Cohort Profile Update: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) 2023 update

Key Features.

• The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) included pregnant women, children, fathers, grandparents, and other family members across Japan between 2013 and 2017.

• The aims of the study were to assess health status following the Great East Japan Earthquake and to aid in regional recovery by promoting advanced medical practices.

• Follow-up efforts focused on updating examinations based on physique, atopic dermatitis, and neurodevelopment, tailored to participant needs and prevailing disease trends. Information from child health check-ups was also gathered from municipalities and schools. Additionally, a computer application was developed to display examination results, administer questionnaires, and integrate data from other sources.

• This study also revealed a relationship between earthquakes and health outcomes, and developed predictive models for pre-eclampsia and being small for gestational age.

• Family members not previously included in the study have been invited to participate again.

• Currently, Japanese research institutions have full access to these data. While phenotypic data and summary statistics are available to researchers in foreign countries, discussions are ongoing regarding the international distribution of genetic data. Interested readers can contact Taku Obara, a member of the TMM BirThree Cohort Study, at obara-t@megabank.tohoku.ac.jp.

The original cohort

The Tohoku Medical Megabank Project (TMM) was established in 2012. It aims to address medical challenges resulting from the Great East Japan Earthquake (GEJE) by enhancing healthcare services in the affected regions. This includes deploying physicians on a rotational basis, monitoring and improving the health of individuals in and around the disaster zones, and pioneering personalized healthcare and medicine, both locally and globally.

Since July 2013, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) has been conducted as a part of the TMM [1]. This study gathers prenatal and postnatal exposure and outcome data from offspring and their family members, including disaster-related information. Additionally, by including family members in the study, the TMM BirThree Cohort Study aims to analyse genetic and environmental factors influencing diseases and to address the issue of missing heritability in personalized healthcare and medicine.

What is the reason for the new data collection?

The TMM BirThree Cohort Study included three generations: children, parents, and grandparents. Due to heritability laws, the family genome presents a limited array of potential genotypes, facilitating more efficient searches for disease-associated genes. Occasionally, a disease might affect only one child in a family or be influenced by other familial factors not outwardly manifested. If a disease is genetic, then it could stem from a new mutation or an inherited homozygous recessive allele. Analyses of parent genomes help to identify these underlying causes. In the TMM BirThree Cohort Study, if the index case is a child or a parent, then tracing genes back to the grandparents’ generation helps to determine which mutations are linked to the disease trait. Initially, not all family members were included; hence, we have re-invited them, starting in 2023, to enrich our findings.

Moreover, most disease predispositions are influenced by both genetic and environmental factors, particularly during embryonic and childhood development [2]. It is crucial to accurately account for and control in utero environmental factors in our life-course health and disease analyses. The research protocol, including a follow-up study based on the stages of child growth and development, was established at the inception of the TMM BirThree Cohort Study. We have conducted a second wave of data collection from 2017 to 2021 and initiated a third wave in 2021. While our focus is on longitudinal data, we also adapt our assessments to meet participant needs and reflect disease prevalence trends. In 2021, we launched the ‘My ToMMo’ app as a novel data-collection method, providing results from questionnaires and assessments, including blood and urine tests and physiological examinations, from the baseline to the follow-up periods in Portable Document Format. Additionally, we have utilized multiple data sources from municipalities, schools, and hospitals to ensure comprehensive tracking. This new data collection is summarized in Table 1.

Table 1.

Summary of the new data collection in the TMM BirThree Cohort Study.

New recruitment	Family members who had not previously participated in the TMM BirThree Cohort Study were invited through mothers from 2023
Updated questionnaires and assessment at a research centre	Questionnaires and assessment focusing on the child growth, development, and disease at susceptible age have been performed since 2017
Expanded data collection from various resources	Child health check-up information was collected from municipalities from 2018 to 2021 School health check-up information has been collected from primary and secondary schools since 2018 Cancer, intractable, and specific paediatric chronic disease registry information has been collected since 2018 Hospital and clinic confirmation of the diagnosis of congenital abnormalities and Kawasaki disease has been collected since 2018
Created a computer app	The app ‘My ToMMo’ was created to return the results of the TMM BirThree Cohort Study in 2021. The participants can look at the health check-up records that were collected from municipalities and schools. Currently, the function has been expanded to include a questionnaire survey and collection of self-reported data about health check-ups, vaccination, and wearable devices

What will be the new areas of research?

From 2017 to 2021, children aged 4–7 years participated in updated examinations focusing on physique and blood lipid profiles, which are indicators of potential lifestyle and cardiovascular diseases in the future. The study also included intensive assessments of atopic dermatitis—a targeted disease in the TMM BirThree Cohort Study. Dermatologists evaluated the presence and clinical symptoms of atopic dermatitis in these children. Additionally, a neurodevelopmental assessment was introduced during the second wave, involving questionnaires and clinical examination, and using eye-tracking technology to evaluate all participants under the age of 20 years. Starting in 2021, during the third wave, screenings for attention-deficit/hyperactivity disorder (ADHD) and verbal communication skills were added to classify the developmental status and seek the mechanism of its heterogeneity.

Medical records of mothers and children from before birth to 1 month post birth have been collected. From 2018 to 2021, we gathered child health check-up data from municipalities. We have also begun collecting health check-up information for siblings from primary and secondary schools, and are planning to extend this to include more comprehensive-school health data. Since 2018, we have compiled data on cancer, intractable diseases, and specific paediatric chronic diseases from all participants in the TMM BirThree Cohort Study. Congenital abnormalities and Kawasaki disease were initially reported through participant questionnaires, with diagnoses confirmed by hospitals and clinics.

The computer application ‘My ToMMo’, launched in 2021, allows participants to view results from questionnaires and examinations. The app is available to all participants with a smartphone or personal computer and it requires individual identification to log in. Its functionality has expanded to enable participants to complete questionnaires and review health check-up records collected from municipalities and schools, and data from maternal and child health handbooks. Participants can also upload their health data, including check-ups, vaccination records, and data from wearable devices. This information, collected with participants’ consent, is utilized for research purposes in the TMM BirThree Cohort Study.

Who is in the cohort?

The first recruitment was conducted between 2013 and 2017. Initially, pregnant women and their fetuses were initially recruited as probands. Subsequently, we recruited the partners of these women (the fathers of the fetuses), their parents (the grandparents of the fetuses), any children (siblings of the fetuses), and extended family members [3]. Detailed cumulative participant numbers—including pregnant women, offspring, fathers, siblings, grandparents, great-grandparents, and extended family members—are documented elsewhere (https://www.megabank.tohoku.ac.jp/english/). While the recruitment of pregnant women and offspring proceeded linearly, the inclusion of additional family members expanded quadratically. In cases involving offspring, twins and higher-order multiples were also included [3], with zygosity determined and noted in medical records.

The second recruitment was started in 2023. We invited 19 781 mothers to participate in a questionnaire, and 2644 mothers replied and indicated their interest in including family members (fathers, grandfathers, siblings, and other relatives), with a total of 5182, to participate in the TMM BirThree Cohort Study. We currently invite fathers, grandparents, and siblings. The number of initial participants who still participated in the TMM BirThree Cohort Study and additional participants at the end of March 2024 is described in Table 2.

Table 2.

The number of family members who were initially recruited and still participated in the TMM BirThree Cohort Study in 2023, and the number of family members who were additionally recruited in 2023

Family members	Number of people initially recruited and still participated	Number of people who were additionally recruited in 2023
Mothers	21 643	N.A.
Children	22 697	N.A.
Siblings	9268	955
Fathers	8621	170
Grandparents	8040	121

N.A., not applicable.

What has been measured?

The TMM BirThree Cohort Study has been collecting prospective data on a variety of diseases, particularly those believed to have increased or worsened following the GEJE. Targeted diseases primarily include allergic diseases, neurodevelopmental disorders, metabolic disorders, and psychiatric disorders. In pursuit of developing personalized medicine, the study combines genomic, omic, and environmental factor analyses; hence, biospecimens, assessments at research centres, and questionnaire data have been collected. Baseline characteristics of pregnant women and children have been previously reported [4]. The physiological assessments along with blood and urine tests were last updated in 2017 (Tables 3 and 4), focusing on metabolism and development in children. Detailed information on the contents and the number of children assessed at the research centres has been documented [5]. In 2021, these assessments and tests were updated once again. Due to the pandemic, COVID-19 antibody tests were conducted on adults. Additionally, information regarding COVID-19 infection rates and vaccination statuses was collected from municipalities. Changes in vaccination uptake and behaviour among family members were also evaluated by using questionnaires (Table 5). Information collected outside of research centres is depicted in Figure 1. We identify the participants by their name, sex, and birthday, and address and phone number are also used if necessary. To date, there have been 880 cases of congenital abnormalities, 239 cases of Kawasaki disease, and 205 specific paediatric chronic diseases identified among children and siblings. Medical records along with child and school health check-up information have been gathered by genome medical research coordinators, who were employed to assist in the research and communicate with participants [6]. They collected information onsite or via mail. Participants can also access child and school health check-up information via the ‘My ToMMo’ app. This information, along with registries and confirmations of congenital abnormalities and Kawasaki disease by hospitals and clinics, has been longitudinally linked with other data such as questionnaires, biospecimens, and assessments in the research centre by research identification. The catalogue of data is available in Japanese at https://dbtmm.megabank.tohoku.ac.jp/catalogue/.

Table 3.

Physiological assessment items at research centres and timing of assessment in the TMM BirThree Cohort Study

	First wave (19 July 2013–31 October 2017)				Second wave (30 June 2017–30 June 2021)		Third wave (15 July 2021–present)
	Pregnant women		Father, grandparents, other adult family members	Siblings, other child family members	Parents, grandparents, other adult family members	Offspring, siblings, other child family members	Parents, grandparents, other adult family members	Offspring, siblings, other child family members
	Antenatal	Postpartum
Height	X	X	X	X	X	X	X	X
Weight	X	X	X	X	X	X	X	X
Body composition	X	X	X	X (10 years–)	X	X (8 years–)	X	X (8 years–)
Head circumference				X		X
Waist circumference	X	X	X	X	X	X	X	X
Estimated central aortic blood pressure	X	X	X		X
Casual blood pressure	X	X	X	X (10 years–)	X	X (8 years–)	X	X (8 years–)
Heart rate	X	X	X		X	X	X	X
Carotid ultrasound imaging	X	X	X		X		X
Calcaneal ultrasound bone mineral density	X	X	X	X	X	X (8 years–)	X
Grip strength		X	X	X	X	X (8 years–)	X	X (8 years–)
Oral examination	X	X	X	X	X	X	X	X
Oral bacteriological examination	X	X	X	X		X	X
Axial length	X	X	X	X	X	X	X	X
Intraocular pressure	X	X	X		X		X
Optical coherence tomography	X	X	X		X		X
Colour retinal photography	X	X	X		X		X
Refraction and keratometry				X	X	X	X	X
Visual acuity						X		X
Hearing acuity	X	X	X	X	X	X	X	X
Respiratory function		X	X	X (10 years–)	X	X (8 years–)	X	X (8 years–)
Respiratory impedance	X	X	X	X (10 years–)
Leg extension strength		X	X
Electrocardiogram					X	X	X	X
Touchscreen questionnaire	X	X	X		X		X	X (8 years–)
Home blood pressure	X	X	X		X	X (8 years–)
Number of steps per day	X	X	X		X
Salt-impregnated test paper, SALSAVE®					X
Exhaled nitric oxide levels (FENO)					X
Gazefinder®						X		X
Magnetic resonance imaging		X	X		X		X	X
ADHD Test Programa								X
Speaking test								X
Mini-Cog®							X

The first wave was conducted in the baseline period (it finished in October 2017 due to postpartum assessment for mothers) and the second and third waves were conducted in the follow-up period in Miyagi Prefecture and some parts of Iwate Prefecture, Japan.

^aCreated by NoruPro Light Systems, Inc.

Table 4.

Biological samples collected in the TMM BirThree Cohort Study.

	Baseline period (first wave), 19 July 2013–31 October 2017					Follow-up period (second wave), 30 June 2017–30 June 2021		Third wave, 15 July 2021–present
	Pregnant women
	1st trimester	2nd trimester	Postpartum	Father, grandparents, other adult family members	Siblings, other child family members	Parents, grandparents, other adult family members	Off-springs, siblings, other child family members	Parents, grandparents, other adult family members	Off-springs, siblings, other child family members
Blood
N-terminal pro-B-type natriuretic peptide	X	X	X	X		X		X
Glycoalbumin	X	X	X	X
Creatinine	X	X	X	X		X		X	X (8 years–)
Urea nitrogen	X	X	X	X		X		X	X (8 years–)
Non-specific IgE antibody test	X	X	X	X	X		X	X	X (8 years–)
Specific IgE antibody test (MAST/VIEW/single allergen)	X			X	X	X	X		X
Helicobacter pylori antibody test			X	X
Serum PG test			X	X
Aspartate aminotransferase	X	X	X	X		X		X	X (8 years–)
Alanine aminotransferase	X	X	X	X		X		X	X (8 years–)
Gamma-glutamyl transferase	X	X	X	X		X		X	X (8 years–)
Uric acid	X	X	X	X		X		X	X (8 years–)
Glucose			X	X		X	X (8 years–)	X	X (8 years–)
Haemoglobin A1c	X	X	X	X		X	X (8 years–)	X	X (8 years–)
Triglycerides	X	X	X	X		X	X (8 years–)	X	X (8 years–)
Total cholesterol	X	X	X	X		X	X (8 years–)	X	X (8 years–)
Low-density lipoprotein cholesterol							X (8 years–)	X	X (8 years–)
High-density lipoprotein cholesterol	X	X	X	X		X	X (8 years–)	X	X (8 years–)
Complete blood count			X	X		X		X	X (16 years–)
Complete blood count with differential			X	X		X		X	X (16 years–)
Cystatin C	X	X	X	X		X
s-Flt-1/PIGF		X
Thyroid stimulating hormone						X	X (8 years–)	X	X (8 years–)
Triiodothyronine						X	X (8 years–)	X	X (8 years–)
Thyroxine						X	X (8 years–)	X	X (8 years–)
C reactive protein						X		X	X (8 years–)
COVID-19 antibody								X
Urine
Microalbumin	X	X	X	X		X		X	X (8 years–)
Creatinine	X	X	X	X		X		X	X (8 years–)
Sodium	X	X	X	X		X		X	X (8 years–)
Chloride	X	X	X	X		X		X	X (8 years–)
Potassium	X	X	X	X		X		X	X (8 years–)

The first wave was conducted in the baseline period (it finished in October 2017 due to postpartum assessment for mothers) and the second and third waves were conducted in the follow-up period in Miyagi Prefecture and some parts of Iwate Prefecture, Japan.

PG, pepsinogen; s-Flt-1, soluble fms-like tyrosine kinase-1; PIGF, placental growth factor; COVID-19, corona virus disease-2019; MAST, Multiple Antigen Simultaneous Test^®; VIEW, View Allergy^®.

Table 5.

Questionnaires during the follow-up period in the TMM BirThree Cohort Study.

Parents and grandparents
Basic information	Height, weight, weight 1 year before the questionnaire, and housing type
Physical activities	Frequency of going out and transportation
Alcohol drinking	Drinking status
Cigarette smoking	Smoking status and information on passive smoking
Psychological stress	Self-reported stress, Kessler Psychological Distress Scale (K6, second and third waves for all family members as well as every 6 months to 1 year for parents until their child become 5 years old)
Medications, dietary supplements, and health foods	Information on drugs and regularly used supplements
Family structure and pet breeding	Marital status, numbers of family members, cohabitation status, and pet breeding (dogs, cats, and others)
Health-related information	Self-rated health; treatment status of hypertension, diabetes, or hyperlipidemia; dental treatment and past history of diseases
Occupation	Employment status
Income	Household income
Sleep	Hours of sleep, Athens Insomnia Scale (AIS), and information on sleep medications
Social network	Lubben social network scale (LSNS-6) and social capital
Depressive symptoms	Center for Epidemiologic Studies Depression Scale (CES-D, second and third waves for all family members as well as every 1 year for parents until their child become 5 years old)
Memory and damage of the GEJE	Post-traumatic stress reaction due to the GEJE
Information on obstetrics and gynaecology (women only)	Age at menarche and age at first pregnancy
Dietary information	Food frequency questionnaire (FFQ) and several diet-related questions
Bonding	Mother–infant bonding scale (MIBS, every 6 months to 1 year for parents until their child became 5 years old)
Neurodevelopment	ADHD Self-Report Scale (ASRS, parents whose child had become 2 years old), AQ/AQ-10
(Only the second wave) Genetic predisposition	Type of eyelid
(Only the third wave) Physical activities	Frequency of physical activities and hours spent per session in the past year
(Only the third wave) COVID-19-related information	Vaccination and lifestyle changes
Offspring and siblings
Dietary information	Breast feeding and food frequency
Basic information	Height, weight, and housing type
Health-related information	Past history of diseases
Medications, dietary supplements, and health foods	Information on drugs and regularly used supplements
Sleep	Hours and place of sleep
Physical activities	Frequency of physical activities and TV/video games
Family structure and pet breeding	Family members living together and pet breeding (dogs, cats, and others)
Housing environment	Coating or construction, use of air conditioner, and use of carpet
Smoking/alcohol	Smoking status, information on passive smoking, and drinking status
Neurodevelopment and behaviour	Ages & Stages Questionnaires, Third Edition (ASQ-3, 6 months, 1 year, 2 years, 3.5 years, 4 years, and 5 years), Child Behavior Checklist (CBCL, 2, 3, 4, and 5 years), Tokyo Autistic Behavior Scale (TABS, 2 and 3 years), Strength and Difficulties Questionnaire (SDQ, 4 years–), ADHD Rating Scale (ADHD-RS, 2nd–6th grades in primary school in the third wave), AQ (7 years)
Vaccination	Japanese encephalitis, DPT, IPV, HPV, influenza, SARS-CoV-2

DPT, diphtheria, pertussis, tetanus; IPV, inactivated poliovirus vaccine; HPV, human papillomavirus.

Figure 1.

Collected information according to generations. Collected data other than examinations at the research centres are illustrated.

Genotyping

Initially, we established Japanese whole-genome reference panels by using another adult cohort study as part of the TMM and developed the Japonica array version 2 (JPAv2). This array has since been updated to JPA NEO. The methodologies and pipelines have been detailed elsewhere [7]. By the end of February 2023, genotyping had been completed for 55 000 adults and children within the TMM BirThree Cohort Study. Whole-genome sequencing is currently underway and is planned for all participants. Omics information is also accessible at https://jmorp.megabank.tohoku.ac.jp/.

What has it found? Key findings and publications

The TMM BirThree Cohort Study has identified a link between the GEJE and several health and lifestyle issues. Although the incidence of being small for gestational age (SGA) among siblings born before and after the GEJE did not differ significantly [8], adult participants who experienced severe damage to their homes reported poorer mental health conditions, persisting even a couple of years later [8]. Overweight and smoking habits, which are risk factors for cardiovascular diseases, were more prevalent among parents who suffered severe home damage due to the earthquake [8]. Additionally, the experience of the GEJE was directly associated with an increased prevalence of hypertensive disorders of pregnancy (HDP) and indirectly through the consequences of being overweight [9]. Women who endured traumatic events during the GEJE prior to pregnancy exhibited a higher incidence of postpartum depressive symptoms 1 month after delivery [10].

To advance precision medicine, we have developed several disease-prediction models. Initially, we created a prediction model for pre-eclampsia based on routine antenatal care screenings, such as blood pressure and urine tests [11]. We also established prediction models and risk scores for SGA during the early and middle stages of gestation, as well as for preterm and term low birthweight, considering both genetic and environmental factors [12, 13]. The relationships between maternal dietary habits and the prevalence of HDP, SGA, and low birthweight have also been verified [14, 15]. These insights will be used to refine prediction models further. Moreover, we plan to make the pre-eclampsia and SGA prediction models available to medical and municipal healthcare providers.

For mothers, studies were conducted during both prenatal and postnatal periods. The medication use among Japanese pregnant women was documented [16]. Blood pressure measurements taken at the research centre and at home during pregnancy correlate with each other [17]. Low maternal birthweight was associated with an increased prevalence of HDP [18]. An independent association between infertility treatments and HDP was confirmed, even among women who were neither overweight nor smokers [19]. Several factors, including pregnant women’s smoking habits, smoking relapse, bonding disorders, and characteristics of their partners’ smoking and drinking behaviours during the prenatal and postnatal periods, were revealed [20–24]. Regarding mental health, intake of polyunsaturated fatty acids may influence psychological distress during pregnancy [25]. Social isolation was associated with insomnia [26] and personality traits were associated with postpartum depression [27].

Short- and long-term impacts on children were also reported. Maternal consumption of sugar-sweetened beverages was associated with an increased risk of the child being overweight at 1 year old [28]. Being overweight at 1 year old was linked to a higher risk of remaining overweight at 11 years old [29]. Relationships between maternal infertility treatment, dietary consumption, HDP subtypes, psychological distress, bonding disorders, social isolation, and children’s neurodevelopment and behaviour were documented [30–36]. Screen time at 1 year of age was associated with developmental delays at ages 2 and 4 years [37]. Additionally, maternal psychological distress was linked to child atopic dermatitis [38].

What are the main strengths and weaknesses?

A specific genomic mutation is considered potentially pathogenic if it is inherited alongside the disease and is not present in healthy family members. Analysing such shared mutations across multiple family lines affected by the same disease can effectively pinpoint the mutation responsible for the disease. Additionally, family-based genome analyses are particularly effective in identifying structural variants. Notably, the Japanese structural variation panel was constructed by using trios from the BirThree Cohort Study in 2022 [39]. This panel achieved high quality by assessing the Mendelian inheritance error rates of structural variants in the trio’s analysis.

Globally, efforts are ongoing to collect health information from multiple generations of community residents and analyse their genomic data. For instance, the Generation R Study from the Netherlands linked multiple single-nucleotide polymorphisms related to adult body mass index (BMI) with childhood BMI [40]. The Lifelines Cohort Study in the Netherlands found that stress exposure could affect genetic susceptibility to depression and anxiety [41]. The UK’s Avon Longitudinal Study of Parents and Children suggested that familial traits might not influence corneal curvature and axial length in a shared environment, but rather determined by genetic factors [42]. We anticipate that the TMM BirThree Cohort Study, with its unique design of recruiting three generations at its inception, will enable the early detection and tracking of the onset and progression of both acute and chronic diseases across these three generations.

On the other hand, maintaining a high follow-up rate is challenging. As of March 2021, the rate was 98.4%, achieved by inviting participants for health assessments and by collecting information through questionnaires, child and school health check-up records, and disease and resident registries. However, sustaining a high response rate to questionnaires and health assessments alone proves difficult. We have facilitated participant responses by offering options to complete questionnaires via mail and online, and we have incorporated a feature in the My ToMMo app specifically for this purpose. Additionally, we have tried to enhance data collection by gathering information on diseases such as cancer, intractable diseases, or death from municipalities. Broadly speaking, we strive to maintain contact with participants through various means such as newsletters, social media, and progress reports, and by setting up booths at municipal and other organizational exhibitions. To uncover disease mechanisms and advance precision medicine, it is crucial to encourage as much cooperation from participants as possible. We anticipate that recruiting additional family members will further enrich our findings.

Can I get hold of the data? Where can I find out more?

Currently, Japanese research institutions have full access to these data. While phenotypic data and summary statistics are available to researchers in foreign countries, discussions are ongoing regarding the international distribution of genetic data. Interested readers can contact Taku Obara, a member of the TMM BirThree Cohort Study, at obara-t@megabank.tohoku.ac.jp. Many collaborative studies are ongoing [43]. We welcome collaborations with researchers.

Ethics approval

The TMM BirThree Cohort Study protocol was reviewed and approved by the Ethics Committee of Tohoku Medical Megabank Organization (ToMMo) (2013–1-103–1). The study adheres to the principles outlined in the Declaration of Helsinki. We implemented broad and ongoing consent procedures for participation [1]. For participants aged 10–15 years, informed consent was obtained from both the individuals and their guardians. For those aged 16–19 years, consent was also required from both the individuals and their guardians. In cases in which participants of any age were unable to fully comprehend the study protocol, informed consent was obtained from their guardians, with the approval of the Ethics Committee.

Author contributions

T.Obara and S.Kuriyama designed this study. T.Obara, M.I., A.Noda, K.M., M.O., G.S., F.U., F.M., T.Onuma, H.Matsubara, H.Metoki, M.Kikuya, R.H., I.C., K.Nakaya, M.Kogure, N.Nakaya, J.S., S.Kure, M.Kobayashi, Tomoko Kobayashi, Y.Suzuki, H.K., M.S.-Y., S.Nagase, N.Nakamura, T.Nakamura, S.M., S.Nagaie, S.O., A.Narita, G.T., S.Koreeda, F.N., T.T., M.G., A.O., M.T., T.H., J.K., E.N.K., A.U., Y.H., H.T., H.H., K.Noguchi, F.K., S.Koshiba, K.Kumada, T.Nobukuni, K.O., S.M., R.S., M.Kambe, Y.Saito, Tadao Kobayashi, Y.I., K.Kinoshita, N.F., N.Y., H.A., M.Y., and S.Kuriyama directed the study’s implementation. T.Obara and M.I. designed the analytical strategy and interpreted the findings. T.Obara, M.I., A.Noda, K.M., M.O., G.S., F.U., F.M., T.Onuma, H.Matsubara, H.Metoki, M.Kikuya, R.H., I.C., K.Nakaya, M.Kogure, N.Nakaya, J.S., S.Kure, M.Kobayashi, Tomoko Kobayashi, Y.Suzuki, H.K., M.S.-Y., S.Nagase, N.Nakamura, T.Nakamura, S.M., S.Nagaie, S.O., A.Narita, G.T., S.Koreeda, F.N., T.T., M.G., A.O., M.T., T.H., J.K., E.N.K., A.U., Y.H., H.T., H.H., K.Noguchi, F.K., S.Koshiba, K.Kumada, T.Nobukuni, K.O., S.M., R.S., M.Kambe, Y.Saito, Tadao Kobayashi, Y.I., K.Kinoshita, N.F., N.Y., A.H., M.Y., and S.Kuriyama conducted the literature review and helped to prepare the Introduction and Methods sections of the text. T.Obara and M.I. drafted the Discussion section.

Conflict of interest

None declared.

Funding

TMM was supported by grants from the Japan Agency for Medical Research and Development (AMED). This research was supported by AMED under grant numbers JP17km0105001, JP17km0105002, and JP21tm0124005. AMED had no role in the design or conduct of the study.

Use of artificial intelligence (AI) tools

AI was not used.