Health data space nodes for privacy-preserving linkage of medical data to support collaborative secondary analyses.

Introduction: The potential for secondary use of health data to improve healthcare is currently not fully exploited. Health data is largely kept in isolated data silos and key infrastructure to aggregate these silos into standardized bodies of knowledge is underdeveloped. We describe the development, implementation, and evaluation of a federated infrastructure to facilitate versatile secondary use of health data based on Health Data Space nodes. Materials and methods: Our proposed nodes are self-contained units that digest data through an extract-transform-load framework that pseudonymizes and links data with privacy-preserving record linkage and harmonizes into a common data model (OMOP CDM). To support collaborative analyses a multi-level feature store is also implemented. A feasibility experiment was conducted to test the infrastructures potential for machine learning operations and deployment of other apps (e.g., visualization). Nodes can be operated in a network at different levels of sharing according to the level of trust within the network. Results: In a proof-of-concept study, a privacy-preserving registry for heart failure patients has been implemented as a real-world showcase for Health Data Space nodes at the highest trust level, linking multiple data sources including (a) electronical medical records from hospitals, (b) patient data from a telemonitoring system, and (c) data from Austria's national register of deaths. The registry is deployed at the tirol kliniken, a hospital carrier in the Austrian state of Tyrol, and currently includes 5,004 patients, with over 2.9 million measurements, over 574,000 observations, more than 63,000 clinical free text notes, and in total over 5.2 million data points. Data curation and harmonization processes are executed semi-automatically at each individual node according to data sharing policies to ensure data sovereignty, scalability, and privacy. As a feasibility test, a natural language processing model for classification of clinical notes was deployed and tested. Discussion: The presented Health Data Space node infrastructure has proven to be practicable in a real-world implementation in a live and productive registry for heart failure. The present work was inspired by the European Health Data Space initiative and its spirit to interconnect health data silos for versatile secondary use of health data.

Correlation of 99mTc-DPD bone scintigraphy with histological amyloid load in patients with ATTR cardiac amyloidosis.

BACKGROUND: The significance of measuring 99mTc-labelled-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in transthyretin (ATTR) cardiac amyloidosis has not been adequately studied. This single-centre observational study evaluated the correlation between 99mTc-DPD scintigraphy and histological amyloid load in endomyocardial biopsy (EMB). METHODS: Twenty-eight patients with biopsy-proven ATTR amyloidosis and concomitantly available 99mTc-DPD scintigraphy were included. Visual Perugini scoring, and (semi-)quantitative analysis of cardiac 99mTc-DPD uptake by planar whole-body imaging and single photon emission computed tomography (SPECT/CT) using regions of interest (ROI) were performed. From this, heart-to-whole-body ratio (H/WB) and heart-to-contralateral-chest ratio (H/CL) were calculated. The histological amyloid load was quantified using two different staining methods. RESULTS: Increased cardiac tracer uptake was documented in all patients (planar: ROImean 129 ± 37 cps; SPECT/CT: ROImean 369 ± 142 cps). Histological amyloid load (19 ± 13%) significantly correlated with Perugini score (r = 0.69, p < .001) as well as with cardiac 99mTc-DPD uptake (planar: r = 0.64, p < .001; H/WB: r = 0.50, p = .014; SPECT/CT: r = 0.53, p = .008; H/CL: r = 0.43, p = .037) (results are shown for correlations with Congo Red-staining). CONCLUSION: In ATTR, cardiac 99mTc-DPD uptake significantly correlated with histological amyloid load in EMB. Further studies are needed to implement thresholds in cardiac 99mTc-DPD uptake measurements for risk stratification and guidance of therapy.

Newborn sequencing is only part of the solution for better child health.

Newborn screening (NBS) aims to detect newborns with severe congenital diseases before the onset of clinical manifestations. Advancements in genomic technologies have led to proposals for the development of genomic-based NBS (G-NBS) in concert with traditional NBS. Proponents of G-NBS highlight how G-NBS could expand the number of diseases screened at birth to thousands and spur the development of new drugs and treatments for rare diseases. Balancing the excitement, some experts have pointed to the ethical dilemmas linked to G-NBS. The dialog, however, has yet to engage with sufficient urgency on how the new G-NBS might chart a course for improving the health of all children. Our analysis of more than 130 million births in the United States between 1959 and 1995 shows that traditional NBS led to improvements in infant mortality and health equity only when it was implemented in association with measures to improve healthcare access for children. We suggest that the new G-NBS will lead to better child health only when the same degree of attention devoted to genomic technologies will be directed to the promotion of public health measures that facilitate access to high-quality healthcare for all children.

Promoting children's rights to health and well-being in the United States.

The United States has a highly sophisticated pediatric healthcare system and spends more than any other country per capita on children's healthcare. However, not all children have access to needed and affordable health care and the life expectancy and health outcomes of children in the country are worse than in any other industrialized nation. These nations typically offer universal healthcare for children as part of a robust recognition of a children's rights framework. In 1989 the United Nations adopted the Convention on the Rights of the Child that recognizes the right of the child to the highest attainable standard of health and to facilities for the treatment of illness and rehabilitation of health. Currently the United States is the only United Nations member country that has not ratified the Convention on the Rights of the Child. This paper outlines the potential benefits of adopting a child rights approach based on the principles and provisions of the Convention on the Rights of the Child. The fact that countries who invest much less in healthcare compared to the United States can achieve better health outcomes provides the certainty that a solution is possible and within reach.

Provision and availability of genomic medicine services in Level IV neonatal intensive care units.

PURPOSE: To describe variation in genomic medicine services across level IV neonatal intensive care units (NICUs) in the United States and Canada. METHODS: We developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children's Hospitals Neonatal Consortium, requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. RESULTS: Overall response rate was 74% (32/43). Although chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites), and pre- and post-test counseling practices varied widely. CONCLUSION: We observed large inter-center variation in genomic medicine services across level IV NICUs: most notably, access to rapid, comprehensive genetic testing in time frames relevant to critical care decision making was limited at many level IV Children's Hospitals Neonatal Consortium NICUs despite a significant burden of genetic disease. Further efforts are needed to improve access to neonatal genomic medicine services.

Exploring collaboration models between geneticists and intensivists for implementing rapid genome sequencing in critical care settings.

The availability of rapid genome sequencing (rGS) for children in a critical-care setting is increasing. This study explored the perspectives of geneticists and intensivists on optimal collaboration and division of roles when implementing rGS in neonatal and pediatric intensive care units (ICUs). We conducted an explanatory mixed methods study involving a survey embedded within an interview with 13 genetics and intensive care providers. Interviews were recorded, transcribed, and coded. Geneticists endorsed higher confidence in performing a physical exam and interpreting/communicating positive results. Intensivists endorsed highest confidence in determining whether genetic testing was appropriate, communicating negative results, and consenting. Major qualitative themes that emerged were: (1) concerns with both "genetics-led" and "intensivist-led" models with workflows and sustainability (2) shift the role of determining rGS eligibility to ICU medical professionals, (3) continued role of geneticists to assess phenotype, and (4) include genetic counselors (GCs) and neonatal nurse practitioners to enhance workflow and care. All geneticists supported shifting decisions regarding eligibility for rGS to the ICU team to minimize time cost for the genetics workforce. Exploring models of geneticist-led phenotyping, intensivist-led phenotyping for some indications, and/or inclusion of a dedicated inpatient GC may help offset the time burden of consenting and other tasks associated with rGS.

Open-Source Artificial Intelligence System Supports Diagnosis of Mendelian Diseases in Acutely Ill Infants.

Mendelian disorders are prevalent in neonatal and pediatric intensive care units and are a leading cause of morbidity and mortality in these settings. Current diagnostic pipelines that integrate phenotypic and genotypic data are expert-dependent and time-intensive. Artificial intelligence (AI) tools may help address these challenges. Dx29 is an open-source AI tool designed for use by clinicians. It analyzes the patient's phenotype and genotype to generate a ranked differential diagnosis. We used Dx29 to retrospectively analyze 25 acutely ill infants who had been diagnosed with a Mendelian disorder, using a targeted panel of ~5000 genes. For each case, a trio (proband and both parents) file containing gene variant information was analyzed, alongside patient phenotype, which was provided to Dx29 by three approaches: (1) AI extraction from medical records, (2) AI extraction with manual review/editing, and (3) manual entry. We then identified the rank of the correct diagnosis in Dx29's differential diagnosis. With these three approaches, Dx29 ranked the correct diagnosis in the top 10 in 92-96% of cases. These results suggest that non-expert use of Dx29's automated phenotyping and subsequent data analysis may compare favorably to standard workflows utilized by bioinformatics experts to analyze genomic data and diagnose Mendelian diseases.

Towards a Verification Approach of a Smart Registry for Chronic Heart Failure Patients.

BACKGROUND: The daily increasing amount of health data from different sources like electronic medical records and telehealth systems go hand in hand with the ongoing development of novel digital and data-driven analytics. Unifying this in a privacy-preserving data aggregation infrastructure can enable services for clinical decision support in personalized patient therapy. OBJECTIVES: The goal of this work was to consider such an infrastructure, implemented in a smart registry for heart failure, as a comparative method for the analysis of health data. METHODS: We analyzed to what extent the dataset of a study on the telehealth program HerzMobil Tirol (HMT) can be reproduced with the data from the smart registry. RESULTS: A table with 96 variables for 251 patients of the HMT publication could theoretically be replicated from the smart registry for 248 patients with 80 variables. The smart registry contained the tables to reproduce a large part of the information, especially the core statements of the HMT publication. CONCLUSION: Our results show how such an infrastructure can enable efficient analysis of health data, and thus take a further step towards personalized health care.

Impact of Professional Background on Inter-Annotator Variability and Accuracy During Annotation of Clinical Notes.

BACKGROUND: The aging population's need for treatment of chronic diseases is exhibiting a marked increase in urgency, with heart failure being one of the most severe diseases in this regard. To improve outpatient care of these patients and reduce hospitalization rates, the telemedical disease management program HerzMobil was developed in the past. OBJECTIVE: This work aims to analyze the inter-annotator variability among two professional groups (healthcare and engineering) involved in this program's annotation process of free-text clinical notes using categories. METHODS: A dataset of 1,300 text snippets was annotated by 13 annotators with different backgrounds. Inter-annotator variability and accuracy were evaluated using the F1-score and analyzed for differences between categories, annotators, and their professional backgrounds. RESULTS: The results show a significant difference between note categories concerning inter-annotator variability (p<0.0001) and accuracy (p<0.0001). However, there was no statistically significant difference between the two annotator groups, neither concerning inter-annotator variability (p=0.15) nor accuracy (p=0.84). CONCLUSION: Professional background had no significant impact on the annotation of free-text HerzMobil notes.

Classification of Clinical Notes from a Heart Failure Telehealth Network.

Heart failure is a common chronic disease which is associated with high re-hospitalization and mortality rates. Within the telemedicine-assisted transitional care disease management program HerzMobil, monitoring data such as daily measured vital parameters and various other heart failure related data are collected in a structured way. Additionally, involved healthcare professionals communicate with one another via the system using free-text clinical notes. Since manual annotation of such notes is too time-consuming for routine care applications, an automated analysis process is needed. In the present study, we established a ground truth classification of 636 randomly selected clinical notes from HerzMobil based on annotations of 9 experts with different professional background (2 physicians, 4 nurses, and 3 engineers). We analyzed the influence of the professional background on the inter annotator reliability and compared the results with the accuracy of an automated classification algorithm. We found significant differences depending on the profession and on the category. These results indicate that different professional backgrounds should be considered when selecting annotators in such scenarios.

Understanding the Clinical Utility of Genome Sequencing in Critically Ill Newborns.

Diagnostic genome sequencing (GS) in newborns may have many benefits. More accurate diagnosis could spur the development of innovative genomic therapies. A precise diagnosis could help doctors and parents anticipate clinical problems and inform a family's future reproductive choices. However, the integration of GS into neonatal care remains associated with a variety of ethical controversies, including concerns about informed consent, about interpreting uncertain results, about resource allocation and whether access to genomic services could exacerbate health disparities, and about the effect of genome diagnostics on people with disabilities. There also remains significant uncertainty about which babies should be tested and when and how the potential benefits of GS ought to be measured. Probably related to these challenges, some payors have been reluctant to cover the cost of GS for critically ill newborns. Much of the reluctance appears to turn on questions about the clinical benefit associated with GS and whether and for whom GS will be cost-effective. These situations point to the urgent need for careful assessments of the clinical utility of GS in critically ill infants. In this paper, we critically examine the ways in which the clinical utility of GS has been evaluated in this patient population. We focus on "change of management" (COM), a widely used measure of clinical utility for diagnostic GS. We suggest that this measure is often ambiguous because not all COMs can be attributed to genomic results and because not all COMs lead to patient benefit. Finally, we suggest ways that measurement of clinical utility could be improved.

Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning.

BACKGROUND: Rapidly and efficiently identifying critically ill infants for whole genome sequencing (WGS) is a costly and challenging task currently performed by scarce, highly trained experts and is a major bottleneck for application of WGS in the NICU. There is a dire need for automated means to prioritize patients for WGS. METHODS: Institutional databases of electronic health records (EHRs) are logical starting points for identifying patients with undiagnosed Mendelian diseases. We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE). RESULTS: MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children's Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85). In addition to effectively identifying patients for WGS, MPSE scores also strongly prioritize diagnostic cases over non-diagnostic cases, with projected diagnostic yields exceeding 50% throughout the first and second quartiles of score-ranked patients. CONCLUSIONS: Our results indicate that an automated pipeline for selecting acutely ill infants in neonatal intensive care units (NICU) for WGS can meet or exceed diagnostic yields obtained through current selection procedures, which require time-consuming manual review of clinical notes and histories by specialized personnel.

Variants in AQP11 may result in autosomal recessive bilateral cystic renal dysgenesis.

Congenital renal cystic dysplasia is a rare disease that occurs in approximately 1 in 4000 children and is often discovered in the antenatal period by ultrasound. It is commonly associated with oligohydramnios in utero and/or renal insufficiency or failure in the postnatal period. Aquaporins are membrane proteins that serve as transport channels in the transfer of water or small solutes across cell membranes. They play a role in the development of renal cysts. Aquaporin 11 (AQP11) deficient mice develop polycystic kidney disease in utero due to disruption of polycystin-1. Here we describe a case of bilateral cystic kidney disease in a patient with novel compound heterozygous variants in AQP11: c.780G>T (p. Trp260Cys) and c.472C>T (p.Pro158Ser) (NM_173039.2) identified by whole genome sequencing. These findings suggest, for the first time, the potential role of AQP11 in congenital renal cystic dysplasia.

Long-Term Clinical Trajectory of Patients with Subarachnoid Hemorrhage: Linking Acute Care and Neurorehabilitation.

BACKGROUND: Despite improvements in the critical care management of subarachnoid hemorrhage (SAH), a substantial number of patients still suffer from disabilities. In most areas of the world, longitudinal follow-up is not routinely performed, and the patient's trajectory remains unknown. METHODS: We prospectively collected data of 298 consecutive patients with spontaneous SAH and evaluated clinical trajectories at discharge, 3 months, and 1 year after SAH. In a subgroup of patients transferred to a local neurorehabilitation center (Rehab-Hochzirl), we studied the effects of rehabilitation intensity on clinical trajectories. Any decrease in the modified Rankin Scale (mRS) was defined as an improvement, with mRS ≤ 2 indicating good outcome. We used multivariate generalized linear models to investigate associations with clinical trajectories. RESULTS: Out of the 250 surviving patients, 35% were transferred directly to Rehab-Hochzirl (n = 87 of 250; mRS at discharge = 4), 11% were transferred to another rehabilitation center (n = 27 of 250; mRS = 1), 1% were transferred to a nursing home (n = 3 of 250; mRS = 5), 21% were transferred to their country of origin (n = 52 of 250; mRS = 4), and 32% (n = 79 of 250; mRS = 1) were discharged home. Functional outcome improved in 57% (n = 122 of 215) of patients during the first 3 months, with an additional 16% (35 of 215) improving between 3 and 12 months, resulting in an overall improvement in 73% (n = 157 of 215) of survivors. After 1 year, 60% (n = 179 of 250) of patients were functionally independent. A lower Hunt and Hess scale score at intensive care unit admission, younger age, a lower mRS at intensive care unit discharge, fewer days on mechanical ventilation, and male sex were independently associated with better functional recovery. Although the subgroup of patients transferred to Rehab-Hochzirl were more severely affected, 60% (52 of 87) improved during inpatient neurorehabilitation. CONCLUSIONS: Our results indicate ongoing functional improvement in a substantial number of patients with SAH throughout a follow-up period of 12 months. This effect was also observed in patients with severe disability receiving inpatient neurorehabilitation.

A salutogenic urban design framework: the case of UK local high streets and older people.

The article provides a novel look at the links between salutogenesis, health promotion, and urban design supported by the findings of recent research on local high streets and their benefits for the well-being of older people. Salutogenesis and the related explanatory concept of sense of coherence (SOC) have provided a theoretical framework for developing healthy settings interventions, shifting the focus from exploring barriers and deficits to assets and resources in promoting people's health and well-being. While these concepts have informed policies and programmes at the level of regions and cities, no attempt has been made to establish more direct links with the disciplines devoted to the organization and design of the built environment at the scale of public spaces and streets. This article advances the idea that the main categories of SOC-comprehensibility, manageability and meaningfulness-have found application in urban design theory. Linking these categories with urban design concepts in a comprehensive framework, it is possible to guide interventions aimed at strenghtening well-being resources available in the public realm. This is corroborated by the findings resulting from a study of the well-being experiences of older people (n = 84) across a range of local high streets in the city of Edinburgh (UK) applying an innovative multi-methods approach. The discussion establishes the links between well-being benefits, SOC constructs and urban design concepts, and underscores the potential of the proposed framework to guide a design-oriented salutogenic approach to the built environment.

In this article, we propose a novel conceptual framework that links health promotion and the theory of salutogenesis with key concepts commonly used in the urban design. The framework is articulated in relation to the findings of recent research on main neighbourhood commercial streets in Edinburgh (UK)­local high streets­and their benefits for the well-being of older people. Salutogenesis theory and related concepts have emphasized the role that everyday environments can have in promoting people's health and well-being, through the opportunities for social interaction and access to material resources they provide. They have informed policies and programmes at city-wide level but not at the scale of streets and public spaces, which is the spatial domain of urban design. The proposed framework establishes the links for a design-oriented salutogenic approach to the built environment and suggests a range of interventions in local high streets that can benefit an ageing population.

Population-Based Screening of Newborns: Findings From the NBS Expansion Study (Part One).

Each year, through population-based newborn screening (NBS), 1 in 294 newborns is identified with a condition leading to early treatment and, in some cases, life-saving interventions. Rapid advancements in genomic technologies to screen, diagnose, and treat newborns promise to significantly expand the number of diseases and individuals impacted by NBS. However, expansion of NBS occurs slowly in the United States (US) and almost always occurs condition by condition and state by state with the goal of screening for all conditions on a federally recommended uniform panel. The Newborn Screening Translational Research Network (NBSTRN) conducted the NBS Expansion Study to describe current practices, identify expansion challenges, outline areas for improvement in NBS, and suggest how models could be used to evaluate changes and improvements. The NBS Expansion Study included a workshop of experts, a survey of clinicians, an analysis of data from online repositories of state NBS programs, reports and publications of completed pilots, federal committee reports, and proceedings, and the development of models to address the study findings. This manuscript (Part One) reports on the design, execution, and results of the NBS Expansion Study. The Study found that the capacity to expand NBS is variable across the US and that nationwide adoption of a new condition averages 9.5 years. Four factors that delay and/or complicate NBS expansion were identified. A companion paper (Part Two) presents a use case for each of the four factors and highlights how modeling could address these challenges to NBS expansion.

Impact Analysis of De-Identification in Clinical Notes Classification.

BACKGROUND: Clinical notes provide valuable data in telemonitoring systems for disease management. Such data must be converted into structured information to be effective in automated analysis. One way to achieve this is by classification (e.g. into categories). However, to conform with privacy regulations and concerns, text is usually de-identified. OBJECTIVES: This study investigated the effects of de-identification on classification. METHODS: Two pseudonymisation and two classification algorithms were applied to clinical messages from a telehealth system. Divergence in classification compared to clear text classification was measured. RESULTS: Overall, de-identification notably altered classification. The delicate classification algorithm was severely impacted, especially losses of sensitivity were noticeable. However, the simpler classification method was more robust and in combination with a more yielding pseudonymisation technique, had only a negligible impact on classification. CONCLUSION: The results indicate that de-identification can impact text classification and suggest, that considering de-identification during development of the classification methods could be beneficial.

Ethical Considerations for Equitable Access to Genomic Sequencing for Critically Ill Neonates in the United States.

Rare diseases impact all socio-economic, geographic, and racial groups indiscriminately. Newborn screening (NBS) is an exemplary international public health initiative that identifies infants with rare conditions early in life to reduce morbidity and mortality. NBS theoretically promotes equity through universal access, regardless of financial ability. There is however heterogeneity in access to newborn screening and conditions that are screened throughout the world. In the United States and some other developed countries, NBS is provided to all babies, subsidized by the local or federal government. Although NBS is an equitable test, infants admitted to neonatal intensive care units (NICUs) may not receive similar benefits to healthier infants. Newborns in the NICU may receive delayed and/or multiple newborn screens due to known limitations in interpreting the results with prematurity, total parenteral nutrition, blood transfusions, infection, and life support. Thus, genomic technologies might be needed in addition to NBS for equitable care of this vulnerable population. Whole exome (WES) and genome sequencing (WGS) have been recently studied in critically ill newborns across the world and have shown promising results in shortening diagnostic odysseys and providing clinical utility. However, in certain circumstances several barriers might limit access to these tests. Here, we discuss some of the existing barriers to genomic sequencing in NICUs in the United States, explore the ethical implications related to low access, consider ways to increase access to genomic testing, and offer some suggestions for future research in these areas.

Evaluating use of changing technologies for rapid next-generation sequencing in pediatrics.

BACKGROUND: Rapid next-generation sequencing (NGS) offers the potential to shorten the diagnostic process and improve the care of acutely ill children. The goal of this study was to report our findings, including benefits and limitations, of a targeted NGS panel and rapid genome sequencing (rGS) in neonatal and pediatric acute clinical care settings. METHODS: Retrospective analysis of patient characteristics, diagnostic yields, turnaround time, and changes in management for infants and children receiving either RapSeq, a targeted NGS panel for 4500+ genes, or rGS, at the University of Utah Hospital and Primary Children's Hospital, from 2015 to 2020. RESULTS: Over a 5-year period, 142 probands underwent rapid NGS: 66 received RapSeq and 76 rGS. Overall diagnostic yield was 39%. In the majority of diagnostic cases, there were one or more changes in clinical care management. Of note, 7% of diagnoses identified by rGS would not have been identified by RapSeq. CONCLUSIONS: Our results indicate that rapid NGS impacts acute pediatric care in real-life clinical settings. Although affected by patient selection criteria, diagnostic yields were similar to those from clinical trial settings. Future studies are needed to determine relative advantages, including cost, turnaround time, and benefits for patients, of each approach in specific clinical circumstances. IMPACT: The use of comprehensive Mendelian gene panels and genome sequencing in the clinical setting allows for early diagnosis of patients in neonatal, pediatric, and cardiac intensive care units and impactful change in management. Diagnoses led to significant changes in management for several patients in lower acuity inpatient units supporting further exploration of the utility of rapid sequencing in these settings. This study reviews the limitations of comparing sequencing platforms in the clinical setting and the variables that should be considered in evaluating diagnostic rates across studies.