Study design

This retrospective database study was conducted from 1 January 2013 to 31 December 2019 using two large-scale healthcare claims databases, the Japan Medical Data Center (JMDC) and the Medical Data Vision Co. Ltd. (MDV). According to the joint guidelines (latest revision 23 March 2021) of MEXT (Ministry of Education, Culture, Sports, Science and Technology), MHLW (Ministry of Health, Labour and Welfare) and METI (Ministry of Economy, Trade and Industry), the current study does not require any ethics committee approval because the data derived from the MDV and JMDC databases used in the study only include anonymized de-identified/de-linked information. In this study, 43 different clinical conditions which are defined by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes were selected based on (1) WHO publications, (2) the studies conducted by Black et al. and Wang Y et al. [8, 9], and (3) clinical importance and frequency advised by medical experts. A detailed list of all 43 conditions and their specific ICD-10 codes are shown in Table 1.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. ICD-10 codes used to identify clinical condition outcomes.

https://doi.org/10.1371/journal.pone.0256379.t001

Data sources

Two major healthcare claim databases in Japan, JMDC and MDV, were used for this study. The JMDC database contains claims data of inpatients and outpatients from the Japanese union-managed health insurance system, comprising 10 health insurance societies with a present dataset of 7.3 million individuals as of April 2020 [10]. The JMDC database includes workers mostly aged < 65 years employed by mid- to large-sized companies and their dependents, and excludes individuals aged ≥ 75 years.

The MDV database contains health insurance claims for inpatients and outpatients primarily from Diagnosis Procedure Combination (DPC) hospitals [11]. DPC is the claims-based payment system used by larger hospitals in Japan. The number of DPC hospitals providing data to the MDV database has increased over the years since its inception. This increase in participation was taken into consideration in the extrapolation of the data from the MDV database to all of Japan. The number of DPC hospitals in Japan and the number providing data to the MDV database in each period in this study are included in Table 2. Each hospital had to be including data in the database for at least 2 years for its data to be included in the evaluation of the occurrence of clinical conditions. The rationale for this is described in the following section.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Number of DPC hospitals in Japan and included in MDV database by year.

https://doi.org/10.1371/journal.pone.0256379.t002

Estimation of incidence

In this study, the number of new cases for each clinical condition was counted from the database according to the following two definitions: (a) Definition 1 included patients with a confirmed diagnosis or suspected diagnosis within a 24-month look-back period and (b) Definition 2 included patients with a confirmed diagnosis only within a 24-month look-back period. A period of 24 months prior to the observed diagnosis was used to identify any subjects that had a previous diagnosis in the study period to separate incident events (i.e., new events) from repeat episodes of the same diagnosis (i.e., prevalent events). For example, for all diagnoses of a clinical condition observed in 2019 we ensured that the same diagnosis was not included in the 24 months prior to the 2019 diagnosis. This approach greatly increased the likelihood that only new cases of the clinical condition were being included for a given year in both the JMDC and MDV databases.

We calculated the estimated incidence of each clinical condition in the Japanese population based on the actual number of new cases identified in the database analysis. Regarding the JMDC database, the age-specific incidence for each clinical condition in a given year was based on the observations of new cases in each age group and the number of individuals in that age group registered in the health insurance system and covered by the database in that year.

For the MDV database, the corresponding calculation of the incidence for each clinical condition was conducted based on the proportion of DPC hospitals included in the MDV database, and the number of DPC hospitals in Japan for each year. The number of new cases observed in a particular year and the population in Japan for that year came from the Statistics Bureau of Japan.

The definition of each clinical condition was based on the ICD-10 codes in both databases, but ICD-10 codes do not specify disease severity. Some patients may have had two or more competing disease events at the same time, and every event was counted separately in the analysis of each disease condition. The MDV database consists of data from DPC hospitals and does not include any data from non-DPC hospitals. Therefore, the number of patients in non-DPC hospitals was assumed to be zero in this analysis for the MDV database.

The results of the analyses for 14 of the 43 clinical conditions listed below are included in the main report. The results for the remaining clinical conditions in this study are included in the accompanying S1 Table. The 14 clinical conditions are:

(1) Bell’s palsy, (2) Guillain-Barre syndrome, (3) Optic Neuritis, (4) Idiopathic Thrombocytopenic Purpura, (5) Multiple Sclerosis, (6) Complex Regional Pain Syndrome, (7) Hypercoagulable States (Autoimmune), (8) Any Death / Sudden Unexplained Death, (9) Acute Transverse Myelitis, (10) Allergic Purpura, (11) Anaphylaxis/Shock, (12) Seizure, (13) Preterm Labor and (14) Spontaneous Abortion.

The 14 conditions have been roughly sorted according to the following conditions: 1–8 are those for which estimated incidence increases by age, 9–12 are those for which estimated incidence is similar among the age groups, and 13–14 are those related to pregnant women.

Literature search

This study performed a comprehensive search of the Japanese medical literature to collate and analyze the available data that describe the background incidence of underlying clinical conditions in Japan. Published papers from PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Ichushi-web (https://www.jamas.or.jp/english/) were searched and retrieved. For the literature searches no date range was specified and results up until the last date of searching (17 March 2021) were considered. Inclusion and exclusion criteria for the literature searches is shown in S2 Table as a PICOST (Population, Intervention, Comparator, Outcomes, Study type and Timeframe) table. An example search strategy in PubMed for the clinical condition encephalitis is shown in S3 Table. Priority was given to the most recent publications and to those literature that focused on age-specific and gender-specific incidence. When Japanese literature was not available global literature was searched to identify those conditions that included incidence. Grey literature such as guidelines and government statistics were also reviewed. In combination with the diagnostic keywords, terms such as incidence, prevalence and epidemiology were also used when searching the literature. Summary information and references for the studies included in the literature search results are shown at the end of each of the 14 clinical condition tables in the main text and in S1 Table.

1) Bell’s palsy

Bell’s palsy is an acute, monosymptomatic disorder characterized by unilateral peripheral facial paresis (partial) or paralysis (complete) resulting in temporary weakness of facial muscles due to facial nerve dysfunction. Since the causality is unknown, an etiology of exclusion approach is adopted based on anatomical structure, history of viral infection, ischemia, inflammation and cold stimulation responsivity [12]. The estimated incidence of Bell’s palsy in MDV and JMDC were 41.7 and 47.9 cases per 100,000 population per year, respectively, which were higher than the incidence reported in European countries. The age-specific estimate tended to increase with age in both databases (Table 3).

2) Guillain-Barre Syndrome

Guillain-Barre Syndrome (GBS) is a typical immune mediated polyradiculoneuropathy characterized by fulminant progression of flaccid muscular weakness and diminished myotatic reflexes thought to be activated by an acute infection. It is estimated that two-thirds of the reported cases resulted from infection caused by several viral species [14]. A predominance in the estimated number and incidence of new cases of the clinical condition was observed in males in comparison with females and the condition also was observed to increase with age in both the MDV and JMDC databases (Table 4).

3) Optic neuritis

Optic neuritis is a clinical presentation of idiopathic optic neuropathy affecting the optimal function of the optic nerve that leads to demyelination. The disease manifests in isolation or in a setting with multiple sclerosis or neuromyelitis optical [19]. The gender-based trend analysis revealed that the incidence (N, per 100,000 population per year) was higher in females than males in both databases and according to both Definitions 1 and 2. Elderly patients (over 65 years) had a considerably higher estimated number of cases / incidence (Table 5).

4) Idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura, which is also known as immune mediated thrombocytopenia, is an immunocompromised acquired bleeding disorder occurring as a result of transient or persistent decrease of the platelet count [22]. The estimated number of new cases / incidence based on Definition 1 reflected a slight female preponderance [MDV Definition 1: N = 10,828; 16.7 per 100,000 population per year], [JMDC Definition 1: N = 13,334; 20.1 per 100,000 population per year)]. This condition was notably higher in the elderly population aged over 75 years (Table 6).

5) Multiple sclerosis

Multiple sclerosis is the prototype chronic inflammatory pathological condition of autoimmune origin. It is characterized by relapses and remissions of demyelination, gliosis and neuronal loss caused by focal lymphocytic infiltration resulting in severe neurological defects [24]. The estimated number of new cases and incidence was higher in females than males in the two databases. Heterogeneity was high among the age groups which made age-specific trend assessment difficult. Individuals in their 50s and early 60s were observed to be more prone to this condition (Table 7).

6) Complex regional pain syndrome

Complex regional pain syndrome, also known as reflex sympathetic dystrophy (RSD), is a post traumatic chronic neurologic disorder. It is characterized by a series of prolonged painful episodes accompanied by sensory, vasomotor, sudomotor and motor functional impairments [27]. Marked female predilection was observed in comparison with males (Table 8). The estimated number and incidence of new cases of the clinical condition were higher in the elderly population (Table 8).

7) Hypercoagulable States (Autoimmune)

Hypercoagulable States (Autoimmune) is often termed as antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), or Hughes syndrome. It is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2 Glycoprotein I antibodies. The array of clinical phenotypes leads to arterial and venous thrombosis, microvascular and obstetrical complications such as pre-eclampsia, pregnancy morbidity and fetal demises [29]. A consistently higher (N, per 100,000 population per year) occurrence of the condition was observed in females with increases across successive age groups (Table 9).

8) Any Death/Sudden Unexplained Death

It was not possible to estimate the occurrence of sudden unexplained death in the MDV and JMDC databases as these deaths almost exclusively occur outside of healthcare institutions and are therefore not included in the health insurance medical records. Only limited numbers of any unexplained death were available from the MDV and JMDC databases and these numbers are provided in Table 10. In a study from Okinawa, for the period 1 January 1992 to 31 December 1994, the incidence of sudden unexpected death was observed to be 37 per 100,000 population per year (age 20–74 years, males = 51 per 100,000 population per year and females = 23 per 100,000 population per year). Importantly, for 53% of these deaths the cause was undetermined [31]. Further, data of the Utstein registry collected by the Fire and Disaster Management Agency noted that the number of sudden cardiac deaths recorded in Japan was 78,884 in 2019, suggesting an incidence of 62 deaths per 100,000 population per year [32]. Finally, the number of deaths due to any cause in 2019 was 1,381,093 according to the Vital Statistics published by the Ministry of Health, Labour and Welfare [33].

9) Acute Transverse Myelitis

Acute Transverse Myelitis (ATM) is a rare etiologically heterogeneous inflammatory subtype of transverse myelopathy. The clinical syndrome has an acute or subacute onset, which on spinal injury affects sensory and motor skills resulting in neurologic deficits [34]. The estimated incidence of confirmed diagnoses of acute transverse myelitis was 0.5–0.6 cases per 100,000 population per year. The incidence in Japan was lower than observed in studies outside of Japan (Table 11).

10) Allergic Purpura

Allergic Purpura, also known as Henoch-Schönlein purpura (HSP), is an IgA-mediated systemic microvasculitis condition associated with the accumulation of antibodies in the blood vessels [37]. The pathology is widely observed in the pediatric population. The proportion of female Allergic Purpura cases was higher than male cases in both databases and taking all study groups together there was higher incidence among the age group 0-11(Table 12).

11) Anaphylaxis/Shock

Anaphylaxis is a life-threatening and acute multisystemic hypersensitivity condition. The episodes often manifest with a potentially fatal outcome, as the risk of rapid-evolving respiratory collapse is anticipated. Despite the causative factor, expeditious cause determination and treatment is critical [41]. With respect to anaphylaxis, estimated incidence appeared to be higher in men and lower in women for both Definitions 1 and 2 in both databases. The numbers of confirmed or suspected diagnoses were similar to those of confirmed diagnoses (Table 13).

12) Seizure

An epileptic seizure is a spontaneous neurological transient array of signs and symptoms resulting from abnormal fulminant or synchronous neuronal activity in the brain [43]. Estimated new cases / incidence varied across different age groups (Table 14).

13) Preterm Labor

Preterm birth is one of the crucial obstetrical complications that is attributed to increased risk of perinatal mortality and morbidity. Preterm is a parturition occurring less than 37 completed weeks or 259 days of gestation [46]. There were an estimated 105.3 and 233.2 new cases per 100,000 population per year with a confirmed diagnosis of preterm in the year 2019 in MDV and JMDC, respectively (Table 15).

14) Spontaneous abortion

Spontaneous abortion is a pregnancy failure occurring before 20 weeks of gestation as result of natural causative factors [50]. Among the female population in the MDV database, the overall estimated number of new cases / incidence of spontaneous abortion were 19,368 cases (15.4 cases per 100,000 population per year) and 19,129 cases (15.2 cases per 100,000 population per year), respectively. In the JMDC database, the estimated number of new cases / incidence according to Definitions 1 and 2 were 82,431 female cases (63.9 cases per 100,000 population per year) and 77,494 cases (60.1 cases per 100,000 population per year), respectively (Table 16).