A High-Fidelity Combined ATC-Rxnorm Drug Hierarchy for Large-Scale Observational Research.

Observational research utilizes patient information from many disparate databases worldwide. To be able to systematically analyze data and compare the results of such research studies, information about exposure to drugs or classes of drugs needs to be harmonized across these data. The NLM's RxNorm drug terminology and WHO's ATC classification serve these needs but are currently not satisfactorily combined into a common system. Creating such system is hampered by a number of challenges, resulting from different approaches to representing attributes of drugs and ontological rules. Here, we present a combined ATC-RxNorm drug hierarchy, allowing to use ATC classes for retrieval of drug information in large scale observational data. We present the heuristic for maintaining this resource and evaluate it in a real world database containing drug and drug classification information.

Fitness for Use of Anatomical Therapeutic Classification for Real World Data Research.

INTRODUCTION: Real-world data (RWD) is gaining importance in research. For instance, the European Medicines Agency (EMA) is currently in the process of establishing a cross-national research network that utilizes RWD for research. However, data harmonization across countries must be carefully considered to avoid misclassification and bias. OBJECTIVES: This paper aims to investigate the extent to which a correct assignment of RxNorm ingredients is possible for medication orders that include only ATC codes. METHODS: In this study, we analyzed 1,506,059 medication orders from the University Hospital Dresden (UKD) and merged them with the ATC vocabulary in the Observational Medical Outcomes Partnership (OMOP) including relevant relationship mappings to RxNorm. RESULTS: We identified 70.25% of all medication orders were single ingredients with direct mapping to RxNorm. However, we also identified a significant complexity in mappings for the other medication orders that was visualized in an interactive scatterplot. DISCUSSION: The majority of medication orders under observation (70.25%) are single ingredients and can be standardized to RxNorm, combination drugs pose a challenge due to the different approaches of ingredient assignments in ATC and RxNorm. The provided visualization can help research teams gain a better understanding of problematic data and further investigate identified issues.

Alignment of two standard terminologies for dosage form: RxNorm from the National Library of Medicine for the United States and EDQM from the European Directorate for the Quality in Medicines and Healthcare for Europe.

BACKGROUND: There is currently no system that aligns pharmaceutically equivalent medicinal products across nations, creating obstacles to transnational medication prescribing and medical research. EDQM has been internationally recognized as the leading system in systematic pharmaceutical product descriptions. RxNorm is a critical terminology based in the US and used widely in applications internationally that would benefit from alignment with EDQM-based dosage form descriptions. GOAL: Demonstrate a method for alignment of RxNorm dosage forms with EDQM terminologies and with EDQM dosage forms. Describe obstacles and advantages of such an alignment for ultimate application in calculating universal Pharmaceutical Product Identifiers. METHODS: A pharmaceutical sciences student and a clinical pharmacology expert in dosage forms used definitions supplied by RxNorm and EDQM technical documentation to align the 120 RxNorm dose forms to EDQM-based dosage form description terms. The alignment of RxNorm to EDQM was then used to fit the RxNorm dose forms into an ontology based on EDQM. RESULTS AND CONCLUSIONS: The alignment of RxNorm and EDQM requires further validation but provides a potential method of establishing interoperability between the two terminologies without cumbersome manual reclassification. There remain ambiguities within each dosage form nomenclature that create obstacles to integrating medication databases rooted in EDQM and RxNorm into a single worldwide database.

Comparing the variability of ingredient, strength, and dose form information from electronic prescriptions with RxNorm drug product descriptions.

OBJECTIVE: To determine the variability of ingredient, strength, and dose form information from drug product descriptions in real-world electronic prescription (e-prescription) data. MATERIALS AND METHODS: A sample of 10 399 324 e-prescriptions from 2019 to 2021 were obtained. Drug product descriptions were analyzed with a named entity extraction model and National Drug Codes (NDCs) were used to get RxNorm Concept Unique Identifiers (RxCUI) via RxNorm. The number of drug product description variants for each RxCUI was determined. Variants identified were compared to RxNorm to determine the extent of matching terminology used. RESULTS: A total of 353 002 unique pairs of drug product descriptions and NDCs were analyzed. The median (1st-3rd quartile) number of variants extracted for each standardized expression in RxNorm, was 3 (2-7) for ingredients, 4 (2-8) for strength, and 41 (11-122) for dosage forms. Of the pairs, 42.35% of ingredients (n = 328 032), 51.23% of strengths (n = 321 706), and 10.60% of dose forms (n = 326 653) used matching terminology, while 16.31%, 24.85%, and 13.05% contained nonmatching terminology, respectively. DISCUSSION: A wide variety of drug product descriptions makes it difficult to determine whether 2 drug product descriptions describe the same drug product (eg, using abbreviations to describe an active ingredient or using different units to represent a concentration). This results in patient safety risks that lead to incorrect drug products being ordered, dispensed, and used by patients. Implementation and use of standardized terminology may reduce these risks. CONCLUSION: Drug product descriptions on real-world e-prescriptions exhibit large variation resulting in unnecessary ambiguity and potential patient safety risks.

Aggregations of Substance in Virtual Drug Models Based on ISO/CEN Standards for Identification of Medicinal Products (IDMP).

In this study representation of chemical substances in IDMP is reviewed, with an exploration of aggregation levels for substance used in the virtual drug data models of RxNorm, SNOMED-CT, ATC/INN, and the Belgian SAM database, for products with a single substance and combinations of substances. Active moiety and available solid states forms are explored for diclofenac, amoxicillin, carbamazepine, amlodipine, with regard to their representation in coding systems such as WHODrug, SMS, UNII, CAS, and SNOMED-CT. By counting the number of medicinal products in Belgium for amlodipine in each level of aggregation, concepts for grouper of substances and two levels of grouper of medicinal products are illustrated. Recommendations are made for the further development of IDMP and its link to international drug classifications.

The U.S. National Library of Medicine and Standards for Electronic Health Records: One Thing Led to Another.

When Donald A.B. Lindberg M.D. became Director in 1984, the U.S. National Library of Medicine (NLM) was a leader in the development and use of information standards for published literature but had no involvement with standards for clinical data. When Dr. Lindberg retired in 2015, NLM was the Central Coordinating Body for Clinical Terminology Standards within the U.S. Department of Health and Human Services, a major funder of ongoing maintenance and free dissemination of clinical terminology standards required for use in U.S. electronic health records (EHRs), and the provider of many services and tools to support the use of terminology standards in health care, public health, and research. This chapter describes key factors in the transformation of NLM into a significant player in the establishment of U.S. terminology standards for electronic health records.

Automated Modeling of Clinical Narrative with High Definition Natural Language Processing Using Solor and Analysis Normal Form.

OBJECTIVE: One important concept in informatics is data which meets the principles of Findability, Accessibility, Interoperability and Reusability (FAIR). Standards, such as terminologies (findability), assist with important tasks like interoperability, Natural Language Processing (NLP) (accessibility) and decision support (reusability). One terminology, Solor, integrates SNOMED CT, LOINC and RxNorm. We describe Solor, HL7 Analysis Normal Form (ANF), and their use with the high definition natural language processing (HD-NLP) program. METHODS: We used HD-NLP to process 694 clinical narratives prior modeled by human experts into Solor and ANF. We compared HD-NLP output to the expert gold standard for 20% of the sample. Each clinical statement was judged "correct" if HD-NLP output matched ANF structure and Solor concepts, or "incorrect" if any ANF structure or Solor concepts were missing or incorrect. Judgements were summed to give totals for "correct" and "incorrect". RESULTS: 113 (80.7%) correct, 26 (18.6%) incorrect, and 1 error. Inter-rater reliability was 97.5% with Cohen's kappa of 0.948. CONCLUSION: The HD-NLP software provides useable complex standards-based representations for important clinical statements designed to drive CDS.

OCRx: Canadian Drug Ontology.

This paper describes the development and evaluation of a Canadian drug ontology (OCRx), built to provide a normalized and standardized description of drugs that are authorized to be marketed in Canada. OCRx aims to improve the usability and interoperability of drugs terminologies for a non-ambiguous access to drugs information that is available in electronic health record systems. We present the first release of OCRx that is described in Web Ontology Language and aligned to the Identification of Medicinal Product (IDMP) standards. For comparison purposes, OCRx is mapped to RxNorm, its US variant.

Assessing automated product selection success rates in transmissions between electronic prescribing and community pharmacy platforms.

OBJECTIVE: Wrong drug product errors occurring in community pharmacies often originate at the transcription stage. Electronic prescribing and automated product selection are strategies to reduce product selection errors. However, it is unclear how often automated product selection succeeds in outpatient pharmacy platforms. MATERIALS AND METHODS: The intake of over 800 e-prescriptions was observed at baseline and after intervention to assess the rate of automated product selection success. A dispensing accuracy audit was performed at baseline and postintervention to determine whether enhanced automated product selection would result in greater accuracy; data for both analyses were compared by 2x2 Chi square tests. In addition, an anonymous survey was sent to a convenience sample of 60 area community pharmacy managers. RESULTS: At baseline, 79.8% of 888 e-prescriptions achieved automated product selection. After the intervention period, 84.5% of 903 e-prescriptions achieved automated product selection (P = .008). Analysis of dispensing accuracy audits detected a slight but not statistically significant improvement in accuracy rate (99.3% versus 98.9%, P = .359). Fourteen surveys were returned, revealing that other community pharmacies experience similar automated product selection failure rates. DISCUSSION: Our results suggest that manual product selection by pharmacy personnel is required for a higher than anticipated proportion of e-prescriptions received and filled by community pharmacies, which may pose risks to both medication safety and efficiency. CONCLUSION: The question of how to increase automated product selection rates and enhance interoperability between prescriber and community pharmacy platforms warrants further investigation.

Unified Medical Language System resources improve sieve-based generation and Bidirectional Encoder Representations from Transformers (BERT)-based ranking for concept normalization.

OBJECTIVE: Concept normalization, the task of linking phrases in text to concepts in an ontology, is useful for many downstream tasks including relation extraction, information retrieval, etc. We present a generate-and-rank concept normalization system based on our participation in the 2019 National NLP Clinical Challenges Shared Task Track 3 Concept Normalization. MATERIALS AND METHODS: The shared task provided 13 609 concept mentions drawn from 100 discharge summaries. We first design a sieve-based system that uses Lucene indices over the training data, Unified Medical Language System (UMLS) preferred terms, and UMLS synonyms to generate a list of possible concepts for each mention. We then design a listwise classifier based on the BERT (Bidirectional Encoder Representations from Transformers) neural network to rank the candidate concepts, integrating UMLS semantic types through a regularizer. RESULTS: Our generate-and-rank system was third of 33 in the competition, outperforming the candidate generator alone (81.66% vs 79.44%) and the previous state of the art (76.35%). During postevaluation, the model's accuracy was increased to 83.56% via improvements to how training data are generated from UMLS and incorporation of our UMLS semantic type regularizer. DISCUSSION: Analysis of the model shows that prioritizing UMLS preferred terms yields better performance, that the UMLS semantic type regularizer results in qualitatively better concept predictions, and that the model performs well even on concepts not seen during training. CONCLUSIONS: Our generate-and-rank framework for UMLS concept normalization integrates key UMLS features like preferred terms and semantic types with a neural network-based ranking model to accurately link phrases in text to UMLS concepts.

iDISK: the integrated DIetary Supplements Knowledge base.

OBJECTIVE: To build a knowledge base of dietary supplement (DS) information, called the integrated DIetary Supplement Knowledge base (iDISK), which integrates and standardizes DS-related information from 4 existing resources. MATERIALS AND METHODS: iDISK was built through an iterative process comprising 3 phases: 1) establishment of the content scope, 2) development of the data model, and 3) integration of existing resources. Four well-regarded DS resources were integrated into iDISK: The Natural Medicines Comprehensive Database, the "About Herbs" page on the Memorial Sloan Kettering Cancer Center website, the Dietary Supplement Label Database, and the Natural Health Products Database. We evaluated the iDISK build process by manually checking that the data elements associated with 50 randomly selected ingredients were correctly extracted and integrated from their respective sources. RESULTS: iDISK encompasses a terminology of 4208 DS ingredient concepts, which are linked via 6 relationship types to 495 drugs, 776 diseases, 985 symptoms, 605 therapeutic classes, 17 system organ classes, and 137 568 DS products. iDISK also contains 7 concept attribute types and 3 relationship attribute types. Evaluation of the data extraction and integration process showed average errors of 0.3%, 2.6%, and 0.4% for concepts, relationships and attributes, respectively. CONCLUSION: We developed iDISK, a publicly available standardized DS knowledge base that can facilitate more efficient and meaningful dissemination of DS knowledge.

AllergyMap: An Open Source Corpus of Allergy Mention Normalizations.

Allergy mention normalization is challenging because of the wide range of possible allergens including medications, foods, plants, animals, and consumer products. This paper describes the process of mapping free-text allergy information from an electronic health record (EHR) system in a university hospital to standard terminologies and migration of those data into an enterprise EHR system. The review, mapping, and migration revealed interesting issues and challenges with the free-text allergy information and the mapping in preparation for implementation in the new EHR system. These findings provide insights that can form the basis of guidelines for future mapping and migration efforts involving free-text allergy data. As part of this process, we generate and make freely available AllergyMap, a mapping between free-text entered allergy medication to standard non-proprietary ontologies. To our knowledge, this is the first such mapping available and could serve as a public resource for allergy mention normalization and system evaluation.

Enhancing the drug ontology with semantically-rich representations of National Drug Codes and RxNorm unique concept identifiers.

BACKGROUND: The Drug Ontology (DrOn) is a modular, extensible ontology of drug products, their ingredients, and their biological activity created to enable comparative effectiveness and health services researchers to query National Drug Codes (NDCs) that represent products by ingredient, by molecular disposition, by therapeutic disposition, and by physiological effect (e.g., diuretic). It is based on the RxNorm drug terminology maintained by the U.S. National Library of Medicine, and on the Chemical Entities of Biological Interest ontology. Both national drug codes (NDCs) and RxNorm unique concept identifiers (RXCUIS) can undergo changes over time that can obfuscate their meaning when these identifiers occur in historic data. We present a new approach to modeling these entities within DrOn that will allow users of DrOn working with historic prescription data to more easily and correctly interpret that data. RESULTS: We have implemented a full accounting of national drug codes and RxNorm unique concept identifiers as information content entities, and of the processes involved in managing their creation and changes. This includes an OWL file that implements and defines the classes necessary to model these entities. A separate file contains an instance-level prototype in OWL that demonstrates the feasibility of this approach to representing NDCs and RXCUIs and the processes of managing them by retrieving and representing several individual NDCs, both active and inactive, and the RXCUIs to which they are connected. We also demonstrate how historic information about these identifiers in DrOn can be easily retrieved using a simple SPARQL query. CONCLUSIONS: An accurate model of how these identifiers operate in reality is a valuable addition to DrOn that enhances its usefulness as a knowledge management resource for working with historic data.

Automatic Identification of Individual Drugs in Death Certificates.

BACKGROUND: Establishing trends of drug overdoses requires the identification of individual drugs in death certificates, not supported by coding with the International Classification of Diseases. However, identifying drug mentions from the literal portion of death certificates remains challenging due to the variability of drug names. OBJECTIVES: To automatically identify individual drugs in death certificates. METHODS: We use RxNorm to collect variants for drug names (generic names, synonyms, brand names) and we algorithmically generate common misspellings. We use this automatically compiled list to identify drug mentions from 703,106 death certificates and compare the performance of our automated approach to that of a manually curated list of drug names. RESULTS: Our automated approach shows a slight loss in recall (4.3%) compared to the manual approach (for individual drugs), due in part to acronyms. CONCLUSIONS: Maintenance of a manually curated list of drugs is not sustainable and our approach offers a viable alternative.

Normalizing Dietary Supplement Product Names Using the RxNorm Model.

The use of dietary supplements (DSs) is increasing in the U.S. As such, it is crucial for consumers, clinicians, and researchers to be able to find information about DS products. However, labeling regulations allow great variability in DS product names, which makes searching for this information difficult. Following the RxNorm drug name normalization model, we developed a rule-based natural language processing system to normalize DS product names using pattern templates. We evaluated the system on product names extracted from the Dietary Supplement Label Database. Our system generated 136 unique templates and obtained a coverage of 72%, a 32% increase over the existing RxNorm model. Manual review showed that our system achieved a normalization accuracy of 0.86. We found that the normalization of DS product names is feasible, but more work is required to improve the generalizability of the system.

Biomedical Informatics Investigator.

The BMI Investigator is a computer human interface built in .Net which allows simultaneous query of structured data such as demographics, administrative codes, medications (coded in RxNorm), laboratory test results (coded in LOINC) and formerly unstructured data in clinical notes (coded in SNOMED CT). The ontology terms identified using SNOMED are all coded as either positive, negative or uncertain assertions. They are then where applicable built into compositional expressions and stored in both a graph database and a triple store. The SNOMED CT codes are stored in a NOSQL database, Berkley DB, and the structured data is stored in SQL using the OMOP/OHDSI format. The BMI investigator also lets you develop models for cohort selection (data driven recruitment to clinical trials) and automated retrospective research using genomic criteria and we are adding image feature data currently to the system. We performed a usability experiment and the users identified some usability flaws which were used to improve the software. Overall, the BMI Investigator was felt to be usable by subject matter experts. Next steps for the software are to integrate genomic criteria and image features into the query engine.

Recent Developments in Clinical Terminologies - SNOMED CT, LOINC, and RxNorm.

OBJECTIVE: To discuss recent developments in clinical terminologies. SNOMED CT (Systematized Nomenclature of Medicine Clinical Terms) is the world's largest clinical terminology, developed by an international consortium. LOINC (Logical Observation Identifiers, Names, and Codes) is an international terminology widely used for clinical and laboratory observations. RxNorm is the standard drug terminology in the U.S. METHODS AND RESULTS: We present a brief review of the history, current state, and future development of SNOMED CT, LOINC and RxNorm. We also analyze their similarities and differences, and outline areas for greater interoperability among them. CONCLUSIONS: With different starting points, representation formalisms, funding sources, and evolutionary paths, SNOMED CT, LOINC, and RxNorm have evolved over the past few decades into three major clinical terminologies supporting key use cases in clinical practice. Despite their differences, partnerships have been created among their development teams to facilitate interoperability and minimize duplication of effort.

Toward a normalized clinical drug knowledge base in China-applying the RxNorm model to Chinese clinical drugs.

Objective: In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Methods: Chinese drugs were collected from 4 major resources-China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia-for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. Results: The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Conclusion: Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems in China.

Terminology Status APIs - Mapping Obsolete Codes to Current RxNorm, SNOMED CT, and LOINC Concepts.

We created the Terminology Status Application Programming Interface (API) to assist users in mapping obsolete codes to current RxNorm, SNOMED CT and LOINC concepts. Use cases include support for information retrieval, maintenance of value sets, and analytics of legacy clinical databases. Our terminology status APIs typically receive over 4 million calls per month on average.

Term Coverage of Dietary Supplements Ingredients in Product Labels.

As the clinical application and consumption of dietary supplements has grown, their side effects and possible interactions with prescribed medications has become a serious issue. Information extraction of dietary supplement related information is a critical need to support dietary supplement research. However, there currently is not an existing terminology for dietary supplements, placing a barrier for informatics research in this field. The terms related to dietary supplement ingredients should be collected and normalized before a terminology can be established to facilitate convenient search on safety information and control possible adverse effects of dietary supplements. In this study, the Dietary Supplement Label Database (DSLD) was chosen as the data source from which the ingredient information was extracted and normalized. The distribution based on the product type and the ingredient type of the dietary supplements were analyzed. The ingredient terms were then mapped to the existing terminologies, including UMLS, RxNorm and NDF-RT by using MetaMap and RxMix. The large gap between existing terminologies and ingredients were found: only 14.67%, 19.65%, and 12.88% of ingredient terms were covered by UMLS, RxNorm and NDF-RT, respectively.