Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Integrating row level security in i2b2: segregation of medical records into data marts without data replication and synchronization.

Objective: i2b2 offers the possibility to store biomedical data of different projects in subject oriented data marts of the data warehouse, which potentially requires data replication between different projects and also data synchronization in case of data changes. We present an approach that can save this effort and assess its query performance in a case study that reflects real-world scenarios. Material and Methods: For data segregation, we used PostgreSQL's row level security (RLS) feature, the unit test framework pgTAP for validation and testing as well as the i2b2 application. No change of the i2b2 code was required. Instead, to leverage orchestration and deployment, we additionally implemented a command line interface (CLI). We evaluated performance using 3 different queries generated by i2b2, which we performed on an enlarged Harvard demo dataset. Results: We introduce the open source Python CLI i2b2rls, which orchestrates and manages security roles to implement data marts so that they do not need to be replicated and synchronized as different i2b2 projects. Our evaluation showed that our approach is on average 3.55 and on median 2.71 times slower compared to classic i2b2 data marts, but has more flexibility and easier setup. Conclusion: The RLS-based approach is particularly useful in a scenario with many projects, where data is constantly updated, user and group requirements change frequently or complex user authorization requirements have to be defined. The approach applies to both the i2b2 interface and direct database access.

MIRACUM-Pipe: An Adaptable Pipeline for Next-Generation Sequencing Analysis, Reporting, and Visualization for Clinical Decision Making.

(1) Background: Next-generation sequencing (NGS) of patients with advanced tumors is becoming an established method in Molecular Tumor Boards. However, somatic variant detection, interpretation, and report generation, require in-depth knowledge of both bioinformatics and oncology. (2) Methods: MIRACUM-Pipe combines many individual tools into a seamless workflow for comprehensive analyses and annotation of NGS data including quality control, alignment, variant calling, copy number variation estimation, evaluation of complex biomarkers, and RNA fusion detection. (3) Results: MIRACUM-Pipe offers an easy-to-use, one-prompt standardized solution to analyze NGS data, including quality control, variant calling, copy number estimation, annotation, visualization, and report generation. (4) Conclusions: MIRACUM-Pipe, a versatile pipeline for NGS, can be customized according to bioinformatics and clinical needs and to support clinical decision-making with visual processing and interactive reporting.

FHIR DataProvider for ReactAdmin: Leveraging User Interface Creation for Medical Web Applications.

In medical data science, FHIR provides an increasingly used information model, which will lead to the creation of FHIR warehouses in the future. To efficiently work with a FHIR-based representation, users need a visual representation. The modern UI framework ReactAdmin (RA) enhances usability by leveraging current web standards such as React and Material Design. Rapid development and implementation of usable modern UIs is made possible by its high modularity and many widgets available in the framework. For data connection to different data sources RA needs a DataProvider (DP), which maps the communication from the server to the provided components. In this work, we present a DataProvider for FHIR that enables future UI developments for FHIR servers using RA. A demo application demonstrates the DP's capabilities. The code is published under MIT license.

Usability Evaluation of a Modern Multilingual MeSH Browser.

Medical Subject Headings (MeSH) is one of the most important vocabularies for information retrieval in medical research. It enables fast and reliable retrieval of research on PubMed/MEDLINE, the world's largest body of medical literature. The original English version of the thesaurus can be accessed via a MeSH Browser developed by the NLM. Recently, a multilingual MeSH Browser was proposed to enable usage across languages. To improve upon the original system, a new user interface (UI) was developed using contemporary web design frameworks in combination with principles from cognitive science. It aims to simplify access for medical professionals and increase overall usability. Evaluating such design improvements continually is necessary to quantify the possible positive impact for online systems in medical research. This study therefore directly compares the resulting system to the NLM Browser, using an established online questionnaire. Results show significant improvements in content and navigation as well as overall user satisfaction, while offering feedback for future improvements. This underlines the benefits of employing contemporary web design in terms of usability and user satisfaction.

AHD2FHIR: A Tool for Mapping of Natural Language Annotations to Fast Healthcare Interoperability Resources - A Technical Case Report.

A significant portion of data in Electronic Health Records is only available as unstructured text, such as surgical or finding reports, clinical notes and discharge summaries. To use this data for secondary purposes, natural language processing (NLP) tools are required to extract structured information. Furthermore, for interoperable use, harmonization of the data is necessary. HL7 Fast Healthcare Interoperability Resources (FHIR), an emerging standard for exchanging healthcare data, defines such a structured format. For German-language medical NLP, the tool Averbis Health Discovery (AHD) represents a comprehensive solution. AHD offers a proprietary REST interface for text analysis pipelines. To build a bridge between FHIR and this interface, we created a service that translates the communication around AHD from and to FHIR. The application is available under an open source license.

A Multilingual Browser Platform for Medical Subject Headings.

The National Library of Medicine (NLM) controls and publishes the thesaurus Medical Subject Headings which is used for indexing PubMed. Besides an XML export, the NLM offers a web based MeSH browser. The platform contains English terms. The German Institute for Medical Documentation and Information (DIMDI) partially translated and published these terms. Recently, the German National Library of Medicine (ZB-MED) overtook the translation of MeSH. However, there is no dedicated platform which focuses on MeSH and covers multiple languages. Here, we address this gap, by offering a modern multilingual searchable MeSH browser. A modular platform using open source technology is presented. The frontend enables the user to search and browse terms and switch between different languages. The current version of the presented MeSH browser contains English and German MeSH terms and can be accessed at https://mesh-browser.de.

Enabling External Inquiries to an Existing Patient Registry by Using the Open Source Registry System for Rare Diseases: Demonstration of the System Using the European Society for Immunodeficiencies Registry.

BACKGROUND: The German Network on Primary Immunodeficiency Diseases (PID-NET) utilizes the European Society for Immunodeficiencies (ESID) registry as a platform for collecting data. In the context of PID-NET data, we show how registries based on custom software can be made interoperable for better collaborative access to precollected data. The Open Source Registry System for Rare Diseases (Open-Source-Registersystem für Seltene Erkrankungen [OSSE], in German) provides patient organizations, physicians, scientists, and other parties with open source software for the creation of patient registries. In addition, the necessary interoperability between different registries based on the OSSE, as well as existing registries, is supported, which allows those registries to be confederated at both the national and international levels. OBJECTIVE: Data from the PID-NET registry should be made available in an interoperable manner without losing data sovereignty by extending the existing custom software of the registry using the OSSE registry framework. METHODS: This paper describes the following: (1) the installation and configuration of the OSSE bridgehead, (2) an approach using a free toolchain to set up the required interfaces to connect a registry with the OSSE bridgehead, and (3) the decentralized search, which allows the formulation of inquiries that are sent to a selected set of registries of interest. RESULTS: PID-NET uses the established and highly customized ESID registry software. By setting up a so-called OSSE bridgehead, PID-NET data are made interoperable according to a federated approach, and centrally formulated inquiries for data can be received. As the first registry to use the OSSE bridgehead, the authors introduce an approach using a free toolchain to efficiently implement and maintain the required interfaces. Finally, to test and demonstrate the system, two inquiries are realized using the graphical query builder. By establishing and interconnecting an OSSE bridgehead with the underlying ESID registry, confederated queries for data can be received and, if desired, the inquirer can be contacted to further discuss any requirements for cooperation. CONCLUSIONS: The OSSE offers an infrastructure that provides the possibility of more collaborative and transparent research. The decentralized search functionality includes registries into one search application while still maintaining data sovereignty. The OSSE bridgehead enables any registry software to be integrated into the OSSE network. The proposed toolchain to set up the required interfaces consists of freely available software components that are well documented. The use of the decentralized search is uncomplicated to use and offers a well-structured, yet still improvable, graphical user interface to formulate queries.

The German National Registry of Primary Immunodeficiencies (2012-2017).

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

The NEW ESID online database network.

SUMMARY: Primary Immunodeficiencies (PIDs) belong to the group of rare diseases. The European Society for Immunodeficiencies (ESID) operates an international research database application for continuous long-term documentation of patient data. The system is a web application which runs in a standard browser. Therefore, the system is easy to access from any location. Technically, the system is based on Gails backed by MariaDB with high standard security features to comply with the demands of a modern research platform. AVAILABILITY AND IMPLEMENTATION: The ESID Online Database is accessible via the official website: https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry. A demo system is available via: https://cci-esid-reg-demo-app.uniklinik-freiburg.de/EERS with user demouser and password Demo-2019.

The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity.

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.