An innovative strategy for standardized, structured, and interoperable results in ophthalmic examinations.

BACKGROUND: Although ophthalmic devices have made remarkable progress and are widely used, most lack standardization of both image review and results reporting systems, making interoperability unachievable. We developed and validated new software for extracting, transforming, and storing information from report images produced by ophthalmic examination devices to generate standardized, structured, and interoperable information to assist ophthalmologists in eye clinics. RESULTS: We selected report images derived from optical coherence tomography (OCT). The new software consists of three parts: (1) The Area Explorer, which determines whether the designated area in the configuration file contains numeric values or tomographic images; (2) The Value Reader, which converts images to text according to ophthalmic measurements; and (3) The Finding Classifier, which classifies pathologic findings from tomographic images included in the report. After assessment of Value Reader accuracy by human experts, all report images were converted and stored in a database. We applied the Value Reader, which achieved 99.67% accuracy, to a total of 433,175 OCT report images acquired in a single tertiary hospital from 07/04/2006 to 08/31/2019. The Finding Classifier provided pathologic findings (e.g., macular edema and subretinal fluid) and disease activity. Patient longitudinal data could be easily reviewed to document changes in measurements over time. The final results were loaded into a common data model (CDM), and the cropped tomographic images were loaded into the Picture Archive Communication System. CONCLUSIONS: The newly developed software extracts valuable information from OCT images and may be extended to other types of report image files produced by medical devices. Furthermore, powerful databases such as the CDM may be implemented or augmented by adding the information captured through our program.

Analysis of antiseizure drug-related adverse reactions from the electronic health record using the common data model.

OBJECTIVE: Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital. METHODS: We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications. RESULTS: From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group. SIGNIFICANCE: The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

Converting clinical document architecture documents to the common data model for incorporating health information exchange data in observational health studies: CDA to CDM.

BACKGROUND: Utilization of standard health information exchange (HIE) data is growing due to the high adoption rate and interoperability of electronic health record (EHR) systems. However, integration of HIE data into an EHR system is not yet fully adopted in clinical research. In addition, data quality should be verified for the secondary use of these data. Thus, the aims of this study were to convert referral documents in a Health Level 7 (HL7) clinical document architecture (CDA) to the common data model (CDM) to facilitate HIE data availability for longitudinal data analysis, and to identify data quality levels for application in future clinical studies. METHODS: A total of 21,492 referral CDA documents accumulated for over 10 years in a tertiary general hospital in South Korea were analyzed. To convert CDA documents to the Observational Medical Outcomes Partnership (OMOP) CDM, processes such as CDA parsing, data cleaning, standard vocabulary mapping, CDA-to-CDM mapping, and CDM conversion were performed. The quality of CDM data was then evaluated using the Achilles Heel and visualized with the Achilles tool. RESULTS: Mapping five CDA elements (document header, problem, medication, laboratory, and procedure) into an OMOP CDM table resulted in population of 9 CDM tables (person, visit_occurrence, condition_occurrence, drug_exposure, measurement, observation, procedure_occurrence, care_site, and provider). Three CDM tables (drug_era, condition_era, and observation_period) were derived from the converted table. From vocabulary mapping codes in CDA documents according to domain, 98.6% of conditions, 68.8% of drugs, 35.7% of measurements, 100% of observation, and 56.4% of procedures were mapped as standard concepts. The conversion rates of the CDA to the OMOP CDM were 96.3% for conditions, 97.2% for drug exposure, 98.1% for procedure occurrence, 55.1% for measurements, and 100% for observation. CONCLUSIONS: We examined the possibility of CDM conversion by defining mapping rules for CDA-to-CDM conversion using the referral CDA documents collected from clinics in actual medical practice. Although mapping standard vocabulary for CDM conversion requires further improvement, the conversion could facilitate further research on the usage patterns of medical resources and referral patterns.

Transformation of Pathology Reports Into the Common Data Model With Oncology Module: Use Case for Colon Cancer.

BACKGROUND: Common data models (CDMs) help standardize electronic health record data and facilitate outcome analysis for observational and longitudinal research. An analysis of pathology reports is required to establish fundamental information infrastructure for data-driven colon cancer research. The Observational Medical Outcomes Partnership (OMOP) CDM is used in distributed research networks for clinical data; however, it requires conversion of free text-based pathology reports into the CDM's format. There are few use cases of representing cancer data in CDM. OBJECTIVE: In this study, we aimed to construct a CDM database of colon cancer-related pathology with natural language processing (NLP) for a research platform that can utilize both clinical and omics data. The essential text entities from the pathology reports are extracted, standardized, and converted to the OMOP CDM format in order to utilize the pathology data in cancer research. METHODS: We extracted clinical text entities, mapped them to the standard concepts in the Observational Health Data Sciences and Informatics vocabularies, and built databases and defined relations for the CDM tables. Major clinical entities were extracted through NLP on pathology reports of surgical specimens, immunohistochemical studies, and molecular studies of colon cancer patients at a tertiary general hospital in South Korea. Items were extracted from each report using regular expressions in Python. Unstructured data, such as text that does not have a pattern, were handled with expert advice by adding regular expression rules. Our own dictionary was used for normalization and standardization to deal with biomarker and gene names and other ungrammatical expressions. The extracted clinical and genetic information was mapped to the Logical Observation Identifiers Names and Codes databases and the Systematized Nomenclature of Medicine (SNOMED) standard terminologies recommended by the OMOP CDM. The database-table relationships were newly defined through SNOMED standard terminology concepts. The standardized data were inserted into the CDM tables. For evaluation, 100 reports were randomly selected and independently annotated by a medical informatics expert and a nurse. RESULTS: We examined and standardized 1848 immunohistochemical study reports, 3890 molecular study reports, and 12,352 pathology reports of surgical specimens (from 2017 to 2018). The constructed and updated database contained the following extracted colorectal entities: (1) NOTE_NLP, (2) MEASUREMENT, (3) CONDITION_OCCURRENCE, (4) SPECIMEN, and (5) FACT_RELATIONSHIP of specimen with condition and measurement. CONCLUSIONS: This study aimed to prepare CDM data for a research platform to take advantage of all omics clinical and patient data at Seoul National University Bundang Hospital for colon cancer pathology. A more sophisticated preparation of the pathology data is needed for further research on cancer genomics, and various types of text narratives are the next target for additional research on the use of data in the CDM.

Trajectories in glycated hemoglobin and body mass index in children and adolescents with diabetes using the common data model.

We evaluated trajectories of glycated hemoglobin (HbA1c) levels and body mass index z-scores (BMIz) for 5 years after diagnosis among Korean children and adolescents with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the common data model. From the de-identified database of three hospitals, 889 patients < 15 years of age diagnosed with T1D or T2D (393 boys, 664 T1D patients) were enrolled. Diagnosis was defined as first exposure to antidiabetic drug at each center. Compared with T2D patients, T1D patients had lower BMIz at diagnosis (- 0.4 ± 1.2 vs. 1.5 ± 1.4, p < 0.001) and 3 months (- 0.1 ± 1.0 vs. 1.5 ± 1.5, p < 0.001), and higher HbA1c levels at diagnosis (10.0 ± 2.6% vs. 9.5 ± 2.7%, p < 0.01). After 3 months, HbA1c levels reached a nadir of 7.6% and 6.5% in T1D and T2D patients, respectively, followed by progressive increases; only 10.4% of T1D and 29.7% of T2D patients achieved the recommended HbA1c target (< 7.0%) at 60 months. T1D patients showed consistent increases in BMIz; T2D patients showed no significant change in BMIz during follow-up. Peri-pubertal girls with T1D had higher HbA1c and BMIz values. Achieving optimal glycemic control and preventing obesity should be emphasized in pediatric diabetes care.

Characterization of Anti-seizure Medication Treatment Pathways in Pediatric Epilepsy Using the Electronic Health Record-Based Common Data Model.

The purpose of this pilot study was to analyze treatment pathways of pediatric epilepsy using the common data model (CDM) based on electronic health record (EHR) data. We also aimed to reveal whether CDM analysis was feasible and applicable to epilepsy research. We analyzed the treatment pathways of pediatric epilepsy patients from our institute who underwent antiseizure medication (ASM) treatment for at least 2 years, using the Observational Medical Outcomes Partnership (OMOP)-CDM. Subgroup analysis was performed for generalized or focal epilepsy, varying age of epilepsy onset, and specific epilepsy syndromes. Changes in annual prescription patterns were also analyzed to reveal the different trends. We also calculated the proportion of drug-resistant epilepsy by applying the definition of seizure persistence after application of two ASMs for a sufficient period of time (more than 6 months). We identified 1,192 patients who underwent treatment for more than 2 years (mean ± standard deviation: 6.5 ± 3.2 years). In our pediatric epilepsy cohort, we identified 313 different treatment pathways. Drug resistance, calculated as the application of more than three ASMs during the first 2 years of treatment, was 23.8%. Treatment pathways and ASM resistance differed between subgroups of generalized vs. focal epilepsy, different onset age of epilepsy, and specific epilepsy syndromes. The frequency of ASM prescription was similar between onset groups of different ages; however, phenobarbital was frequently used in children with epilepsy onset < 4 years. Ninety-one of 344 cases of generalized epilepsy and 187 of 835 cases of focal epilepsy were classified as medically intractable epilepsy. The percentage of drug resistance was markedly different depending on the specific electro-clinical epilepsy syndrome [79.0% for Lennox-Gastaut syndrome (LGS), 7.1% for childhood absence epilepsy (CAE), and 9.0% for benign epilepsy with centrotemporal spikes (BECTS)]. We could visualize the annual trend and changes of ASM prescription for pediatric epilepsy in our institute from 2004 to 2017. We revealed that CDM analysis was feasible and applicable for epilepsy research. The strengths and limitations of CDM analysis should be carefully considered when planning the analysis, result extraction, and interpretation of results.

Multi-step column leaching using low-molecular-weight organic acids for remediating vanadium- and chromium-contaminated soil.

In soil, vanadium (V) contamination is commonly concomitant with chromium (Cr) contamination, which poses potential risks to humans, animals, and plants due to the transfer of toxic metals and the increase in their concentrations via the food chain or through direct exposure. This study applied a multi-step column leaching process using low-molecular-weight organic acids (LMWOAs) to treat V-contaminated soil from a smelter site that contains 2015.1 mg V kg-1 and 1060.3 mg Cr kg-1. After leaching three times with an equivalent solution/soil ratio of 0.3 mL/g using 1.0 M oxalic acid solution, the total removal rates reached 77.2% and 7.2% for V and Cr, respectively, while the removal rates of the extractable fractions reached 118.6% and 99.2% due to the reduction in residual fraction (F4) of toxic metals. Simultaneously, the distribution and redistribution of geochemical fractions of V and Cr were determined with a sequential extraction technique, and the greater proportion of potential mobile fractions of V (65.1%) may increase its leaching from soil relative to Cr (7.1%). In addition, a lower pH of the leaching agent increased the efficiency of the leaching process to an extent. Compared with batch extraction with a typical solution to soil ratio of 10 mL/g, multi-step column leaching used less agent and hence produced less wastewater. This strategy could reduce the mobilization and bioavailability of toxic metals, and potentially enhance in situ soil flushing for the remediation of V- and Cr- contaminated soil.

A variant 2677A allele of the MDR1 gene affects fexofenadine disposition.

BACKGROUND AND OBJECTIVES: There have been considerable disagreements regarding the influence of MDR1 (ABCB1) polymorphisms on the disposition of P-glycoprotein (P-gp) substrates. We speculated that the unknown function of the A allele of exon 21 G2677T/A (Ala893Ser/Thr) provides one of the reasons for the contradictory results. This study was performed to clarify the effects of major MDR1 gene polymorphisms, including a variant A allele in exon 21, on fexofenadine pharmacokinetics. METHODS: We investigated the occurrence of 3 high-frequency single-nucleotide polymorphisms (SNPs) in exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) of the MDR1 gene in 232 healthy Koreans, using a polymerase chain reaction-restriction fragment length polymorphism method, and performed haplotype analysis on these 3 SNPs. A single oral dose of 180 mg fexofenadine hydrochloride was administered to 33 healthy Korean male volunteers, who were divided into 6 groups based on the MDR1 genotype for the G2677T/A polymorphism in exon 21 and the C3435T polymorphism in exon 26. RESULTS: A strong linkage disequilibrium was observed among the 3 SNPs. The frequencies of the 4 major haplotypes, 1236C-2677A-3435C, C-G-C, T-G-C, and T-T-T, were 16.4%, 18.6%, 21.6%, and 32.2%, respectively. Fexofenadine disposition varied considerably among the groups. In the 2677AA/3435CC genotype group (n=3), the values of area under the concentration-time curve from time 0 to 24 hours [AUC(0-24)] were significantly lower (P=.014) than those of the other 5 genotype groups (GG/CC, GT/CT, TT/TT, GA/CC, and TA/CT). As compared with the 2677GG/3435CC subjects, the AUC(0-24) values were 17% lower in the 2677AA/3435CC subjects and 47% higher in the 2677TT/3435TT subjects (GG/CC versus AA/CC versus TT/TT, 4017 +/- 1137 ng . h/mL versus 3315 +/- 958 ng . h/mL versus 5934 +/- 2,064 ng . h/mL; P=.018). By stratification for genotypes at position 3435, homozygous 3435TT subjects were found to have significantly higher AUC(0-24) (P=.024) and maximum plasma concentration (P=.040) values than CC subjects [AUC(0-24), 5934 +/- 2064 ng . h/mL versus 3998 +/- 1241 ng . h/mL; maximum plasma concentration, 958 +/- 408 ng/mL versus 673 +/- 242 ng/mL]. CONCLUSIONS: The plasma concentrations of fexofenadine after a single oral administration were lower in 2677AA/3435CC subjects than in subjects with the other 5 genotype combinations of the SNPs of G2677T/A and C3435T. These findings confirm the importance of analyzing MDR1 haplotypes and provide a plausible explanation for the conflicting results regarding the effect of MDR1 polymorphisms on the disposition of P-gp substrates.

Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states.

OBJECTIVE: Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions. METHODS: Nineteen healthy volunteers were grouped with regard to the CYP3A5*3 allele, into homozygous wild-type (CYP3A5*1/*1, n = 6), heterozygous (CYP3A5*1/*3, n = 6), and homozygous variant-type (CYP3A5*3/*3, n = 7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days) and also after rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between. RESULTS: The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the CYP3A5*3/*3 group showed a greater decrease in systemic clearance than was seen in the CYP3A5*1/*1 group (8.5 +/- 3.8 L. h(-1). 70 kg(-1) versus 13.5 +/- 2.7 L. h(-1). 70 kg(-1), P =.027). The 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratio was also significantly lower in the CYP3A5*3/*3 group (0.58 +/- 0.35 versus 1.09 +/- 0.37 for the homozygous wild-type group, P =.026). CONCLUSIONS: The CYP3A5 genotype did not affect the pharmacokinetics of intravenous midazolam in the basal or induced states. However, during cytochrome P450 (CYP) 3A inhibition by itraconazole, individuals carrying the CYP3A5*1 allele were found to be less susceptible to changes in systemic clearance and showed higher 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratios, probably resulting from the relatively CYP3A4-specific inhibition caused by itraconazole.

Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers.

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.

Involvement of hydrogen peroxide in repression of catalase in TMV-infected resistant tobacco.

Catalases are ubiquitous, and play a role in plant defense against pathogens. We have reported that catalase mRNA and enzyme activity are repressed in the vicinity of hypersensitive tobacco lesions following TMV infection. We wished to identify the signals involved in this repression. Inoculation with TMV reduced catalase levels 26 to 28 h following infection, coincident with the known timing of endogenous salicylic acid (SA) accumulation. Application of SA caused a transient reduction in Ngcat1 mRNA level and catalase activity 4 to 6 h after treatment. However, repression was also observed in transgenic plants harboring the salicylate hydroxylase gene (NahG) and in TMV susceptible plants, which do not accumulate SA following TMV infection. In the same blots there was no induction of PR-1 or enhanced expression of H2O2-inducible glutathione-S-transferase and found that exposure to H2O2 also repressed Ngcat1 mRNA. Our findings suggest that repression of catalase transcription may be caused by the accumulation of H2O2 rather than of SA.

Pathogen-induced expression of cyclo-oxygenase homologue in hot pepper (Capsicum annuum cv. Pukang).

The hypersensitive reaction (HR) in plants is typified by a rapid and localized cell death at the site of pathogen infection. To understand better the molecular and cellular defence mechanism controlling HR, hot pepper leaves (Capsicum annuum cv. Pukang) were inoculated with the soybean pustule pathogen Xanthomonas campestris pv. glycine 8ra. By using the DD-PCR technique, a cDNA fragment was identified that exhibited a sequence similarity to the recently identified tobacco pathogen-induced oxygenase (PIOX) with homology to animal cyclo-oxygenase (COX). Subsequently, the full-length cDNA clone, pCa-COX1, encoding the COX homologue from the pathogen-inoculated hot pepper leaf cDNA library was isolated. The deduced amino acid sequence of Ca-COX1 shares 85.8% identity with tobacco PIOX and displays a significant degree of sequence identity (21.7-23.7%) with mammalian COXs. The expression of Ca-COX1 was markedly induced at 4-12 h after pathogen infection, while HR cell death on pepper leaves appeared at approximately 15 h post-inoculation. These results are consistent with the notion that the lipid-derived signalling pathway is involved in the initial response of hot pepper plants to pathogen infection.