Detection Algorithms for Gastrointestinal Perforation Cases in the Medical Information Database Network (MID-NET®) in Japan.

BACKGROUND: The Medical Information Database Network (MID-NET®) in Japan is a vast repository providing an essential pharmacovigilance tool. Gastrointestinal perforation (GIP) is a critical adverse drug event, yet no well-established GIP identification algorithm exists in MID-NET®. METHODS: This study evaluated 12 identification algorithms by combining ICD-10 codes with GIP therapeutic procedures. Two sites contributed 200 inpatients with GIP-suggestive ICD-10 codes (100 inpatients each), while a third site contributed 165 inpatients with GIP-suggestive ICD-10 codes and antimicrobial prescriptions. The positive predictive values (PPVs) of the algorithms were determined, and the relative sensitivity (rSn) among the 165 inpatients at the third institution was evaluated. RESULTS: A trade-off between PPV and rSn was observed. For instance, ICD-10 code-based definitions yielded PPVs of 59.5%, whereas ICD-10 codes with CT scan and antimicrobial information gave PPVs of 56.0% and an rSn of 97.0%, and ICD-10 codes with CT scan and antimicrobial information as well as three types of operation codes produced PPVs of 84.2% and an rSn of 24.2%. The same algorithms produced statistically significant differences in PPVs among the three institutions. Combining diagnostic and procedure codes improved the PPVs. The algorithm combining ICD-10 codes with CT scan and antimicrobial information and 80 different operation codes offered the optimal balance (PPV: 61.6%, rSn: 92.4%). CONCLUSION: This study developed valuable GIP identification algorithms for MID-NET®, revealing the trade-offs between accuracy and sensitivity. The algorithm with the most reasonable balance was determined. These findings enhance pharmacovigilance efforts and facilitate further research to optimize adverse event detection algorithms.

[Development of Preventive Methods for Drug-induced Cardiotoxicity Using a Large-scale Medical Information Database].

Cancer therapies have evolved considerably thereby substantially improving the survival of patients with cancer. However, cardiotoxicity, such as myocarditis and heart failure, induced by anticancer drugs, including immune checkpoint inhibitor(ICI)s and doxorubicin, present serious challenges. Numerous observations have indicated increased risks of cardiotoxicity- and cancer-related mortality in patients with drug-induced cardiotoxicity. Therefore, the prevention and management of drug-induced cardiotoxicity should be prioritized to enable sustainable long-term treatment while preserving patients' quality of life. Recently, medical research has been primarily focused on elucidation of therapeutic benefits and adverse events using medical big data, including worldwide databases of adverse events. The aim of the present study was to establish prevention strategies for drug-induced cardiotoxicity and advance data analytics. A data-driven approach was adopted to comprehensively analyze patient data and drug-induced cardiotoxicity. These data analytics revealed numerous risk factors, leading to the development of drugs that mitigate these factors. Furthermore, many unknown adverse events with molecularly targeted drugs were brought to light. Consequently, the importance of managing adverse events, guided by insights from data science, is predicted to increase. In this symposium review, we introduce our research exemplifying pharmaceutical studies utilizing medical big data. In particular, we discuss in detail the risk factors associated with myocarditis induced by immune checkpoint inhibitors along with prophylactic agents to mitigate doxorubicin-induced cardiotoxicity.

[Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database].

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen : Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.

Duration of influenza vaccine effectiveness in the elderly in Japan: A retrospective cohort study using large-scale population-based registry data.

BACKGROUND: The immune response to influenza vaccination in the elderly is likely to be lower than that in young adults. Clinical protection may not persist year-round in the elderly. However, the effectiveness of influenza vaccine in the elderly has not been adequately studied, especially in terms of the duration of effectiveness. METHODS: We used a linked database of healthcare administrative claims data and vaccination records maintained by the municipality of a city in Kanto region of Japan. We studied individuals who were aged 65 years or older at baseline and were followed up between April 1, 2014 to March 31, 2020. The duration of influenza vaccine effectiveness by age category was analyzed using a time-dependent piecewise Cox proportional hazard model with time-dependent vaccine status, prior season vaccination and covariates confirmed in the baseline period (age, sex, cancer, diabetes, chronic obstructive pulmonary diseases, asthma, chronic kidney diseases, and cardiovascular diseases). RESULTS: We identified an analysis population of 83,146 individuals, of which 7,401 (8.9%) had experienced influenza and 270 (0.32%) underwent influenza-related hospitalization. Individuals who were vaccinated during the first season (n = 47,338) were older than non-vaccinated individuals (n = 35,808) (average age, 75.8 vs. 74.1 years, respectively). The multivariable analysis showed a lower incidence of influenza in vaccinated individuals (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.43-0.51; P < 0.001), while the incidence of hospitalization for influenza did not differ significantly by vaccination status (HR, 0.79; 95% CI, 0.53-1.18; P = 0.249). Protective effectiveness against incidence was maintained for 4 or 5 months after vaccination in those aged 65-69 and 80-years, 5 months in 70-79 years. CONCLUSIONS: Our study identified moderate vaccine effectiveness in preventing the incidence of influenza in the Japanese elderly. Vaccine effectiveness showed a trend of gradual attenuation. Clinicians should suspect influenza infection even in those vaccinated, especially in elderly individuals who had received vaccination more than 4 or 5 months previously.

The utility of the self-controlled study design for pharmacoepidemiological studies without an active comparator medication using a medical information database: An application to assess the risk of varenicline on cardiovascular outcomes.

PURPOSE: To illustrate the utility of the self-controlled study design for studies without an active comparator, we compared the results of a cohort design study with a non-user comparator with those of a self-controlled design study in evaluating the risk of varenicline on cardiovascular outcomes, using a Japanese medical claims database. METHODS: The participating smokers were identified from health-screening results collected between May 2008 and April 2017. Using a non-user-comparator cohort study design, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of varenicline on initial hospitalization with cardiovascular outcomes using Cox's model adjusted for patients' sex, age, medical history, medication history, and health-screening results. Using a self-controlled study design, the within-subject HR was estimated using a stratified Cox's model adjusted for medical history, medication history, and health-screening results. The estimate from a recent meta-analysis was considered the gold standard (risk ratio: 1.03). RESULTS: We identified 460 464 smokers (398 694 males [86.6%]; mean (standard deviation) age: 42.9 [10.8] years) in the database. Of these, 11 561 had been dispensed varenicline at least once, and 4511 had experienced cardiovascular outcomes. The estimate of the non-user-comparator cohort study design exceeded the gold standard (HR [95% CI]: 2.04 [1.22-3.42]), whereas that of the self-controlled study design was close to the gold standard (within-subject HR [95% CI]: 1.12 [0.27-4.70]). CONCLUSIONS: The self-controlled study design is useful alternative to a non-user-comparator cohort design when evaluating the risk of medications relative to their non-use, based on a medical information database.

A post-marketing safety assessment of COVID-19 mRNA vaccination for serious adverse outcomes using administrative claims data linked with vaccination registry in a city of Japan.

INTRODUCTION: The safety profiles of COVID-19 vaccines are incompletely evaluated in Japan. OBJECTIVES: To examine the risk of serious adverse effects after COVID-19 mRNA vaccination (BNT162b2 and mRNA-1273) in cohort studies and self-controlled case series (SCCS). METHODS: Using an administrative claims database linked with the COVID-19 vaccination registry in a city in Japan between September 2020 and September 2021, we identified health insurance enrolees aged ≥ 18 years. We evaluated the risk of acute myocardial infarction, appendicitis, Bell's palsy, convulsions/seizures, disseminated intravascular coagulation, immune thrombocytopenia, pulmonary embolism, haemorrhagic or ischemic stroke, venous thromboembolism, and all-cause mortality, 21 days following any COVID-19 mRNA vaccination, compared with non-vaccination periods. For the cohort studies, we estimated incidence rate ratios (IRRs) by Poisson regression and rate differences (IRDs) by weighted least-squares regression, adjusting for sex, age, and Charlson comorbidity index. We applied a modified SCCS design to appropriately treat outcome-dependent exposures. For the modified SCCS, we estimated within-subject IRRs by weighted conditional Poisson regression. Subgroup analyses stratified by sex and age were also conducted. RESULTS: We identified 184,491 enrolees [male: 87,218; mean (standard deviation) age: 64.2 (19.5) years] with 136,667 first and 127,322 s dose vaccinations. The risks of any outcomes did not increase in any analyses, except for the fact that the modified SCCS indicated an increased risk of pulmonary embolism after the first dose in women (within-subject IRR [95%CI]: 3.97 [1.18-13.32]). CONCLUSION: The findings suggested that the COVID-19 mRNA vaccine was generally safe, whilst a signal of pulmonary embolism following the first dose of the COVID-19 mRNA vaccine was observed.

Drug-Repositioning Approaches Based on Medical and Life Science Databases.

Drug repositioning is a drug discovery strategy in which an existing drug is utilized as a therapeutic agent for a different disease. As information regarding the safety, pharmacokinetics, and formulation of existing drugs is already available, the cost and time required for drug development is reduced. Conventional drug repositioning has been dominated by a method involving the search for candidate drugs that act on the target molecules of an organism in a diseased state through basic research. However, recently, information hosted on medical information and life science databases have been used in translational research to bridge the gap between basic research in drug repositioning and clinical application. Here, we review an example of drug repositioning wherein candidate drugs were found and their mechanisms of action against a novel therapeutic target were identified via a basic research method that combines the findings retrieved from various medical and life science databases.

Examination of the antiepileptic effects of valacyclovir using kindling mice- search for novel antiepileptic agents by drug repositioning using a large medical information database.

Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.

Establishment of the MID-NET® medical information database network as a reliable and valuable database for drug safety assessments in Japan.

PURPOSE: To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. METHODS: This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). RESULTS: MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. CONCLUSIONS: MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.

Effect of Governance Functionality for Data Standardization Management of the Medical Information Database Network Project.

Data standardiztion an important aspect to ensure data quality for utilizing large-scale, medical information databases such as the Medical Information Database Network (MID-NET) Project in Japan. We established a governance center to assess the consistency of standard codes across MID-NET-cooperating medical institutions. Moreover, we developed a real-time validation tool and determined its effect in improving data quality in medical institutions by providing a central feedback on the detected differences in standard disease-name codes.

Evaluating the impact of regulatory action on denosumab-induced hypocalcaemia in Japan.

WHAT IS KNOWN AND OBJECTIVE: Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). METHODS: We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. RESULTS AND DISCUSSION: The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. WHAT IS NEW AND CONCLUSION: There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

The utilization and challenges of Japan's MID-NET® medical information database network in postmarketing drug safety assessments: A summary of pilot pharmacoepidemiological studies.

PURPOSE: To examine the potential role of Medical Information Database Network (MID-NET® ), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. METHODS: The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark® ) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. RESULTS: The pilot studies were successfully conducted and demonstrated the value of MID-NET® in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. CONCLUSIONS: MID-NET® was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET® , including its advantages and limitations.

From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR).

Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.

Development of a novel algorithm for detecting glucocorticoid-induced diabetes mellitus using a medical information database.

WHAT IS KNOWN AND OBJECTIVE: Glucocorticoid-induced diabetes mellitus (GIDM) increases the risk of diabetes mellitus (DM)-related complications but is generally difficult to detect in clinical settings. The criteria for diagnosing GIDM have not been established. Recently, medical information databases (MIDs) have been used in post-marketing surveillance (PMS) studies. We conducted a pharmacoepidemiological study to develop an algorithm for detecting GIDM using MID. METHODS: We selected 1214 inpatients who were newly prescribed with a typical glucocorticoid, prednisolone, during hospitalization from 2008 to 2014 from an MID of Hamamatsu University Hospital in Japan. GIDM was screened based on fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) levels according to the current Japan Diabetes Society (JDS) DM criteria, and its predictability was evaluated by an expert's review of medical records. We investigated further candidate screening factors using receiver operating characteristics analysis. RESULTS: Sixty-three inpatients were identified by the JDS DM criteria. Of these, 33 patients were definitely diagnosed as having GIDM by expert's review (positive predictive value = 52·4%). To develop a highly predictive algorithm, we compared the characteristics of inpatients diagnosed with definite GIDM and those diagnosed as non-GIDM. The maximum levels of HbA1c in patients with GIDM were significantly higher than those of patients with non-GIDM (66·9 mmol/mol vs. 58·7 mmol/mol, P < 0·001). The patients with GIDM had significantly higher relative increase in maximum level of HbA1c (RIM-HbA1c) than those with non-GIDM (0·3 vs. 0·03, P < 0·001). However, we did not observe a significant difference in those of fasting blood glucose (FBG) levels. We applied the RIM-HbA1c as a second screening factor to improve the detection of GIDM. It showed that a 13% increase in RIM-HbA1c separated patients with from patients without GIDM. WHAT IS NEW AND CONCLUSIONS: Patients with GIDM had significantly higher RIM-HbA1c than patients with non-GIDM. There was a 13% increase in RIM-HbA1c in patients with GIDM compared to the others. Our detection algorithm for GIDM using an MID achieved high sensitivity and specificity, and was superior to one based only on the current JDS DM criteria. Our results suggest that monitoring changes in HbA1c levels is important for detecting GIDM and adds to current diagnostic criteria for type 2 DM.

A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale.

PURPOSE: Drug-induced liver injury (DILI) is one of the primary targets for pharmacovigilance using medical information databases (MIDs). Because of diagnostic complexity, a standardized method for identifying DILI using MIDs has not yet been established. We applied the Digestive Disease Week Japan 2004 (DDW-J) scale, a Japanese clinical diagnostic criteria for DILI, to a DILI detection algorithm, and compared it with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale to confirm its consistency. Characteristics of DILI cases identified by the DDW-J algorithm were examined in two Japanese MIDs. METHODS: Using an MID from the Hamamatsu University Hospital, we constructed a DILI detection algorithm on the basis of the DDW-J scale. We then compared the findings between the DDW-J and CIOMS/RUCAM scales. We examined the characteristics of DILI after antibiotic treatment in the Hamamatsu population and a second population that included data from 124 hospitals, which was derived from an MID from the Medical Data Vision Co., Ltd. We performed a multivariate logistic regression analysis to assess the possible DILI risk factors. RESULTS: The concordance rate was 79.4% between DILI patients identified by the DDW-J and CIOMS/RUCAM; the Spearman rank correlation coefficient was 0.952 (P < 0.0001). Men showed a significantly higher risk for DILI after antibiotic treatments in both MID populations. CONCLUSIONS: The DDW-J and CIOMS/RUCAM algorithms were equivalent for identifying the DILI cases, confirming the utility of our DILI detection method using MIDs. This study provides evidence supporting the use of MID analyses to improve pharmacovigilance.

Evaluation of two Japanese regulatory actions using medical information databases: a 'Dear Doctor' letter to restrict oseltamivir use in teenagers, and label change caution against co-administration of omeprazole with clopidogrel.

WHAT IS KNOWN AND OBJECTIVE: The implementation of appropriate epidemiological methodology using medical information databases (MIDs) to evaluate the effects of regulatory actions has been highly anticipated. To assess scientific methods for active pharmacovigilance using MIDs, we conducted a quantitative assessment of the impact of two regulatory actions by the Japanese government: (i) restriction of use of oseltamivir in teenagers in March 2007 and (ii) caution against the co-administration of omeprazole (OPZ) with clopidogrel (CPG) in April 2010. METHODS: Data were obtained from four hub hospitals in Japan. We measured the seasonal proportion of patients prescribed oseltamivir to those prescribed neuraminidase inhibitors for the 2002/2003 to 2010/2011 seasons. The monthly proportion of patients co-administered OPZ and CPG (OPZ+CPG) to those prescribed CPG was measured from May 2009 to April 2011. We evaluated the changes observed with implementation of the regulatory actions. To estimate the impact of the actions, we conducted segmented regression analysis using interrupted time series data. The impact was assessed by two parameter estimates of the regression model: the change in level for short-term effects and change in trend for long-term effects. RESULTS AND DISCUSSION: The use of oseltamivir in the target 10-19 years age group showed a significant and large decline (63·16%) immediately after the intervention (P = 0·0008). No change was observed in OPZ+CPG, although there was a relative inhibitory trend for OPZ+CPG compared with co-administration of lansoprazole or rabeprazole with CPG as the control group. When restricted to new users of CPG, the stratified results were consistent with the overall results. WHAT IS NEW AND CONCLUSION: The current analysis demonstrates the effectiveness of two regulatory actions. The results of the current study indicate that MID research can contribute to assessing and improving pharmacovigilance activities.

<b>Assessment of Medical Information Databases to Estimate Patient Numbers</b> / 薬剤疫学

<b>Objective</b>: Medical information databases provide useful Real World Evidence (RWE) and a comprehensive view of medical activities. However, since each database has limited coverage and cannot be self-sufficient, combining information from multiple databases is a useful research technique. In this study, we examined methods of estimating patient numbers by combining information from multiple databases in order to assess the respective databases and identify the respective characteristics, biases and idiosyncrasies. This process also allowed us to propose improvements in the grand design of medical information databases in Japan.<br><b>Design</b>: Retrospective observational cohort study<br><b>Methods</b>: We attempted to estimate the numbers of patients treated for certain diseases and the numbers prescribed a drug by three methods: i) We estimated patient numbers for seven diseases using an insurance claims database, adjusting the proportion of elderly patients according to a hospital medical records database; ii) Sales information for drug X was combined with the prescribed volume per person estimated from pharmacy claims databases to estimate the number of patients administered X; this number was divided by the prescription rate obtained from a medical claims database to calculate patient numbers for the associated disease; and iii) We examined two surveys of the National Institute of Infectious Diseases (NIID) for timely estimation of patient numbers for influenza, referring to estimates from an insurance claims database.<br><b>Results</b>: In Method i)-iii), we proved that it is possible to estimate patient numbers for many diseases and administered drugs by effectively combining multiple medical information databases. Validation could be claimed when multiple methods lead to similar results.<br><b>Conclusion</b>: These databases provided by government agencies and private corporations are separately managed, and there is no grand plan to integrate them into one platform. It is crucial that databases, rather than being designed to stand alone, are standardized according to widely used systems under a solid master data management strategy. This will make it easier to combine information from multiple databases and to maximize their values. Mutual use of these databases by academic researchers for epidemiological and clinical studies and by government policy makers and data scientists of pharmaceutical companies may improve the usefulness of these databases and expand their application in research.

An algorithm for the identification of heparin-induced thrombocytopenia using a medical information database.

WHAT IS KNOWN AND OBJECTIVE: Using effective algorithms for extracting relevant drug and patient information from electronic medical information data systems is likely to form an increasingly important aspect of pharmacovigilance. To this end, we aimed to develop and validate a novel algorithm for detecting heparin-induced thrombocytopenia (HIT) using a medical information database (MID) and for identifying possible risk factors for HIT. METHODS: We developed a new algorithm for detecting HIT based on platelet count at distinct time-points and diagnostic information from patients treated with unfractionated heparin (UFH) from April 2008 through March 2012 at Hospital of Hamamatsu University School of Medicine, Japan. Definitive diagnoses of HIT were made through reviews of the medical records by a skilled haematologist. The performance of the algorithm was assessed using the positive predictive value (PPV). Multivariate logistic regression analysis was used to identify possible risk factors for HIT. RESULTS AND DISCUSSION: This algorithm detected 47 patients with suspected HIT in the source population (n = 2875). Of these, 41 were identified as patients with definitive HIT after review of the medical records. The PPV for the algorithm was 87·2%, and the frequency of definitive HIT was 1·4%. Longer-term treatment (≥4 days) with UFH was identified as a risk factor for HIT, with an odds ratio of 5·38 (95% CI: 2·35-12·32) for definitive HIT. WHAT IS NEW AND CONCLUSION: We developed a novel, high-PPV detection algorithm for HIT and identified longer-term treatment with UFH as a risk factor for HIT. Our results support the utility of MIDs for improving pharmacovigilance.

<b>Utilization of SS-MIX in Electronic Medical Record Networking Project in Japan </b> / 薬剤疫学

An adverse drug reaction report system has played an important role to obtain safety information and to consider safety measures in Japan. However, there are some limitations in the system; for example, the number of prescribed patients cannot be found; it is difficult to differentiate between disease symptoms and adverse drug reactions; and no information can be grasped without a report from a health care professional. Therefore, Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA) started an electronic medical information networking project since FY2011 in order to develop a new method to consider safety measures. In this project, MHLW/PMDA plan to establish medical information databases in 10 hospitals and a data analysis system in PMDA. The first database prepared by the University of Tokyo Hospital and the data analysis system in PMDA are almost available, and discussions for rules to utilize electronic medical records are ongoing. After the development of the rules, MHLW/PMDA will experimentally run the system in PMDA, support accumulating data from electronic medical records in the 10 hospitals and create analytical methods where the databases in these hospitals are leveraged. (Jpn J Pharmacoepidemiol 2013；18(1)：15-21)