Validation of algorithms to identify colorectal cancer patients from administrative claims data of a Japanese hospital.

BACKGROUND: Administrative claims data are a valuable source for clinical studies; however, the use of validated algorithms to identify patients is essential to minimize bias. We evaluated the validity of diagnostic coding algorithms for identifying patients with colorectal cancer from a hospital's administrative claims data. METHODS: This validation study used administrative claims data from a Japanese university hospital between April 2017 and March 2019. We developed diagnostic coding algorithms, basically based on the International Classification of Disease (ICD) 10th codes of C18-20 and Japanese disease codes, to identify patients with colorectal cancer. For random samples of patients identified using our algorithms, case ascertainment was performed using chart review as the gold standard. The positive predictive value (PPV) was calculated to evaluate the accuracy of the algorithms. RESULTS: Of 249 random samples of patients identified as having colorectal cancer by our coding algorithms, 215 were confirmed cases, yielding a PPV of 86.3% (95% confidence interval [CI], 81.5-90.1%). When the diagnostic codes were restricted to site-specific (right colon, left colon, transverse colon, or rectum) cancer codes, 94 of the 100 random samples were true cases of colorectal cancer. Consequently, the PPV increased to 94.0% (95% CI, 87.2-97.4%). CONCLUSION: Our diagnostic coding algorithms based on ICD-10 codes and Japanese disease codes were highly accurate in detecting patients with colorectal cancer from this hospital's claims data. The exclusive use of site-specific cancer codes further improved the PPV from 86.3 to 94.0%, suggesting their desirability in identifying these patients more precisely.

Association Between Second-hand Smoke Exposure and Depressive Symptoms Among Japanese Adults: A Cross-sectional Study.

BACKGROUND: Second-hand smoke exposure has been associated with poor mental health. However, among Japanese adults, little is known about the association between second-hand smoking and depressive symptoms. We examined this association in a cross-sectional study among a Japanese general adult population sample. METHODS: Japanese adults were recruited from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2012 and 2017. Second-hand smoke exposure and smoking status were assessed using a self-administered questionnaire. Based on their frequency of exposure to second-hand smoke, non-smokers and smokers were categorized as "almost never," "sometimes," and "almost every day". Depressive symptoms were defined by a Kessler 6 score ≥5 points. We performed a multivariable Poisson regression analysis to obtain adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for depressive symptoms. RESULTS: Overall, 5,121 participants (4,547 non-smokers and 574 smokers) were included whose mean age was 63.6 (standard deviation [SD], 10.3) years for non-smokers and 59.33 (SD, 10.2) years for smokers. The association between second-hand smoking and depressive symptoms was significant among non-smokers, but not among smokers. Among non-smokers, PRs compared with "almost never" were 1.25 (95% CI, 1.09-1.42) for "sometimes" and 1.41 (95% CI, 1.09-1.84) for "almost every day" (P for trend <0.001); among smokers, PRs compared with "almost never" were 1.30 (95% CI, 0.82-2.06) for "sometimes" and 1.44 (95% CI, 0.90-2.33) for "almost every day" (P for trend = 0.144). CONCLUSIONS: Second-hand smoking and depressive symptoms were associated among non-smokers. Our findings indicate the importance of tobacco smoke control for mental health.

Physical Activity Earlier in Life Is Inversely Associated With Insulin Resistance Among Adults in Japan.

BACKGROUND: It is known that physical activity affects glucose metabolism. However, there have been no reports on the influence of physical activity earlier in life on subsequent glucose metabolism. Therefore, we analyzed the influence of physical activity in earlier decades of life on insulin resistance in middle aged and older residents in Japan. METHODS: The subjects were 6,883 residents of Okazaki City between the ages of 40 and 79 years who underwent physical examinations at the Okazaki City Medical Association Public Health Center from April 2007 through August 2011. They gave informed consent for participation in the study. Data on individual characteristics were collected via a questionnaire and from the health examination records. Fasting blood glucose and insulin levels were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). HOMA-IR >1.6 was considered to indicate insulin resistance for the purpose of logistic regression models. RESULTS: The study sample included 3,683 men and 3,200 women for whom complete information was available. For those who exercised regularly throughout their teens to their 30s-40s, the odds ratio for having insulin resistance was 0.75 (95% confidence interval [CI], 0.58-0.96) for men and 0.76 (95% CI, 0.58-0.99) for women after adjusting for other variables, including age, body mass index, and present physical activity. A linear trend was also observed in both men and women. CONCLUSIONS: Subjects who have exercised regularly in the early decades of life are less likely to have insulin resistance later in life.

Handling missing data in an FFQ: multiple imputation and nutrient intake estimates.

OBJECTIVE: We aimed to examine missing data in FFQ and to assess the effects on estimating dietary intake by comparing between multiple imputation and zero imputation. DESIGN: We used data from the Okazaki Japan Multi-Institutional Collaborative Cohort (J-MICC) study. A self-administered questionnaire including an FFQ was implemented at baseline (FFQ1) and 5-year follow-up (FFQ2). Missing values in FFQ2 were replaced by corresponding FFQ1 values, multiple imputation and zero imputation. SETTING: A methodological sub-study of the Okazaki J-MICC study.ParticipantsOf a total of 7585 men and women aged 35-79 years at baseline, we analysed data for 5120 participants who answered all items in FFQ1 and at least 50% of items in FFQ2. RESULTS: Among 5120 participants, the proportion of missing data was 3·7%. The increasing number of missing food items in FFQ2 varied with personal characteristics. Missing food items not eaten often in FFQ2 were likely to represent zero intake in FFQ1. Most food items showed that the observed proportion of zero intake was likely to be similar to the probability that the missing value is zero intake. Compared with FFQ1 values, multiple imputation had smaller differences of total energy and nutrient estimates, except for alcohol, than zero imputation. CONCLUSIONS: Our results indicate that missing values due to zero intake, namely missing not at random, in FFQ can be predicted reasonably well from observed data. Multiple imputation performed better than zero imputation for most nutrients and may be applied to FFQ data when missing is low.

Implementation of Guideline-Based HBV Reactivation Management in Patients with Chronic HBV Infections of HBsAg or Resolved HBV Infection Undergoing Immunosuppressive Therapy.

INTRODUCTION: Although patients with HBV have a risk of reactivation after immunosuppressive therapy (IST), the status of their risk management is unclear in Japan. This study aims to describe the proportion of patients who received preventive management of HBV reactivation during ISTs in patients with chronic HBV infection of HBsAg or resolved HBV infection. METHOD: A retrospective cohort study was conducted using the JMDC Japanese claims database from April 2011 to June 2021. Patients with HBV infections of HbsAg who received ISTs or patients who had resolved HBV infections who received ISTs were identified from the database and evaluated for appropriate management to prevent HBV reactivation. RESULTS: In total, 6242 eligible patients were identified. The proportions of patients with appropriate HBV reactivation management, stratified by the HBV reactivation risk level of IST, was 43.1% (276/641) for high-risk, 40.2% (223/555) for intermediate-risk and 14.9% (741/4965) for low-risk patients. When the evaluation period for the outcome calculation was shortened from 360 to 180 days, the proportion for high risk increased to 52.7%. The odds ratios of large hospitals for receiving appropriate management were 2.16 (95% CI 1.12-4.44) in the high-risk, 4.63 (95% CI 2.34-10.25) in the intermediate-risk and 3.60 (95% CI 3.07-4.24) in the low-risk patients. CONCLUSION: HBV reactivation management was tailored according to the reactivation risk associated with IST. However, adherence to HBV reactivation management guidelines was sub-optimal, even among high-risk patients. This is especially the case for ensuring smaller-sized medical institutions, highlighting the need for further educational activities.

The study assesses the implementation of guideline-based management of hepatitis B virus reactivation during immunosuppressive therapy in Japan. The appropriate management of hepatitis B virus treatment involves prophylactic nucleos(t)ide analog (NUC) therapy and regular monitoring of hepatitis B virus DNA. This study aims to assess the extent to which these management practices are implemented in a clinical setting in Japan using a retrospective cohort study using the Japanese Medical Claims Database. The analysis identified 6242 eligible patients and identified whether they received appropriate management to prevent hepatitis B virus reactivation based on the level of risk associated with their immunosuppressive therapy. Based on the guidelines, the proportions of patients receiving appropriate reactivation management were 43.1% for high-risk, 40.2% for intermediate-risk and 14.9% for low-risk immunosuppressive therapy patients. Shortening the evaluation period from 360 to 180 days showed an increase in the proportion of high-risk patients to 52.7%, which indicated the potential challenge for continued monitoring after immunosuppressive therapy administration. The study shows that large hospitals present higher odds of patients receiving appropriate management. Overall, adherence to hepatitis B virus reactivation management guidelines was suboptimal, especially in smaller medical institutions, emphasizing the need for additional educational activities.

An Attempt to Replicate Randomized Trials of Diabetes Treatments Using a Japanese Administrative Claims and Health Checkup Database: A Feasibility Study.

BACKGROUND: Use of real-world evidence (RWE) has been limited for evaluating effectiveness because of the lack of confidence in its reliability. Examining whether a rigorously designed observational study using real-world data (RWD) can reproduce the results of a randomized controlled trial (RCT) will provide insights into the implementation of high-quality RWE studies that can produce valid conclusions. OBJECTIVE: We aimed to replicate published RCTs using a Japanese claims and health checkup database and examine whether the emulated RWE studies' results agree with those of the original RCTs. METHODS: We selected three RCTs on diabetes medications for replication in patients with type 2 diabetes. The study outcome was either the change or percentage change in HbA1c levels from baseline. We designed three observational studies using the RWD to mimic the critical study elements of the respective RCTs as closely as possible. We performed 1:1 propensity score nearest-neighbor matching to balance the groups for potential confounders. The differences in outcomes between the groups and their 95% confidence intervals (CIs) were calculated in each RWE study, and the results were compared with those of the RCT. RESULTS: Patient characteristics, such as age, sex, and duration of diabetes, differed between the RWE studies and RCTs. In Trial 1 emulation, the percentage changes in HbA1c levels were larger in the treatment group than in the comparator group (difference -6.21, 95% confidence interval (CI) -11.01 to -1.40). In Trial 2, the change in HbA1c level was larger in the treatment group (difference -0.01; 95% CI -0.25 to 0.23), and in Trial 3, it was smaller in the treatment group (difference 0.46; 95% CI -0.01 to 0.94). These results did not show regulatory or estimate agreement with the RCTs. CONCLUSIONS: None of the three emulated RWE studies using this claims and health checkup database reproduced the same conclusions as the RCTs. These discrepancies could largely be attributed to design differences between RWE studies and RCTs, primarily due to the lack of necessary data in the database. This particular RWD source may not be the best fit for evaluating treatment effects using laboratory data as the study outcome.

Validation of Algorithms to Identify Bone Metastases Using Administrative Claims Data in a Japanese Hospital.

BACKGROUND: Validated coding algorithms are essential to generate high-quality, real-world evidence from claims data studies. OBJECTIVE: We aimed to evaluate the validity of the algorithms to identify patients with bone metastases using claims data from a Japanese hospital. PATIENTS AND METHODS: This study used administrative claims data and electronic medical records at Juntendo University Hospital from April 2017 to March 2019. We developed two candidate claims-based algorithms to detect bone metastases, one based on diagnosis codes alone (Algorithm 1) and the other based on the combination of diagnosis and imaging test codes (Algorithm 2). Of the patients identified by Algorithm 1, 100 patients were randomly sampled. Among these 100 patients, 88 patients met the conditions of Algorithm 2; further, 12 additional patients were randomly sampled from those identified by Algorithm 2, thus obtaining a total of 100 patients for Algorithm 2. They were evaluated for their true diagnosis using the patient chart review as the gold standard. The positive predictive value (PPV) was calculated to assess the accuracy of each algorithm. RESULTS: For Algorithm 1, 82 patients were analyzed after excluding 18 patients without diagnostic imaging reports. Of these, 69 patients were true positive by chart review, resulting in a PPV of 84.1% (95% confidence interval (CI) 74.5-90.6). For Algorithm 2, 92 patients were analyzed after excluding eight patients whose diagnoses were not judged by chart review. Of these, 76 patients were confirmed positive by chart review, yielding a PPV of 82.6% (95% CI 73.4-89.1). CONCLUSION: Both claims-based algorithms yielded high PPVs of approximately 85%, with no improvement in PPV by adding imaging test conditions. The diagnosis code-based algorithm is sufficient and valid for identifying bone metastases in this Japanese hospital.

Impact of "time zero" of Follow-Up Settings in a Comparative Effectiveness Study Using Real-World Data with a Non-user Comparator: Comparison of Six Different Settings.

BACKGROUND: Time-related bias can lead to misleading conclusions. Properly setting the "time zero" of follow-up is crucial for avoiding these biases. However, the time-zero setting is challenging when comparing users and non-users of a study drug because the latter do not have a time point for starting treatment. OBJECTIVE: This methodological study aimed to illustrate the impact of different time-zero settings on effect estimates in a comparative effectiveness study using real-world data with a non-user comparator. METHODS: Data for type 2 diabetes patients were extracted from an administrative claims database, and the onset of diabetic retinopathy (study outcome) was compared between users (treatment group) and non-users (non-use group) of lipid-lowering agents. We applied six time-zero settings to the same dataset. The adjusted hazard ratio (HR) for the outcome was estimated using a Cox regression model in each time-zero setting, and the obtained results were compared among the settings. RESULTS: Of the six settings, three (study entry date [SED] vs SED [naïve approach], treatment initiation [TI] vs SED, TI vs Matched [random order]) showed that the treatment had a reduced risk of the outcome (HR [95% CI]: 0.65 [0.61-0.69], 0.92 [0.86-0.97], and 0.76 [0.71-0.82], respectively), one (TI vs Random) had an increased risk (HR [95% CI]: 1.52 [1.40-1.64]) , and two (SED vs SED [cloning method], and TI vs Matched [systematic order]) had neither increased nor decreased risk (HR [95% CI]: 0.95 [0.93-1.13], and 0.99 [0.93-1.07], respectively). CONCLUSIONS: This study demonstrates that different time-zero settings can lead to different conclusions, even if the same dataset is analyzed for the same research question, probably because improper settings can introduce bias. To minimize such biases, researchers should carefully define time zero, particularly when designing a non-user comparator study using real-world data.

Strategies to Address Current Challenges in Real-World Evidence Generation in Japan.

The generation of real-world evidence (RWE), which describes patient characteristics or treatment patterns using real-world data (RWD), is rapidly growing more popular as a tool for decision-making in Japan. The aim of this review was to summarize challenges to RWE generation in Japan related to pharmacoepidemiology, and to propose strategies to address some of these challenges. We first focused on data-related issues, including the lack of transparency of RWD sources, linkage across different care settings, definitions of clinical outcomes, and the overall assessment framework of RWD when used for research purposes. Next the study reviewed methodology-related challenges. As lack of design transparency impairs study reproducibility, transparent reporting of study design is critical for stakeholders. For this review, we considered different sources of biases and time-varying confounding, along with potential study design and methodological solutions. Additionally, the implementation of robust assessment of definition uncertainty, misclassification, and unmeasured confounders would enhance RWE credibility in light of RWD source-related limitations, and is being strongly considered by task forces in Japan. Overall, the development of guidance for best practices on data source selection, design transparency, and analytical methods to address different sources of biases and robustness in the process of RWE generation will enhance credibility for stakeholders and local decision-makers.

Changes in renal function over time in outpatients with eGFR ≥ 30 mL/min/1.73 m2: implication for timing of renal function testing before contrast-enhanced CT imaging.

PURPOSE: To evaluate the associations between comorbidities and kidney function decline at 6-month and 1-year follow-up in outpatients with initial estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2. MATERIALS AND METHODS: Outpatients aged 18 and older with confirmed diagnosis, who had eGFR ≥ 30 mL/min/1.73 m2 measured between April 2017 and March 2019, were included in this retrospective observational study. Of them, 30,595 included outpatients had 6-month eGFR test and 27,698 included outpatients had 1-year eGFR test. The outpatients were further divided into two groups based on initial eGFR: between 30 and 59 and ≥ 60 mL/min/1.73 m2. Impaired renal function was defined as eGFR declined to below 30 mL/min/1.73 m2. The comorbidities with P values less than 0.1 identified in univariable logistic regression models were entered into the multivariable analysis with backward selection, thereby identifying comorbidities that increased the risk of eGFR decline at 6-month and 1-year follow-up. RESULTS: Outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2 were 175.94 times more likely to have eGFR decline at 6 months, and were 94.10 times more likely to have eGFR decline at 1 year, compared with their corresponding initial eGFR ≥ 60 counterparts. Multivariable logistic regression analyses disclosed that chronic kidney disease, hypertension, and heart failure were independent risk factors for eGFR decline in outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2. CONCLUSIONS: Outpatients with initial eGFR ≥ 60 mL/min/1.73 m2 might not need routine eGFR test prior to contrast-enhanced CT scan for 1 year. In addition, chronic kidney disease, hypertension, and heart failure increased the risk of declined renal function, particularly, in outpatients with initial eGFR between 30 and 59 mL/min/1.73 m2.

Perioperative Analgesics and Anesthesia as Risk Factors for Postoperative Chronic Opioid Use in Patients Undergoing Total Knee Arthroplasty: A Retrospective Cohort Study Using Japanese Hospital Claims Data.

BACKGROUND: Patients with chronic postsurgical pain are commonly prescribed opioids chronically because of refractory pain although chronic opioid use can cause various severe problems. OBJECTIVE: We aimed to investigate postoperative chronic opioid use and its association with perioperative pain management in patients who underwent a total knee arthroplasty in a Japanese real-world clinical setting. METHODS: We conducted a retrospective cohort study using an administrative claims database. We used a multivariate logistic regression analysis to examine the association between perioperative analgesic and anesthesia prescriptions and postoperative chronic opioid use. We calculated all-cause medication and medical costs for each patient. RESULTS: Of the 23,537,431 patient records, 14,325 patients met the criteria and were included in the analyses. There were 5.4% of patients with postoperative chronic opioid use. Perioperative prescriptions of weak opioids, strong and weak opioids, and the α2δ ligand were significantly associated with postoperative chronic opioid use (adjusted odds ratio [95% confidence interval], 7.22 [3.89, 13.41], 7.97 [5.07, 12.50], and 1.45 [1.13, 1.88], respectively). Perioperative combined prescriptions of general and local anesthesia were also significantly associated with postoperative chronic opioid use (3.37 [2.23, 5.08]). These medications and local anesthesia were more commonly prescribed on the day following surgery, after routinely used medications and general anesthesia were prescribed. The median total direct costs were approximately 1.3-fold higher among patients with postoperative chronic opioid use than those without postoperative chronic opioid use. CONCLUSIONS: Patients who require supplementary prescription of analgesics for acute postsurgical pain are at high risk of postoperative chronic opioid use and these prescriptions should be given careful consideration to mitigate the patient burden.

Context and Considerations for Use of Two Japanese Real-World Databases in Japan: Medical Data Vision and Japanese Medical Data Center.

In Japan, an increasing interest in real-world evidence for hypothesis generation and decision-making has emerged in order to overcome limitations and restrictions of clinical trials. We sought to characterize the context and concrete considerations of when to use Medical Data Vision (MDV) and JMDC databases, the main Japanese real-world data (RWD) sources accessible by pharmaceutical companies. Use cases for these databases, and related issues and considerations, were identified and summarized based on a literature search and experience-based knowledge. Studies conducted using MDV or JMDC were mostly descriptive in nature, or explored potential risk factors by evaluating associations with a target outcome. Considerations such as variable ascertainment at different time points, including issues relating to treatment identification and missing data, were highlighted for these two databases. Although several issues were commonly shared (e.g., only month of event occurrence reported), some database-specific issues were also identified and need to be accounted for. In conclusion, MDV and JMDC present limitations that are relatively typical of RWD sources, though some of them are unique to Japan, such as the identification of event occurrence and the inability to track patients visiting different healthcare settings. Addressing study design and careful result interpretation with respect to the specificities and uniqueness of the Japanese healthcare system is of particular importance. This aspect is especially relevant with respect to the growing global interest of conducting RWD studies in Japan.

The Impact of Job Conditions on Health-Related Quality of Life among Working Japanese Older Adults: A Five-Year Longitudinal Study Using J-MICC Okazaki Study Data.

OBJECTIVES: The number of older adults who continue working after retirement is increasing in Japan. Little is known about how job conditions affect older adults' health. We examined the association between job conditions and health-related quality of life (HRQOL) during a five-year follow-up study. METHODS: This study included participants aged 65 years or older from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area recruited at baseline between 2007 and 2011 and followed up five years later. Participants completed a self-reported questionnaire on the physical and mental health aspects of HRQOL (SF-8™), employment status, and job conditions (job satisfaction, skill use, and job suitability). RESULTS: Data of 1,146 men and 522 women were analyzed (mean age: 69.1 and 68.6 years, respectively). Generalized mixed linear regression analysis revealed that, compared to the not-working group, skill use was positively associated with mental health aspects among men (skill use × time: ß = 0.16, SE = 0.08, p < 0.05), while poor job satisfaction and job suitability were negatively associated with mental health aspects among women (job satisfaction, not satisfied × time: ß = -0.93, SE = 0.47, p < 0.05; job suitability, not suitable × time: ß = -1.06, SE = 0.50, p < 0.05). CONCLUSIONS: Regarding job conditions among older adults, skill use in men was marginally associated with mental health, and poor job satisfaction and suitability in women were negatively associated with mental health. Considering the job conditions of older workers is necessary to protect their mental health.

The Association between Family Caregiver Burden and Subjective Well-Being and the Moderating Effect of Social Participation among Japanese Adults: A Cross-Sectional Study.

We examined the association between family caregiver burden and subjective well-being with social participation's moderating effect among Japanese adults. Data were obtained from a cross-sectional survey by the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2013 and 2017. Study participants included 5321 adults who visited the Public Health Center for annual health check-ups and answered a questionnaire regarding health status and lifestyle. Subjective well-being was assessed by a single item, out of 10 points, and analyzed with multivariable linear regression analysis models by subjective family caregiver burden ("none", "mild", "severe"), stratified by gender. Ultimately, 2857 men and 2223 women were included. Mean participant age (standard deviation) in years was 64.7 (10.4) for men and 61.3 (10.0) for women. Multivariable analysis revealed that, among women, higher caregiver burden was inversely associated with subjective well-being (p for trend < 0.001), and the interaction of severe caregiver burden and social participation on subjective well-being was positive and significant (p for interaction < 0.05). High family caregiver burden was inversely associated with subjective well-being among Japanese women, but moderated by the caregiver's social participation, suggesting the importance of community development that enables family caregivers' social participation to protect their subjective well-being.