Papers - Urushihara, Hisashi

Validation of algorithms in studies based on routinely collected health data: General principles

Ehrenstein V., Hellfritzsch M., Kahlert J., Langan S.M., Urushihara H., Marinac-Dabic D., Lund J.L., Sørensen H.T., Benchimol E.I.

American Journal of Epidemiology 193 ( 11 ) 1612 - 1624 2024.11

Last author, Corresponding author,  ISSN  00029262

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Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. In this paper, we aim to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy, gold/reference standards, study size, prioritization of accuracy measures, algorithm portability, and implications for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome, or covariate). Validation work should be part of routine maintenance of RWD sources. This article is part of a Special Collection on Pharmacoepidemiology.

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Prescribing Cascades of Loop Diuretics and Anti-vertigo Drugs Following Treatment with Gabapentinoids and Benzodiazepines: Prescription Sequence Symmetry Analysis of a Large-Scale Claims Database Including Japanese Older Adults

Omata R., Asami A., Hara A., Urushihara H.

Drugs - Real World Outcomes 11 ( 3 ) 529 - 540 2024.09

Last author, Corresponding author,  ISSN  21991154

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Background: Gabapentinoids (GBP) and benzodiazepines (BZ) are commonly prescribed in older adults and their package inserts list edema and vertigo as adverse drug reactions. These adverse drug reactions may be treated with symptomatic drug therapies without discontinuing the culprit drugs or decreasing their dose, thereby initiating a prescribing cascade and often resulting in polypharmacy. Whether prescribing cascades occur in the treatment of edema and dizziness among Japanese patients treated with GBP and BZ has not been investigated, including treatment with mirogabalin, a class drug of GBP marketed in Japan. Objective: We aimed to investigate prescribing cascades with GBP-induced and BZ-induced edema and dizziness treated with loop diuretics (LD) and anti-vertigo drugs (AVD), respectively, among older adults. Methods: A prescription sequence symmetry analysis design was used to detect signals of prescribing cascades associated with edema and dizziness induced by GBP and BZ (exposure drugs). Loop diuretics and AVD were the outcome drugs used to identify prescribing cascades following the initiation of exposure drugs. The study population consisted of enrollees of a large-scale health claims database provided by DeSC Healthcare, Inc., between April 2014 and March 2021. Subjects eligible for a prescription sequence symmetry analysis were patients aged ≥ 65 years prescribed an outcome drug within 90 days before and after exposure drug initiation. A signal of a prescribing cascade was detected if secular trend-adjusted sequence ratios were statistically significant on comparison of the frequencies of outcome drug initiation before and after exposure drug initiation. Results: We identified 2671 patients with prescriptions of a GBP-LD combination, 4009 with a GBP-AVD combination, 8675 with a BZ-LD combination, and 9462 with a BZ-AVD combination. The adjusted sequence ratios for GBP-LD and BZ-LD cascades were significantly larger than one (adjusted sequence ratio [95% confidence interval], 1.69 [1.56–1.83]; 1.35 [1.29–1.41], respectively), indicating positive signals of prescribing cascades. No signal was detected for the GBP-AVD or BZ-AVD cascade (0.89 [0.83–0.94]; 0.90 [0.87–0.94], respectively). The adjusted sequence ratio for the mirogabalin cascade was higher than that for pregabalin (2.23 [1.84–2.71] vs 1.59 [1.46–1.73]). Conclusions: Our study provides good evidence that LD-prescribing cascades associated with edema would be a class effect of GBP and BZ. Edema emerging around 1 month after GBP initiation should be carefully differentiated from pathological edema, and undue LD prescription as a prescribing cascade should be avoided.

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Comparison of Regulations for Arsenic and Heavy Metals in Herbal Medicines Using Pharmacopoeias of Nine Counties/Regions

Inada I., Kiuchi F., Urushihara H.

Therapeutic Innovation and Regulatory Science (Therapeutic Innovation and Regulatory Science)  57 ( 5 ) 963 - 974 2023.09

Last author, Corresponding author,  ISSN  21684790

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Introduction: Standardization is an import factor in ensuring the safety, efficacy, and quality of herbal medicines, and facilitates their international commerce. Heavy metal poisoning due to herbal medicines has been reported in many countries. Here, to better understand the current state of harmonization, we compared regulations for arsenic and heavy metals in herbal medicines across seven countries and two regions with two international standards. Methods: We studied the monographs of herbal medicines of seven countries and two regions, as well as the WHO guidelines and ISO standards. We then compared the limits and test methods adopted for elemental impurities in herbal medicines listed in the monographs and standards among countries. Results: The number of herbal medicines assessed amounted to over 2000. Limits and test methods adopted for elemental impurities in herbal medicines varied by country/region and organization. Although WHO recommends a uniform upper limit for lead and cadmium for all herbal medicines, some countries set unique upper limits for individual herbal medicines. ISO 18664:2015 lists only instrumental analysis methods, whereas Japan and India list only chemical methods. Conclusions: Many countries do not adhere to the WHO or ISO recommendations on elemental impurities in herbal medicines. These findings suggest the presence of differences in regulations for herbal medicines among countries/regions, likely rooted in cultural differences and policies aimed at maintaining the diversity of herbal medicines. Regulatory convergence by “loose harmonization” to internationally agreed standards appears a feasible option to maintain diversity and safety, and promote international trade in herbal medicines.

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A quality management system aiming to ensure regulatory-grade data quality in a glaucoma registry

Wada S., Tsuda S., Abe M., Nakazawa T., Urushihara H.

PLoS ONE (PLoS ONE)  18 ( 6 June )  2023.06

Last author, Corresponding author,  ISSN  1932-6203

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Background Disease/patient registries are underutilized despite their multiple advantages over clinical trials in the clinical evaluation of drugs, such as the capacity for long-term curation, provision of patient outcome data in routine clinical practice, and provision of benchmark data for comparison. Ensuring the fit-for-purpose quality of data generated from such registries is important to informing regulatory decision making. Here, we report the construction of a quality management system aiming to ensure regulatory-grade data quality for a registry of Japanese patients with glaucoma to evaluate long-term patient outcomes. Methods The quality management system was established by reference to the risk-based approach in the ICH-E6 (R2) recommendations. The following three-component approach was taken: establishment of governance, computerized system validation (CSV), and implementation of risk assessment and control. Compliance of the system with the recommendations of regulatory guidelines relevant to use of the registry was assessed. Results Governance by academic collaboration was established. This was followed by the development of a total of 15 standard operating procedures, including CSV, data management, monitoring, audit, and management of imaging data. The data management system was constructed based on a data management plan, which specified data/paper flow and data management procedures. The electronic data capture (EDC) system was audited by an external vendor, and configured and validated using the V-model framework as recommended in the GAMP5 guideline. Informed consent, eligibility assessment and major ophthalmology measurements were determined as Critical to Quality (CTQ) factors. A total of 22 risk items were identified and classified into three categories, and operationalized in the form of a risk control plan, which included training sessions and risk-based monitoring. The glaucoma registry addressed most quality recommendations in official guidelines issued by multiple health authorities, although two recommendations were not met. Conclusions We established and configured a quality management system for a glaucoma registry to ensure fit-for-purpose data quality for regulatory use, and to curate long-term follow-up data of glaucoma patients in a prospective manner.

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Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antibiotic Use: A Case-Crossover Study

Fukasawa T., Urushihara H., Takahashi H., Okura T., Kawakami K.

Journal of Allergy and Clinical Immunology: In Practice (Journal of Allergy and Clinical Immunology: In Practice)   2023

Last author, Corresponding author,  ISSN  22132198

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Background: Evidence is lacking on the association between antibiotic use and risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians. Objective: We assessed the risk of SJS/TEN associated with different antibiotic classes in Japanese. Methods: We conducted a case-crossover study using a claims database. Firth conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SJS/TEN associated with antibiotic use in a 56-day hazard period versus 3 control periods. We created 18 cohorts for each antibiotic class and calculated 56-day cumulative incidence per 100,000 new users. The association between antibiotic class and SJS/TEN was also evaluated in each case using the ALgorithm of Drug causality for Epidermal Necrolysis (ALDEN). Results: Our case-crossover study included 170 SJS/TEN cases. Increased ORs were observed for lincomycins (OR, 33.00 [95% CI, 3.74-4332.05]), trimethoprim-sulfamethoxazole (21.20 [6.73-105.98]), penicillins (14.39 [6.95-34.21]), glycopeptides (14.37 [3.17-136.10]), cephalosporins (7.06 [4.25-12.21]), aminoglycosides (6.55 [1.97-26.84]), quinolones (5.98 [3.34-11.20]), fosfomycin (5.40 [1.20-30.97]), carbapenems (5.09 [1.85-15.64]), tetracyclines (4.95 [1.78-15.27]), and macrolides (3.78 [2.13-6.83]). Cumulative incidence of SJS/TEN was 67.4 for trimethoprim-sulfamethoxazole, 86.2 for glycopeptides, and below 10.0 for the others. Despite the high incidence, only 2 cases had a probable causal relationship with glycopeptides. Conclusion: Some antibiotic classes, including lincomycins, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, were newly suggested to be associated with risk of SJS/TEN; considered together with the high incidence for trimethoprim-sulfamethoxazole and glycopeptides, these findings warrant caution in clinical practice.

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【薬剤疫学の医療への貢献】日本薬剤疫学会専門家認定制度「認定薬剤疫学家」について

漆原 尚巳, 大場 延浩

Precision Medicine(2434-3625) 5 ( 14 ) 1264 - 1266 2022.12

Research paper (scientific journal), Lead author

診療報酬請求情報データベースを用いた、妊婦における抗精神病薬使用実態調査

座古 梨央(慶応義塾大学 薬学部薬学科医薬品開発規制科学講座), 原 梓, 汐月 雄一, 漆原 尚巳

薬剤疫学(1342-0445) 27   S42 - S43 2022.11

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高齢者におけるベンゾジアゼピン系睡眠薬・ガバペンチノイドによるめまい及び浮腫に関する処方カスケードの検討

小俣 理奈(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 漆原 尚巳

薬剤疫学(1342-0445) 27   S58 - S59 2022.11

Corresponding author

医療情報データベース研究のためのアウトカム定義レポジトリ　Relevance of Outcome Definition Repository

漆原 尚巳

薬剤疫学(1342-0445) 27   S67 2022.11

Research paper (scientific journal), Lead author

The Kawasaki Aging and Wellbeing Projectのデータを用いた生活習慣病に関する診療報酬請求データによる疾患定義の妥当性の検討

猪澤 一樹(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 原 梓, 佐々木 貴史, 安藤 崇之, 阿部 由紀子, 色本 涼, 新井 康通, 漆原 尚巳

薬剤疫学(1342-0445) 27   S81 - S82 2022.11

Research paper (scientific journal), Corresponding author

BERTを用いた糖尿病治療薬における有害事象間の潜在的関連性の探索

八重樫 昇吾(慶応義塾大学 薬学研究科医薬品開発規制科学講座), 石川 智貴, 安藤 崇之, 原 梓, 大石 尚央, 漆原 尚巳

薬剤疫学(1342-0445) 27   S99 - S100 2022.11

Corresponding author

大規模診療報酬請求情報データベースを用いた小児インフルエンザ外来患者に対する抗菌薬処方実態調査

鎗田 大地(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 木村 真也, 野口 亮, 漆原 尚巳

薬剤疫学(1342-0445) 27   S116 - S117 2022.11

Corresponding author

日本・米国・英国における小児用医薬品の開発推進策と承認状況

諏訪 美月(慶応義塾大学 薬学部医薬品開発規制科学講座), 三宅 真二, 漆原 尚巳

臨床薬理(0388-1601) 53巻 ( 6号 ) 225 - 234 2022.11

Research paper (scientific journal), Corresponding author

Real-Time Survey of Vaccine Safety of the mRNA-1273 SARS-CoV-2 Vaccine in Workplace Vaccination at Keio University

Okumura K, Hara A, Inada I, Sugiyama D, Hoshino T, Yakoh T, Yokoyama H, Urushihara H.

Vaccines (Basel) (Vaccines)  31 ( 9 ) 425 - 425 2022.09

Research paper (scientific journal),  ISSN  1053-8569

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The mRNA-1273 Moderna COVID-19 vaccine was introduced to combat the COVID-19 global pandemic in 2020. Although the safety of the vaccine has been investigated worldwide, real-world safety data is scarce in Japan. An online, real-time survey of adverse events following immunization (AEFIs) with mRNA-1273 was conducted in the setting of a workplace vaccination program at the School of Pharmacy, Keio University from 26 June 2021, to 11 June 2022. Participants were requested to take four surveys during a seven-day follow-up period after each of the first, second, and third booster doses. The maximum number of responses, from 301 respondents, was obtained on day 0 (vaccination date) for the first dose. 98% of respondents reported local and systemic AEFIs for the second dose on day 1. No noticeable difference in local reactions was seen among the three doses. Females reported more AEFIs than males, and the young group (18–29 years) reported a higher rate than the middle age group (≥30 years) after the first dose. Age and gender differences in rates decreased at the second and third doses. This survey confirmed that the safety profile of mRNA-1273 in a real-world setting was similar to that derived from the clinical trials, and that the agent was well-tolerated.

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解説　2021年6月施行「人を対象とする生命科学・医学系研究に関する倫理指針」の概要について

漆原 尚巳

日本臨床腫瘍薬学会雑誌(2189-129X) 26   23 - 27 2022.07

Research paper (scientific journal), Lead author

リアルワールドデータを用いて行われた研究の評価項目に関する検討

阿左美 茜(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 原 梓, 漆原 尚巳

日本医薬品情報学会総会・学術大会講演要旨集24回    102 2022.06

Research paper (other academic), Corresponding author

機械学習を用いた降圧薬および高脂血症用剤における潜在的リスクの予測

佐立 悠(慶応義塾大学 薬学部), 漆原 尚巳, 原 梓

日本薬学会年会要旨集(0918-9823)142年会    28 2022.03

Research paper (scientific journal), Corresponding author

大規模診療報酬請求情報データベースを用いた小児インフルエンザ外来患者に対する抗菌薬処方実態調査

安藤 梨花子(慶応義塾大学 薬), 原 梓, 木村 真也, 野口 亮, 漆原 尚巳

日本薬学会年会要旨集(0918-9823)142年会    27 2022.03

Research paper (scientific journal), Corresponding author

川崎市在住高齢者を対象としたウェルビイングコホートにおける使用薬剤数と医療・薬剤・介護費の関連についての検討　ベースライン調査

仙石 彩(慶応義塾大学 薬学部薬学科医薬品開発規制科学講座), 原 梓, 佐々木 貴史, 阿部 由紀子, 新井 康通, 漆原 尚巳

日本薬学会年会要旨集(0918-9823)142年会    27 2022.03

Research paper (scientific journal), Corresponding author

An NLP-Inspired Data Augmentation Method for Adverse Event Prediction Using an Imbalanced Healthcare Dataset

Ishikawa T., Yakoh T., Urushihara H.

IEEE Access (IEEE Access)  10   81166 - 81176 2022

Last author, Corresponding author,  ISSN  2169-3536

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This paper proposes a data augmentation method for imbalanced healthcare datasets. This method was inspired by a data augmentation method in natural language processing (NLP) that generates synthetic sentences for training by replacing some words with similar words. The proposed method generates synthetic patient records by replacing patient backgrounds with similar backgrounds. In this paper, the cosine similarity of the distributed representations was used as the similarity metric between patient backgrounds. The distributed representations of the patient backgrounds were generated by the skip-gram model. To confirm the performance improvement with the proposed data augmentation method, the prediction performance of adverse events (AEs) caused by drug administration was experimentally evaluated on a real-world medical dataset with 1,510,137 records. The combination of the proposed data augmentation method and a conventional undersampling method resulted in an 80.0% improvement in accuracy and a 40.0% improvement in the precision and F1-score. The multifaceted evaluation demonstrated that the proposed method is effective, especially for predicting AEs with positive ratios ranging from 1.0% to 2.1%, which are difficult to predict with conventional machine learning methods but should be predictable in the medical field.

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