Progress report of the Tohoku Medical Megabank Community-Based Cohort Study: Study profile of the repeated center-based survey during second period in Miyagi Prefecture.

BACKGROUND: The purpose of this study was to report the basic profile of the Miyagi Prefecture part of a repeated center-based survey during the second period (2nd period survey) of the Tohoku Medical Megabank Community-Based Cohort Study (TMM CommCohort Study), as well as the participants' characteristics based on their participation type in the baseline survey. METHODS: The 2nd period survey, conducted from June 2017 to March 2021, included participants of the TMM CommCohort Study (May 2013 to March 2016). In addition to the questionnaire, blood, urine, and physiological function tests were performed during the 2nd period survey. There were three main ways of participation in the baseline survey: Type 1, Type 1 additional, or Type 2 survey. The 2nd period survey was conducted in the same manner as the Type 2 survey, which was based on the community support center (CSC). RESULTS: In Miyagi Prefecture, 29,383 (57.7%) of 50,967 participants participated in the 2nd period survey. The participation rate among individuals who had visited the CSC was approximately 80%. Although some factors differed depending on the participation type in the baseline survey, the 2nd period survey respondents in the Type 1 and Type 2 survey groups at baseline had similar traits. CONCLUSIONS: The 2nd period survey of the TMM CommCohort Study provided detailed follow-up information. Following up on the health conditions of the participants will clarify the long-term effects of disasters and contribute to personalized prevention.

Reduced antiviral seropositivity among patients with inflammatory bowel disease treated with immunosuppressive agents.

BACKGROUND: Although live-attenuated vaccines are contraindicated under immunosuppression, the immune status of patients with inflammatory bowel disease (IBD) has not been fully assessed prior to immunosuppressive therapy. AIMS: To investigate antiviral serostatus against viruses requiring live vaccines for prevention in IBD patients undergoing immunosuppressive therapy. METHODS: This multicenter study included IBD patients who were aged <40 years and were treated with thiopurine monotherapy, molecular-targeted monotherapy, or combination therapy. Gender- and age-matched healthy subjects (HS) living in the same areas were included as control group. Antibody titers against measles, rubella, mumps, and varicella were measured by enzyme-linked immunosorbent assays. RESULTS: A total of 437 IBD patients (163 ulcerative colitis [UC] and 274 Crohn's disease [CD]) and 225 HS were included in the final analysis. Compared with HS, IBD patients had lower seropositivity rates for measles (IBD vs. HS = 83.91% vs. 85.33%), rubella (77.55% vs. 84.89%), mumps (37.50% vs. 37.78%), and varicella (91.26% vs. 96.44%). Gender- and age-adjusted seropositivity rates were lower in UC patients than in both CD patients and HS for measles (UC, CD, and HS = 81.60%, 85.29%, and 85.33%), rubella (76.40%, 78.23%, and 84.89%), mumps (27.16%, 43.70%, and 37.78%), and varicella (90.80%, 91.54%, and 96.44%); the difference was significant for all viruses except measles. Divided by the degree of immunosuppression, there were no significant differences in seropositivity rates among IBD patients. CONCLUSIONS: IBD patients, especially those with UC, exhibit reduced seropositivity rates and may benefit from screening prior to the initiation of immunosuppressive therapy.

Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project.

The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project.

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

A proposal on the first Japanese practical guidance for the return of individual genomic results in research settings.

Large-scale, low-cost genome analysis has become possible with next-generation sequencing technology, which is currently used in research and clinical practice. Many attempts of returning individual genomic results have commenced not only in clinical practice, but also in research settings of several countries. In Japan, the government guidelines include a section on the disclosure of genetic information regarding genome analysis in research. However, no practical guidance for the return of individual genomic results in research settings (ROGRR) currently exists. We propose practical guidance regarding ROGRR in Japan based on extensive research, including a literature review of related previous studies, an examination of the relevant legislation in Japan, and interviews with stakeholders. The guidance we developed consists of "Points to consider" and "Issues for further discussion and consideration." The "Points to consider" were divided into five parts, from preliminary review before discussion of policy, to the actual return and follow-up process, in the order of the assumed ROGRR process. It is anticipated that a situation will arise where numerous research projects will consider ROGRR carefully and realistically in the future, and in the process of drafting such practical guidance, various issues requiring continuous discussion will emerge. The necessities of continuous discussion concerning ROGRR in Japan's context is increasing, particularly in terms of the ethical, legal, and social implications. We believe such discussions and considerations may contribute to creating a new system that will increase availability of personalized medicine and prevention using genetic information, allowing them to become useful to the broader population.

Public Relations and Communication Strategies in Construction of Large-Scale Cohorts and Biobank: Practice in the Tohoku Medical Megabank Project.

The Tohoku Medical Megabank Project was designed as part of the national reconstruction project for addressing the damage from the 2011 Great East Japan Earthquake. It is an integrated project involving the genome cohort study of 150,000 participants, integrated biobank construction, and multi-omics analyses. Public relations and communication activities emerged to be extremely important in the successful development of this project. To gain insights into the contributions of these activities, we divided the public relations and communication activities for the project into three phases based on the situations surrounding the project. Prior to the start of the cohort study (Phase I), a cooperative relationship was established with a focus on concluding cooperation agreements with local governments. Until the participants reached the target number (Phase II), we actively communicated with the media to publicize the project. During the phase in which use of the constructed biobank is promoted (Phase III), for ensuring the industrial utilization of the biobank, visits from the industry are promoted. Throughout the execution of these activities, we explored the best strategies for building relationships with multiple stakeholders like local government, media and industry. By paying attention to these phases that have been changing according to the project's progress, we were able to adapt the strategies and methods of public relations and communication. The success of these activities has enabled the overall project to progress smoothly. We hope that the process of designing our project's public relations and communication activities will be useful for other similar initiatives.

Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project.

In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.

A training and education program for genome medical research coordinators in the genome cohort study of the Tohoku Medical Megabank Organization.

BACKGROUND: Genome cohort studies are used to analyze interactions between genetic and environmental factors, providing valuable information for personalized healthcare. Large-scale and long-term cohort studies require a number of specially trained personnel, of whom those involved in obtaining informed consent play a vital role, especially during the initial phase of such studies. The Japanese Society of Human Genetics (JSHG) previously established a certification system for genome medical research coordinators (GMRCs) responsible for obtaining written consent via face-to-face explanation. Meanwhile, in the Tohoku Medical Megabank Organization (ToMMo), GMRCs are expected to play important roles not only in obtaining informed consent and conducting various assessments, but also in communicating with participants throughout the long-term follow-up. Based on the JSHG program, we therefore developed a specific education and training program for ToMMo GMRCs consisting of 17 lectures, one practical training session on the informed consent procedure, and written and interview examinations. Re-education workshops aimed at self-improvement are also carried out following certification. In this study, we evaluated the education and training program in terms of overall understanding, usefulness, and satisfaction using an anonymous questionnaire. METHODS: An anonymous questionnaire addressing each aspect of the education and training program (understanding, usefulness, and satisfaction) was distributed among 152 qualified ToMMo GMRCs. Responses were received from 94 participants (61.8%). RESULTS: There was a significant association between the level of overall understanding of lectures and medical qualification (nurse or clinical laboratory technologist), but not with age or educational background. The level of understanding and overall usefulness were lower in sessions related to genetics and epidemiology than those dealing with ToMMo practices. In the re-education workshops, GMRCs showed a preference for and hoped to learn more about both background knowledge and research progress in the ToMMo. CONCLUSIONS: The results of our questionnaire suggest that not all ToMMo GMRCs are able to understand everything during the initial education and training program, especially in terms of genomic medicine. Continuous re-education is therefore vital in improving knowledge, skills and motivation, and preparing GMRCs for a specialist role in community-based personalized healthcare.

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals.

Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

Strategic Methods for Recruiting Grandparents: The Tohoku Medical Megabank Birth and Three-Generation Cohort Study.

Involvement of family members, especially grandparents, in genome epidemiological research is important to investigate both genetic and environmental factors of common diseases. The aim of the present study was to establish strategies to obtain enough number of family recruitment, especially focusing on grandparents, for the Tohoku Medical Megabank Birth and Three-Generation Cohort Study. Our main strategies are summarized below. 1) We standardized informed consent process with reference materials to help people understand the consent form, 2) we created an invitation letter to contact family members, and 3) we recruited family members in several settings. To obtain informed consent, we were careful of explaining clearly the complex reasons as well as drawing people's attention. By the end of March 2017, the number of invitation letters distributed to family members through the pregnant women was 23,806, including 18,702 grandparents. Among the grandparents who received invitation letters, 2,935 (15.7%) responded to us. Furthermore, some grandparents were asked to provide informed consent with other family members by staff at maternal clinics or Community Support Centers, and others directly booked Community Support Centers without responding to the invitation letter. Grandparents joined the study anytime during mother's maternal check-ups or delivery. Overall, 8,054 grandparents participated in our birth cohort study. The setting in which most grandparents were recruited was our own facilities. Importantly, both paternal and maternal grandparents more frequently participated in the study if the father also participated. In conclusion, we are able to recruit not only pregnant women but also fathers and grandparents.

Severity of eczema and mental health problems in Japanese schoolchildren: The ToMMo Child Health Study.

BACKGROUND: The association between eczema and mental health problems in schoolchildren has been underexplored. We aimed to investigate this association with the validated questionnaires. METHODS: Of 46,648 invited children, we analyzed 9954 (21.3%) in the 2nd to the 8th grades from the ToMMo Child Health Study conducted in 2014 and 2015, a cross-sectional survey in Miyagi Prefecture, Japan. We defined eczema status as "normal," "mild/moderate," or "severe," based on the presence of persistent flexural eczema and sleep disturbance, according to the International Study of Asthma and Allergies in Childhood (ISAAC) Eczema Symptom Questionnaire. Clinical ranges of Strengths and Difficulties Questionnaire (SDQ) total difficulties scores and four SDQ subcategories of emotional symptoms, conduct problems, hyperactivity/inattention, and peer problems were defined as scores ≥16, ≥5, ≥5, ≥7, and ≥5, respectively. RESULTS: The mean SDQ total difficulties score significantly increased as eczema status worsened (all P ≤ 0.004 for trend). The OR of scores in the clinical range for SDQ total difficulties were 1.51 (95% CI, 1.31-1.74) for mild/moderate eczema and 2.63 (95% CI, 1.91-3.63) for severe eczema (P < 0.001 for trend), adjusted for sex, school grade, current wheeze, and disaster-related factors, using normal eczema as a reference. The association between severity of eczema and four SDQ subcategories showed a similar trend (all P ≤ 0.017 for trend). CONCLUSIONS: We found a significant association between severity of eczema and mental health problems. The presence of eczema was associated with four SDQ subcategories.

Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design.

BACKGROUND: With the goal of realizing genome-based personalized healthcare, we have developed a biobank that integrates personal health, genome, and omics data along with biospecimens donated by volunteers of 150,000. Such a large-scale of data integration involves obvious risks of privacy violation. The research use of personal genome and health information is a topic of global discussion with regard to the protection of privacy while promoting scientific advancement. The present paper reports on our plans, current attempts, and accomplishments in addressing security problems involved in data sharing to ensure donor privacy while promoting scientific advancement. METHODS: Biospecimens and data have been collected in prospective cohort studies with the comprehensive agreement. The sample size of 150,000 participants was required for multiple researches including genome-wide screening of gene by environment interactions, haplotype phasing, and parametric linkage analysis. RESULTS: We established the T ohoku M edical M egabank (TMM) data sharing policy: a privacy protection rule that requires physical, personnel, and technological safeguards against privacy violation regarding the use and sharing of data. The proposed policy refers to that of NCBI and that of the Sanger Institute. The proposed policy classifies shared data according to the strength of re-identification risks. Local committees organized by TMM evaluate re-identification risk and assign a security category to a dataset. Every dataset is stored in an assigned segment of a supercomputer in accordance with its security category. A security manager should be designated to handle all security problems at individual data use locations. The proposed policy requires closed networks and IP-VPN remote connections. CONCLUSION: The mission of the biobank is to distribute biological resources most productively. This mission motivated us to collect biospecimens and health data and simultaneously analyze genome/omics data in-house. The biobank also has the mission of improving the quality and quantity of the contents of the biobank. This motivated us to request users to share the results of their research as feedback to the biobank. The TMM data sharing policy has tackled every security problem originating with the missions. We believe our current implementation to be the best way to protect privacy in data sharing.

The Tohoku Medical Megabank Project: Design and Mission.

The Great East Japan Earthquake (GEJE) and resulting tsunami of March 11, 2011 gave rise to devastating damage on the Pacific coast of the Tohoku region. The Tohoku Medical Megabank Project (TMM), which is being conducted by Tohoku University Tohoku Medical Megabank Organization (ToMMo) and Iwate Medical University Iwate Tohoku Medical Megabank Organization (IMM), has been launched to realize creative reconstruction and to solve medical problems in the aftermath of this disaster. We started two prospective cohort studies in Miyagi and Iwate Prefectures: a population-based adult cohort study, the TMM Community-Based Cohort Study (TMM CommCohort Study), which will recruit 80 000 participants, and a birth and three-generation cohort study, the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study), which will recruit 70 000 participants, including fetuses and their parents, siblings, grandparents, and extended family members. The TMM CommCohort Study will recruit participants from 2013 to 2016 and follow them for at least 5 years. The TMM BirThree Cohort Study will recruit participants from 2013 to 2017 and follow them for at least 4 years. For children, the ToMMo Child Health Study, which adopted a cross-sectional design, was also started in November 2012 in Miyagi Prefecture. An integrated biobank will be constructed based on the two prospective cohort studies, and ToMMo and IMM will investigate the chronic medical impacts of the GEJE. The integrated biobank of TMM consists of health and clinical information, biospecimens, and genome and omics data. The biobank aims to establish a firm basis for personalized healthcare and medicine, mainly for diseases aggravated by the GEJE in the two prefectures. Biospecimens and related information in the biobank will be distributed to the research community. TMM itself will also undertake genomic and omics research. The aims of the genomic studies are: 1) to construct an integrated biobank; 2) to return genomic research results to the participants of the cohort studies, which will lead to the implementation of personalized healthcare and medicine in the affected areas in the near future; and 3) to contribute the development of personalized healthcare and medicine worldwide. Through the activities of TMM, we will clarify how to approach prolonged healthcare problems in areas damaged by large-scale disasters and how useful genomic information is for disease prevention.

Eczema and Asthma Symptoms among Schoolchildren in Coastal and Inland Areas after the 2011 Great East Japan Earthquake: The ToMMo Child Health Study.

After the Great East Japan Earthquake of 2011, there has been a concern about health problems among children. Therefore, we investigated the prevalence of wheeze and eczema symptoms and associated factors among children in areas primarily affected by the disaster. From 2012 to 2014, we distributed the parent-administered questionnaire to 25,198 children in all 233 public schools in the 13 municipalities of Miyagi Prefecture in northeast Japan. A total of 7,155 responses (mean age 10.5 ± 2.2 years) were received (response rate: 28.4%). The prevalence of allergic symptoms according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire in 2nd, 4th, 6th, and 8th graders was 12.4%, 9.9%, 9.3%, and 5.6% for wheeze, and 20.1%, 18.0%, 14.0%, and 12.4% for eczema. In multivariate logistic analysis, younger age, history of hospitalization, and difficulties in children's daily lives as assessed by the Strengths and Difficulties Questionnaire (SDQ), were significantly and consistently associated with both allergic symptoms (both P < 0.05). Living in a coastal municipality was also associated with eczema symptoms (P = 0.0278). The prevalence of eczema symptoms in the 2nd (20.1%) and 8th (12.4%) grades was significantly higher than previously reported in Japan. Living in a coastal municipality was independently associated with eczema symptoms, and psychometric properties were also closely linked to allergic symptoms. These findings are clinically important for understanding the risks of allergic disorders after natural disasters.

Protocol and Research Perspectives of the ToMMo Child Health Study after the 2011 Great East Japan Earthquake.

Residents of areas affected by the Great East Japan Earthquake may suffer from diseases or health problems. We are conducting a cross-sectional study from 2012 to 2015 to investigate and address the health needs of schoolchildren affected by this disaster. In this paper, we describe the protocol and research perspectives of our long-term child health study, and present the results obtained immediately after the disaster. The parent-administered questionnaire includes the International Study of Asthma and Allergies in Childhood questionnaire for asthma and eczema symptoms, the Strengths and Difficulties Questionnaire (SDQ), and a questionnaire on influenza infection and vaccination status. In 2012, we distributed the questionnaire to 3,505 (2nd, 4th, 6th, and 8th graders) in three municipalities located in southern coastal area among the 28 municipalities, and 1,277 (36.4%) returned the completed questionnaire. Mean age was 11.1 ± 2.2 years old. The number of children with symptoms of wheeze and eczema in the past 12 months was 146 (11.4%) and 199 (15.6%), respectively. The SDQ total difficulties score revealed 174 (13.6%) children with some form of difficulty in their daily lives. From May 2011 to April 2012, 195 (15.3%) and 649 (50.8%) children received the influenza vaccination once and twice, respectively, and 532 (41.7%) had suffered from influenza. The prevalence of eczema symptoms or some form of difficulty was higher than the Japanese average. However, careful interpretation was required because of potential self-selection bias from the low response rate. We will continue this study of schoolchildren to provide aggregate findings.

The Health History of First-Degree Relatives' Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.

Stakeholder Perception of the Implementation of Genetic Risk Testing for Twelve Multifactorial Diseases.

Genome-wide association studies have been employed to develop numerous risk prediction models using polygenic risk scores (PRSs) for multifactorial diseases. However, healthcare providers lack confidence in their understanding of PRS risk stratification for multifactorial diseases, which underscores the need to assess the readiness of PRSs for clinical use. To address this issue, we surveyed the perceptions of healthcare providers as stakeholders in the clinical implementation of genetic-based risk prediction for multifactorial diseases. We conducted a web-based study on the need for risk prediction based on genetic information and the appropriate timing of testing for 12 multifactorial diseases. Responses were obtained from 506 stakeholders. Positive perceptions of genetic risk testing were found for adult-onset chronic diseases. As per participant opinion, testing for adult-onset diseases should be performed after the age of 20 years, whereas testing for psychiatric and allergic disorders that manifest during childhood should be performed from birth to 19 years of age. The stakeholders recognized the need for genetic risk testing for diseases that develop in adulthood, believing that the appropriate testing time is after maturity. This study contributes to the discussion on the clinical implementation of the PRS for genetic risk prediction of multifactorial diseases.

Returning individual genomic results to population-based cohort study participants with BRCA1/2 pathogenic variants.

BACKGROUND: Recent advances in human genome research have provided evidence for genotype-phenotype associations, pathogenicity, and clinical actionability of variants and genomic risk prediction of disease. However, the return of individual genomic results to healthy individuals is fraught with ethical and practical complexity. METHODS: Individual genomic results were returned to BRCA1/2 pathogenic variant (PV) carriers of the Tohoku Medical Megabank cohort study participants with an information on hereditary breast and ovarian cancer syndrome (HBOC). One hundred and eighty participants, including 9 BRCA1/2 PV carriers, were asked about their willingness to receive individual genomic results, without revealing the gene name and related disorders, prior to the study. Of the 142 participants who responded, 103 showed willingness to know their genomic information. Each of the six BRCA1/2 PV carriers who consented to participate in the study received information about HBOC in person and underwent validation testing with blood resampling. RESULTS: All participants were in their 60s or 70s; of the four females and two males, two had a history of breast cancer and five had a family history of HBOC-related cancers. All participants appreciated the information, without remarkable negative psychological impact of the return, and intended to undergo clinical risk surveillance. Five participants were accompanied by family members while receiving the results, and three first-degree female relatives wished to undergo genomic testing at the hospital. CONCLUSIONS: Our results suggest that returning actionable genomic information to participants in a population-based genome cohort study is beneficial for preventing or providing early-stage intervention for associated diseases.

Association Between Olfactory Test Data with Multiple Levels of Odor Intensity and Suspected Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND: Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. OBJECTIVE: We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. METHODS: The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. RESULTS: We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60-74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p = 0.024). CONCLUSIONS: The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60-74 years.

Comprehensive evaluation of machine learning algorithms for predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability.

Introduction: Perinatal women tend to have difficulties with sleep along with autonomic characteristics. This study aimed to identify a machine learning algorithm capable of achieving high accuracy in predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability (HRV). Methods: Nine HRV indicators (features) and sleep-wake conditions of 154 pregnant women were measured for 1 week, from the 23rd to the 32nd weeks of pregnancy. Ten machine learning and three deep learning methods were applied to predict three types of sleep-wake conditions (wake, shallow sleep, and deep sleep). In addition, the prediction of four conditions, in which the wake conditions before and after sleep were differentiated-shallow sleep, deep sleep, and the two types of wake conditions-was also tested. Results and Discussion: In the test for predicting three types of sleep-wake conditions, most of the algorithms, except for Naïve Bayes, showed higher areas under the curve (AUCs; 0.82-0.88) and accuracy (0.78-0.81). The test using four types of sleep-wake conditions with differentiation between the wake conditions before and after sleep also resulted in successful prediction by the gated recurrent unit with the highest AUC (0.86) and accuracy (0.79). Among the nine features, seven made major contributions to predicting sleep-wake conditions. Among the seven features, "the number of interval differences of successive RR intervals greater than 50 ms (NN50)" and "the proportion dividing NN50 by the total number of RR intervals (pNN50)" were useful to predict sleep-wake conditions unique to pregnancy. These findings suggest alterations in the vagal tone system specific to pregnancy.