfrastructure, however the present IT-infrastructure does not allow for the sharing of NGS data. Technological solutions currently used for NGS data sharing includes externally hosted platforms, both nationally (Norwegian e-Infrastructure for Life Science; NeLS, the Sensitive Data Service; TSD) and internationally (GISAID, ENA, NCBI). There is an urgent need for development of an IT-infrastructure for NGS data at NIPH. The first step towards establishment of an IT-infrastructure is a needs assessment from of all stakeholders, both nationally and internationally. A detailed plan should follow that includes considerations for security, scalability, and analytical capabilities for all intended users. UNITED4Surveillance Grant Agreement Number 101102070 Background Infectious disease surveillance involves the continuous and systematic collection, organization, and analysis of data on diseases, pathogens, immunity, vaccination, and associated behaviours. This process is vital to the responsibilities of public health institutions. Laboratory data is a cornerstone of effective disease surveillance, providing accurate and timely insights into the presence and spread of infectious diseases. This enables public health authorities to detect outbreaks early, monitor disease trends, and implement control measures efficiently. In Norway, the Norwegian Institute of Public Health (NIPH) serves as the data controller for the Norwegian Surveillance System for Communicable Diseases (MSIS). Both clinicians and medical microbiological laboratories (MMLs) contribute data to MSIS. Additionally, MMLs report all test results—covering both positive and negative findings—to the MSIS-laboratory database (MSIS-lab). MMLs also submit infectious agents to National Reference Laboratories (NRLs) for confirmation and for surveillance purposes. Norway's national laboratory network includes 19 MMLs across the country and over 50 national reference laboratory functions, many of which are housed at NIPH. As such, NIPH serves as a central hub for laboratory data reported by clinicians, MMLs, and NRLs in Norway. Historically, disease surveillance has relied heavily on epidemiological data reported by clinicians. However, laboratory data, particularly from NRLs, has proven indispensable for early warning and outbreak detection of numerous infectious diseases. The importance of microbiological data has become even more evident with advancements in next generation sequencing (NGS) and the establishment of the MSIS-lab in 2020. The integration of NGS data, currently stored at NRLs, with diagnostic test data stored in MSIS-lab, offers significant potential for real-time disease surveillance. However, integrating genome sequence data with epidemiological data and other registries presents substantial challenges, with legal and technical barriers limiting NIPH’s ability to fully leverage laboratory data for a comprehensive surveillance system. Shiga toxin-producing Escherichia coli (STEC) is an important pathogen due to its potential to cause severe illness, including haemorrhagic colitis, and life-threatening complications such as haemolytic uremic syndrome (HUS). STEC infections can lead to outbreaks associated with contaminated food, water, or person-to-person transmission. Effective surveillance and rapid detection are crucial for preventing outbreaks, protecting public health, and guiding timely interventions to reduce morbidity and mortality. Enhancing the STEC surveillance system by integrating sequencing data with diagnostic test results and epidemiological data would significantly improve NIPH’s ability to detect and respond to outbreaks more effectively. In this pilot project we used STEC as a test case to identify gaps in reporting practices to MSIS-lab and to describe the current legal and technical challenges hindering the development of an integrated surveillance system at NIPH. By addressing these issues, Norway can establish a more robust system for infectious disease surveillance, benefiting the public health nationally and globally. UNITED4Surveillance Grant Agreement Number 101102070 Legal framework for laboratory data collection The Communicable Diseases Act 1 (§ 7-9) assigns the responsibility for monitoring the national epidemiological situation on infectious diseases to the NIPH. This responsibility is enacted thorough the Norwegian Surveillance System for Communicable Diseases (MSIS), which is run by NIPH since 1975 (MSIS regulation 2 § 1-6). The MSIS regulation further outlines the obligation of clinicians to report all notifiable diseases (§ 2-1), and the MMLs to report test results to MSIS (§ 2-3). In addition, included in the MSIS regulations is the obligation for MMLs to submit infectious agents and/or sample material to the relevant NRL holding the function for the identified pathogen when one has been assigned by the Ministry of Health and Care Services (HOD) (§ 2-4a). As data controller of MSIS, the NIPH is tasked with assisting in the response to notified signals and events and uphold the countries notification duties according to International Health Regulations to any international system under the auspices of the World Health Organization or the European Commission. The NRLs are mandated (MSIS regulation § 2-5) to fulfil both patient-focused and public health-oriented core functions, including: I. Reference diagnostics, II. Maintaining reference material resources, III. Providing scientific advice, IV. Collaborating on research, and V. Performing surveillance, issuing alerts, and responding to outbreaks. During the COVID-19 pandemic, Norway established the MSIS-lab for real-time monitoring of SARS-CoV-2 testing activity. While the MSIS-lab has been instrumental in laboratory-based surveillance of SARS-CoV-2, it is not yet routinely utilized for other pathogens. Reporting of Shiga toxin-producing Escherichia coli (STEC) in Norway STEC Reporting to MSIS MSIS is a national registry in Norway that monitors infectious diseases and related laboratory results. It is managed by the NIPH and consists of two main components: 1. MSIS: Collects case-based notifications from physicians about notifiable infectious diseases, including clinical and epidemiological details and supportive laboratory diagnostic findings from MMLs in accordance with case definitions. 2. MSIS Laboratory Database: Receives test results (positive and negative) whether from notifiable or non-notifiable diseases from all MMLs in Norway. The system integrates clinical and laboratory data using unique national identifiers, enabling real-time surveillance, outbreak investigation, and research. MSIS is essential for public health monitoring, aiding in national and international reporting, and supporting timely responses to infectious disease threats. 1 https://lovdata.no/dokument/NL/lov/1994-08-05-55 2 https://lovdata.no/dokument/SF/forskrift/2003-06-20-740 UNITED4Surveillance Grant Agreement Number 101102070 STEC Reporting to the MSIS registry (MSIS) All positive laboratory results that meet the notification criteria for clinical STEC cases are reported to MSIS, along with clinical notifications from the patient's doctor. These case-based records are stored in a centralized server environment in Norway. Reporting is conducted both on paper and electronically via the Norwegian Health Network (NHN), which is a secure, closed network designed for healthcare sector communication in Norway. Notification criteria for STEC, incl. diarrhoea-associated HUS Criteria for notification is a clinically compatible case with epidemiological link or laboratory detection of: • STEC by isolating E. coli that produces Shiga toxin or with genes that code for the Shiga toxins Stx1 or Stx2 or • the genes stx1 or stx2, by nucleic acid examination (independent of isolation of strain) or • free Shiga toxin in faeces (independent of isolation of strain) or • specific antibodies (as the only notification criterion, only in HUS) Isolation of STEC strain and further detection of stx1/stx2, eae and serotype, is recommended. Clinical criteria for STEC infection are at least one of the following symptoms: diarrhoea, abdominal pain. Clinical criteria for diarrhoea-associated HUS are acute renal failure within 14 days from episode of acute diarrhoea and at least one of the following conditions: microangiopathic haemolytic anaemia, thrombocytopenia. With epidemiological link at least one of the following conditions should be considered probable: • transmission from animals to humans, • person-to-person transmission, • exposure to a common source, • consumption of food or water where STEC has been detected, or • exposure for other infectious factors in the environment. STEC Reporting to the MSIS Laboratory Database (MSIS-lab) All laboratory results, including both positive and negative findings, from all MMLs in Norway—whether public or private—are reported to the MSIS-lab. These results are stored in a centralized server environment within Norway, and reporting utilizes the technical infrastructure within NHN. The data is accessible to the NIPH within minutes after laboratories submit the test results, facilitating real-time surveillance and daily reporting both nationally and internationally. The use of unique national identity numbers ensures that the data can be linked to other national data sources. STEC Submission to the National Reference Laboratory (NRL) The NRL for Enteropathogenic Bacteria in Norway is hosted by NIPH. It is responsible for verifying and characterizing bacterial pathogens such as STEC isolated from human samples. All MMLs in Norway are required to send samples or isolates, along with preliminary laboratory results, to the NRL according to NRLs outlined specifications (see below). The requisition form, including metadata and laboratory results, is sent by mail from MMLs to the NRL. At the NRL a rapid microbiological risk assessment is performed using PCR for shiga toxin 2 (stx2) subtyping to identify STEC strains with the potential to cause haemolytic uremic syndrome. These isolates are then subjected to NGS to identify serotype, virulence genes, and clusters. Molecular data, UNITED4Surveillance Grant Agreement Number 101102070 along with metadata, are stored in the NRL Laboratory Information Management System (LIMS). Results from the different characterizations are reported to both MSIS and MSIS-lab. Obligation to submit First-time isolates of STEC must be sent as a pure culture to the NRL for: • confirmed and suspected cases of HUS irrespective of the isolates’ virulence profile, • case with diarrhoea (including bloody) when: o STEC with detection of stx2 alone or in combination with stx1 or o STEC when the primary laboratory is unable to distinguish between stx1 and stx2 Control samples and isolates detected in the event of disease recurrence less than 3 months after the last positive sample if there is reason to suspect a new STEC infection. STEC Laboratory Data Model Medical microbiological laboratories (MMLs) are required to submit an electronic copy of all reports that include microbiological investigation results to the MSIS-lab, including identifiers for both the person (Person ID) and the sample (Sample ID), as well as corresponding investigation codes from the standardized national codebook and their associated results. The MMLs automatically report their findings to NIPH at the same time as reporting to the treating physician. This is an important factor contributing to making the surveillance timely. For pathogens with an assigned NRL, such as STEC, MMLs must also submit sample materials to the NRL for confirmation and in-depth characterization, including NGS. At the NRL, all received samples are registered in the NRL LIMS with a unique Reference Laboratory Identifier (Reflab-ID). Tests are requested within LIMS for the confirmation and characterization of the pathogen, including culture, PCR (stx-subtyping), NGS, and occasionally multiple locus variable number tandem repeats analysis (MLVA) during outbreak investigations. At NRL NGS of STEC is performed using the Illumina platform, and raw sequences are stored on an in-house server hosted by NHN. Bioinformatic pipelines are run to identify serotype, stx-subtype, virulence genes, antimicrobial resistance (AMR) markers, mobile genetic elements, sequence type (MLST), and cluster type (core genome MLST). These pipelines run in two separate workflows: an in-house Linux script and the commercial Ridom SeqSphere software. The output data from these workflows is stored in a SQL database on a server hosted by NHN (Figure 1). Sequencing results are reported and stored in the NRL LIMS. The LIMS generates a unique Sample-ID and reports NGS-generated results to the MSIS-lab. The MSIS-lab is a SQL database that organizes data submitted by MMLs and the NRL using a standardized format (.xml). Data elements, such as Person ID, Sample ID, and other relevant information, can be linked using these identifiers. While sequencing data is not stored directly in the MSIS-lab, the Sample-ID and Person-ID keys can be used to trace back to the corresponding Reflab-IDs, allowing access to sequence data stored on the NHN sequence server. UNITED4Surveillance Grant Agreement Number 101102070 Figure 1. Logical data model structure for laboratory-based surveillance of STEC in Norway. Medical microbiology laboratories (MMLs) submit samples with unique identifiers to the national reference laboratory (NRL) for confirmation and characterization of isolated pathogens. The NRL request tests on the received samples through their laboratory information management system (LIMS), and results are reported back to LIMS using a unique identifier (Reflab-ID). Next generation sequencing is performer using the Illumina platform and raw sequences are stored on servers located at Norwegian Health Network (NHN). Results from various bioinformatical pipelines run in an in-house Linux script and the SeqSphere software are reported to NRL LIMS. The MMLs and the NRL submit results to the MSIS laboratory database (MSIS-lab). MSIS-lab is a SQL-database that partitions and stores results and metadata using unique identifiers. Aim of the pilot This pilot aim to explore the possibility for improved laboratory-based surveillance of Shiga toxin-producing Escherichia coli (STEC) in Norway by harmonizing data reporting practices and develop protocols for data analyses. Objectives i. To develop a data management protocol for diagnostic test data on STEC reported to the MSIS-lab, covering the range of all possible tests, methodology and reporting forms. The data management protocol will be based upon the existing SARS-CoV-2 model. ii. To explore the possibility of data transfer protocols between NRL and MSIS-lab and use diagnostic data from the MSIS-lab and genome sequence data from the NRL to enable an integrated real-time laboratory surveillance of STEC in Norway. UNITED4Surveillance Grant Agreement Number 101102070 Activities to achieve set objectives i. Map diagnostic test data on STEC reported to MSIS laboratory database: We will survey the MMLs to understand the diagnostic test workflow and reporting practices to MSIS-lab. Results from the survey will guide recommendation for harmonized reporting practices. ii. Integrated Surveillance of STEC: We will explore the legal and technical requirements for integration of laboratory data from NRL with data reported to MSIS-lab to allow for an integrated laboratory surveillance system. Mapping STEC data reported to the MSIS laboratory database In December 2023, a survey was created using MS Forms and distributed to all MMLs in Norway that perform faeces diagnostics (n=17). By the close of the survey, NIPH had received responses from 13 out of 17 (76%) MMLs. Of the 13 participating MMLs, all but one tested all faecal samples for STEC. This included samples from patients with diarrhoea or gastroenteritis where testing for enteropathogenic bacteria had been requested. The remaining laboratory tested for STEC only under specific clinical indications: HUS, bloody diarrhoea, and diarrhoea in children under seven years of age. Nine laboratories used broad-spectrum PCRs for the detection of a wide range enteropathogenic bacteria as a first step in their STEC diagnostics. Three laboratories use STEC-specific PCRs in the first diagnostic step, while the final laboratory cultured their faecal sample as the first step of STEC diagnostics. Laboratories reported using either 3 or 4 steps in their STEC detection and characterisation, which included: detection, culture, stx-typing (PCR) and stx2-subtyping (PCR). All laboratories used codes from the Norwegian Laboratory Code System (NLK) in addition to local codes to report their findings to MSIS-lab.. Out of the 18 available NLK codes for STEC, only 9 were used. Two of the unused codes were replaced by local code variants. About the Norwegian Laboratory Code System (NLK) The NLK is a clinical and administrative tool maintained by The Directorate of e-health that ensures a standardized ordering and reporting of laboratory tests. In addition, the coding system contributes to increased data quality and since 2018 it has been mandatory in reimbursement requirements for outpatient laboratory analyses. NLK is a monoaxial coding system, where each analysis/test has a unique code. The code is defined with system, component, kind-of-property and unit. These elements compile into a code definition, which is unique for each code (https://www.helsedirektoratet.no/digitalisering-og-e-helse/helsefagligekodeverk/nlk). Although a high proportion of results reported by MMLs used NLK codes, laboratories differed in their adherence to the kind-of-property standards set for the NLK codes, especially when using taxon and arbitrary concentration. In addition, laboratories were more inclined to use comment fields to describe their findings, thus posing significant challenges for MSIS-lab technicians to interpret and accurately categorise reported findings. NIPH has summarized the findings of the survey in a report which outlines the range of diagnostic tests used for the identification of STEC at the different MMLs, their reporting practices to MSIS-lab, and NIPHs recommendations for harmonized reporting. The report will be sent out to the laboratories during the first quarter of 2025. Recommendations for harmonized reporting to ensure uniform interpretation include: