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

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. This paper aims 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 standard; study size; prioritizing accuracy measures; algorithm portability; and implication 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.

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

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.

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

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.

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

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.

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

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.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

PURPOSE: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. METHODS: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. RESULTS: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90-0.99 compared to other therapies). CONCLUSIONS: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Lifestyle behaviors associated with the initiation of renal replacement therapy in Japanese patients with chronic kidney disease: a retrospective cohort study using a claims database linked with specific health checkup results.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for progression to an end-stage renal disease requiring dialysis or kidney transplantation. We investigated the association of lifestyle behaviors with the initiation of renal replacement therapy (RRT) among CKD patients using an employment-based health insurance claims database linked with specific health checkup (SHC) data. METHODS: This retrospective cohort study included 149,620 CKD patients aged 40-74 years who underwent a SHC between April 2008 and March 2016. CKD patients were identified using ICD-10 diagnostic codes and SHC results. We investigated lifestyle behaviors recorded at SHC. Initiation of RRT was defined by medical procedure claims. Lifestyle behaviors related to the initiation of RRT were identified using a Cox proportional hazards regression model with recency-weighted cumulative exposure as a time-dependent covariate. RESULTS: During 384,042 patient-years of follow-up by the end of March 2016, 295 dialysis and no kidney transplantation cases were identified. Current smoking (hazard ratio: 1.87, 95% confidence interval, 1.04─3.36), skipping breakfast (4.80, 1.98─11.62), and taking sufficient rest along with sleep (2.09, 1.14─3.85) were associated with the initiation of RRT. CONCLUSIONS: Among CKD patients, the lifestyle behaviors of smoking, skipping breakfast, and sufficient rest along with sleep were independently associated with the initiation of RRT. Our study strengthens the importance of monitoring lifestyle behaviors to delay the progression of mild CKD to RRT in the Japanese working generation. A substantial portion of subjects had missing data for eGFR and drinking frequency, warranting verification of these results in prospective studies.

Study factors associated with the incompletion of clinical trials that include pediatric patients: a retrospective analysis of the European Clinical Trials Database and a lesson from the European region.

BACKGROUND: Incomplete clinical trials for pediatric drug development result in a lack of adequate scientific evidence for providing appropriate medication to pediatric populations; this is especially true for Japan. Thus, using the European Clinical Trials Database (EudraCT), this study aimed to identify the factors related to the study design and administration that lead to incompletion of clinical trials that included pediatric patients. METHODS: We focused on clinical trials that included patients under the age of 18 registered in the database, named as the European Clinical Trials Database between January 1, 2014, and December 31, 2018. Two groups of trials were identified: "all cases completed" and "not all cases completed," reflecting whether they were completed in all participating countries/regions or not. To identify the factors of the occurrence of "not all cases completed," a logistic regression analysis was performed to calculate the odds ratios and 95% confidence intervals. In total, 142 clinical trials (95 "all cases completed" and 47 "not all cases completed") were analyzed. RESULTS: The logistic regression analysis showed the number of countries in which a clinical trial was conducted to be the only significant factor (odds ratio: 1.3; 95% confidence interval: 1.1-1.5); this was identified as the primary factor for the occurrence of "not all cases completed" in the clinical trials that included pediatric patients. CONCLUSION: Our findings suggest that the feasibility of clinical trials that include pediatric patients, such as whether the countries in which the trial is to be conducted are suitable, must be considered prior to the trial.

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case-control and cohort studies.

BACKGROUND: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. METHODS: We conducted a matched case-control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of "probable" or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated "unlikely" in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were "very unlikely". CONCLUSIONS: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

Behavioral changes and hygiene practices of older adults in Japan during the first wave of COVID-19 emergency.

BACKGROUND: On April 7, 2020, Japan declared a state of emergency due to the first wave of coronavirus disease 2019 (COVID-19) with the associated social distancing likely to have had a great impact on older adults' lifestyle and health. This study aimed to explore the behavioral changes and personal hygiene practices in relation with background psychosocial and health characteristics of older adults during the COVID-19 emergency. METHODS: A cross-sectional telephonic survey was conducted with the participants of the Kawasaki Aging and Wellbeing Project (KAWP), an on-going longitudinal cohort study of older adults aged 85 or older. The interviews were conducted using a structured questionnaire consisting of 11 closed questions regarding behavioral changes and personal hygiene practices during the state of emergency. Sociodemographic and health data were obtained from the KAWP baseline survey conducted 2.2 years before the telephonic survey. RESULTS: Overall, 487 participants from the KAWP responded to the telephonic survey (response rate: 89.2%). 94.5% of the respondents reported no changes in basic lifestyle habits, such as eating, sleeping, smoking, and drinking, whereas 28.1% reported a decrease in physical activity, and 54.6% reported going out less frequently. One-third of the respondents reported a decrease in the number of people to converse with, as well as the amount of time to converse. For personal hygiene practices, 93.8% reported wearing a mask when they went out, and 50.3% reported an increased frequency of handwashing. Multiple logistic regression analysis revealed that engagement in physical activity at baseline (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.23-3.08), smartphone ownership (OR = 2.15, 95% CI = 1.33-3.47), and visual impairment (OR = 1.79; 95% CI = 1.10-2.91) were independently associated with decreased physical activity during the COVID-19 emergency. Female respondents and smartphone ownership were significantly associated with more frequent handwashing. CONCLUSIONS: The study revealed that older adults in an urban setting responded to the COVID-19 emergency with behavioral changes. The findings of this study have implications for the design of preventive strategies to maintain the health and wellbeing of at-risk older adults.

Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer.

BACKGROUND: The purpose of this study was to investigate the correlation between overall survival (OS) and other clinical outcomes in patients with prostate cancer. Further, we conducted subgroup analysis in the correlation of OS. AIM: This study intended to investigate potential surrogate endpoints of OS for prostate cancer by examining the correlation between OS and the other endpoints. METHODS: We performed a systematic review through a literature search by computer-based searches of the Medline database (January 1965 and May 2014). RESULTS: The contents of 115 studies with endpoint as OS were analyzed in our study. Our results showed that 47.8% (55/115) of the studies used progression-free survival as an endpoint besides OS, followed by time to progression (43.5% [50/115]) and PSA response (40.9% [47/115]). Also, the relationship between OS and each surrogate endpoint was examined using the hazard ratio (HR) by a Bayesian hybrid model for random effect multivariate meta-analysis. Our results showed that the endpoint that had the highest correlation with OS was progression-free survival (PFS) with an estimated marginal correlation of 0.939 (95%CI: 0.900, 0.967). Furthermore, our stratified analysis identified PFS in castration-resistant prostate cancer patients (0.937), in sensitive patients (0.932), in none of chemotherapy patients (0.929), in first line of the chemotherapy (0.948), in patients who received no Docetaxel previously (0.942), in both symptomatic and asymptomatic patients (0.950), in patients who received only chemotherapy (0.956), and in phase III (0.960), time to progression (TTP) in castration-resistant prostate cancer (CRPC) patients (0.942), in metastasis patients (0.948), in both symptomatic and asymptomatic patients (0.953), in patients who received only chemotherapy (0.938), and in Phase III (0.927) as endpoints, which showed a lower limit for 95% CI of estimated marginal correlation ≥0.850 with overall survival. CONCLUSIONS: Our study suggests that PFS is a potential surrogate endpoint of OS in clinical trials for patients with prostate cancer. It also suggests potential surrogate endpoints for CRPC and locally advanced prostate cancer.

Real World Survey of Patient Engagement Status in Clinical Research: The First Input from Japan.

BACKGROUND: The updated international draft guidelines, the "General Considerations for Clinical Studies, ICH E8 (R1)", state that patient engagement ensures that all perspectives are captured in the research process; however, this is not well understood, specifically in Japan. OBJECTIVE: This study examined the current status and perceptions of patient engagement in clinical research from the perspectives of patient groups, pharmaceutical corporations, and researchers in Japan, using anonymous self-administered questionnaires. METHODS: Three online surveys were conducted with patient groups (n = 100), pharmaceutical corporations (n = 66), and researchers (n = 300) in May and June 2019. The main variables were the current status and the current perception of patient engagement in clinical research. RESULTS: The response rate was 71% for patient groups and 85% for pharmaceutical corporations, and there were 300 valid responses (emergence rate: 4.9%) from researchers. Experiences with clinical research involving patient engagement were reported by 76.5% of the patients, 21.4% of the pharmaceutical corporations, and 51.7% of the researchers. Patient groups reported three major factors that negatively impacted their relationship with pharmaceutical corporations and researchers: (1) 'lack of understanding of the benefits of partnering'; (2) 'lack of transparency or openness'; and (3) 'unclear or ill-defined processes'. CONCLUSIONS: Pharmaceutical corporations in Japan have less experience with patient engagement in clinical research than other stakeholders. A neutral connecting system among the stakeholders with a constructive co-learning system will allow effective involvement/engagement of patient groups for enhancing the effectiveness of clinical research.

Utility of a Specific Health Checkup Database Containing Lifestyle Behaviors and Lifestyle Diseases for Employee Health Insurance in Japan.

BACKGROUND: The Japanese Ministry of Health, Labour and Welfare introduced Specific Health Checkups (SHC) to identify individuals at risk of metabolic syndrome (MS). This study aimed to describe the SHC database developed by the Japan Medical Data Center Co., Ltd. (JMDC) as a means of exploring lifestyle behaviors and lifestyle diseases among working generations. METHODS: We conducted a retrospective, cross-sectional study of employees and their families using the JMDC-SHC database to describe the prevalence of lifestyle behaviors (smoking, exercise, dietary habits, drinking habits, and sleeping) and lifestyle diseases (MS, hypertension, dyslipidemia, and diabetes mellitus). Results were compared with data from the 2015 National Health and Nutrition Survey (NHNS) in Japan as a benchmark. RESULTS: All 646,869 enrollees in the JMDC-SHC database were included, of whom 66.5% were men. Age ranged from 40-74 years. Compared with the results of the NHNS, the JMDC-SHC subjects were younger and had fewer MS components and a lower prevalence of diabetes and hypertension. Subjects in their 40s were most likely to have unhealthy lifestyle behaviors in all age groups (eg, smoking: 41.0% in men and 10.2% in women). The SHC group had more favorable behaviors overall, but underweight was more prevalent in the SHC females. CONCLUSIONS: The JMDC-SHC population showed different lifestyle and lifestyle disease profiles to the NHNS population, probably due to its different age, gender, and employment distributions. Development of healthcare policies and plans for working generations would benefit from the selection of an age- and employment-appropriate database.

Medications and fall risk: a case-control study in nursing home residents in Japan.

AIM: Falls are a significant problem for older people, but are few studies of the risk of falling in residents of nursing homes in Japan. We aimed to investigate the risk factors for falls and the association of medication use and falls in nursing home residents in Japan. METHODS: This case-control study reviewed the records of residents of who were ≥ 65 years of age and had fallen in 2012 and an age-, sex-, and facility-matched control group selected from 58 nursing homes in Japan. The odds ratios of potential risk factors and current medications were determined by conditional logistic regression. RESULTS: A total of 1832 residents (916 cases and 916 controls) were included. Falls were significantly associated with an inability to walk without assistance or stand up without assistance, need for toileting assistance, visual impairment, insomnia, and dementia. Current prescription of antithrombotic, nonsteroidal anti-inflammatory, or antiparkinson drugs, muscle relaxants, antiepileptics, antipsychotics, antidepressants, opioids, selective serotonin reuptake inhibitors, and memantine was also associated with increased risk of falling. CONCLUSIONS: Many medications were associated with falls in nursing homes residents in Japan. To prevent these falls, caregivers should provide adequate care, and healthcare professionals should consider switching or dose reduction for these medications.

Differences in efficacy evaluation endpoints in clinical trials for claiming reduction of post-prandial glycemic response between Japan and the European Union.

When evaluating the efficacy of foods with health claims (FHC), each country sets different standards for efficacy evaluation endpoints in clinical trials, which may result in a barrier, namely the case that the claim that is allowed in Japan cannot be used on the label in another region and vice versa. We aimed to investigate the efficacy evaluation endpoints used in clinical trials of FFCs containing ID and submitted in Japan, in reference to the EU requirements for substantiating the claim, namely "reduction of post-prandial glycemic responses". We detected only one difference in efficacy evaluation endpoints, which was insulin levels. We found 67 such clinical trials cited in systematic literature reviews on finished products or functional substance(s). Of these, 43 (64%) trials lacked insulin assessment. Particularly, for foods that were claimed to reduce post-prandial glycemic responses, the EU does not consider a claim to be substantiated unless insulin levels have been evaluated. Our findings suggest the need for standardization of requirements for FHC between Japan and the EU. This consideration will strengthen the evidence for clinical significance of ID and allow products labeled with this health claim to be more widely distributed.

[Effects of polypharmacy and anticholinergic/sedative drugs on the physical/cognitive/mental related outcomes of community-dwelling elderly people: The Kawasaki Wellbeing Project].

AIM: To assess the burdens of polypharmacy and the drug burden index in community-dwelling elder people. METHODS: The survey was conducted on 396 participants who participated in The Kawasaki Wellbeing Project from March to December 2017. We investigated the associations between the drug burden and the physical/cognitive/mental outcomes. The drug burden was determined by calculating the number of medications and the drug burden index (DBI) based on the use of anticholinergic and sedative drugs. A multivariate regression analysis was conducted for the outcome measures ADL, IADL, MMSE, J-CHS, and EQ5D5L after adjusting for the sex, age, number of diseases, education level, smoking history, and alcohol history. RESULTS: A total of 389 subjects were analyzed, the mean age of the population was 86 years old, and 187 people (48%) were male. Polypharmacy was reported in 243 people (62%), and DBI exposure was reported for 142 people (36.5%). We found that this population was physically healthy, with a median ADL of 100, and had high quality of life, with a median EQ5D5L of 0.895. Polypharmacy was found to be related to the J-CHS (ß: 0.04) and EQ5D5L (-0.01). The DBI was also related to the EQ5D5L (-0.04). CONCLUSION: These results showed that even though this population was healthier than the general Japanese elderly population, the drug burden of polypharmacy and high dosages of anticholinergic/sedative drugs exerted significant negative effects on frailty and the quality of life. Additional research should be conducted to investigate the long-term effects of polypharmacy and anticholinergic/sedative drugs on elderly people.

Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.

Correction to: Influenza vaccination effectiveness for people aged under 65 years in Japan, 2013/ 2014 season: application of a doubly robust method to a large-scale, real-world dataset.

After publication of the original article [1], in Table 1, in the second and third column, "Vacnee" and "Non-vacnee" should be replaced with "Vaccinee" and "Non-vaccinee".

Influenza vaccination effectiveness for people aged under 65 years in Japan, 2013/2014 season: application of a doubly robust method to a large-scale, real-world dataset.

BACKGROUND: Influenza vaccination is recognized as a primary public health intervention which prevents the illness of patients and relieves the societal burdens of influenza for medical community as well as the economy. To date, no effectiveness study of influenza vaccination has been conducted including a large population with a wide age span, in Japan. Here, we evaluated the clinical effectiveness of influenza vaccination in a large Japanese population. METHODS: We conducted a cohort study using a large-scale claims database for employee health care insurance plans. Vaccination status was identified using plan records for influenza vaccination subsidies. We excluded people aged 65 years or more because of the unavailability of vaccination records. Effectiveness of vaccination in preventing influenza and its complication was evaluated with doubly robust methods using inversed probability treatment weighting to adjust health conscious behaviours and other confounders. RESULTS: During the 2013/2014 influenza season, 369,425 subjects with age range from 1 to 64 years were eligible. Vaccination rate was 39.5% and an estimated odds ratio (OR) for influenza onset was 0.775 after doubly robust adjustment. Age-stratified ORs were significantly reduced in all age groups; lowest in subjects aged 1 to 4 years (0.600) and highest in those aged 13 to 19 (0.938). ORs for all the influenza complication outcomes were also statistically significant (0.403-0.709). CONCLUSIONS: We confirmed the clinical effectiveness of influenza vaccination in people aged 1 to 64 years. Influenza vaccination significantly prevented influenza onset and was more effective in reducing secondary risks of influenza complications.