Factors Associated With the Prevalence of Irritable Bowel Syndrome: The Miyagi Part of the Tohoku Medical Megabank Project Community-based Cohort Study.

Background/Aims: The objective of this research is to examine factors related to irritable bowel syndrome (IBS) prevalence in a large population-based study. Methods: A cross-sectional study was conducted with participants in the Miyagi part of the Tohoku Medical Megabank Project Community-Based cohort study who completed the Rome II Modular Questionnaire. Multivariate odds ratios (ORs) for the presence of IBS and 95% confidence intervals (95% CIs) for the reference group were calculated for each factor. Additionally, a stratified analysis was performed by sex and age group (20-49 years, 50-64 years, and ≥ 65 years). Results: Among 16 252 participants, 3025 (18.6%) had IBS, comprising 750 men (15.5%) and 2275 women (19.9%). Multivariate ORs for the presence of IBS decreased significantly with each year of age (OR, 0.98; 95% CI, 0.98-0.99). Moreover, compared with the reference group, ORs for the presence of IBS were significantly higher in individuals whose home was partially damaged by the Great East Japan Earthquake, those with < 16 years of education, those who spent less time walking, those with high perceived stress (1.77, 1.57-2.01), those with high psychological distress (1.58, 1.36-1.82), and those with high symptoms of depression (1.76, 1.60-1.94). In stratified analyses, a significant relationship was found between psychological factors and IBS prevalence in all sex and age groups. Conclusions: This large cross-sectional population-based cohort study identified several factors associated with IBS prevalence. Psychological factors were significantly associated with IBS prevalence across all age groups and sexes.

Low Hemoglobin Level and Elevated Inflammatory Hematological Ratios Associated With Depression and Sleep Disturbance.

BACKGROUND: The relationship between blood cell profiles, including hemoglobin (Hb) levels and inflammatory hematological ratios, and mental health problems currently remains unclear. AIM: This study aimed to investigate the relationship between blood cell profiles and mental health issues, including depressive state and sleep disturbance, while adjusting for potential demographic confounders. METHODOLOGY: This retrospective, cross-sectional, observational study used a population-based medical database from the Tohoku Medical Megabank Project with more than 60,000 volunteers. Data on age, sex, daily tobacco use, body mass index, and self-reported scores on the Kessler Psychological Distress Scale (K6), Athens Insomnia Scale (AIS), and the Center for Epidemiologic Studies Depression Scale (CES-D) were collected. RESULTS: A total of 62,796 volunteers (23,663 males and 39,133 females), aged ≥20 years at the time of the blood test, agreed to participate in this study. Among the evaluated blood cell profiles, Hb, hematocrit, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were significantly correlated with the K6, AIS, and CES-D scores, with strong statistical significance (p<0.0001 for all) in bivariate correlation analyses. A significant adjusted odds ratio (aOR) of the Hb level for elevated CES-D scores (aOR=0.965 [95% CI: 0.949-0.981], p<0.0001) was confirmed after adjusting for demographic data and daily tobacco use using a logistic regression model. Sensitivity analyses revealed that these associations existed in both males and females but were more prominent in the former. In male participants, a low Hb level was significantly associated with an elevated AIS score. The evaluated inflammatory hematological ratios, including NLR, PLR, and monocyte-to-lymphocyte ratio (MLR), also showed significant aORs with the K6, AIS, and CES-D scores after adjusting for demographic background. CONCLUSION: Low Hb levels and elevated inflammatory hematological ratios (NLR, MLR, and PLR) were associated with depressive state and sleep disturbances in the general population.

Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women.

Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

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.

Relationships of Fat Mass Index and Fat-Free Mass Index with Low-Density Lipoprotein Cholesterol Levels in the Tohoku Medical Megabank Community-Based Cohort Study.

AIMS: Although fat mass (FM) and fat-free mass (FFM) have an impact on lipid metabolism, the relationship between different body composition phenotypes and lipid profiles is still unclear. By dividing the FM and FFM by the square of the height, respectively, the f at mass index (FMI) and fat-free mass index (FFMI) can be used to determine the variations in body composition. This study aimed to investigate the relationship of combined FMI and FFMI with low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This cross-sectional study comprised 5,116 men and 13,630 women without cardiovascular disease and without treatment for hypertension, and diabetes. Following sex-specific quartile classification, FMI and FFMI were combined into 16 groups. Elevated LDL-C levels were defined as LDL-C ≥ 140 mg/dL and/or dyslipidemia treatment. Multivariable logistic regression models were used to examine the relationships between combined FMI and FFMI and elevated LDL-C levels. RESULTS: Overall, elevated LDL-C levels were found in 1,538 (30.1%) men and 5,434 (39.9%) women. In all FFMI subgroups, a higher FMI was associated with elevated LDL-C levels. Conversely, FFMI was inversely associated with elevated LDL-C levels in most FMI subgroups. Furthermore, the groups with the highest FMI and lowest FFMI had higher odds ratios for elevated LDL-C levels than those with the lowest FMI and highest FFMI. CONCLUSIONS: Regardless of FFMI, FMI was positively associated with elevated LDL-C levels. Conversely, in the majority of FMI subgroups, FFMI was inversely associated with elevated LDL-C levels.

Relationship between traditional risk factors for hypertension and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study.

Risk factors for hypertension have been emphasized in the Japanese Society of Hypertension Guidelines for the Management of Hypertension. However, large-scale studies on the association of smoking, potassium excretion, and gamma-glutamyl transferase level with BP in the Japanese population are limited. We conducted a cross-sectional study to examine the association between hypertension risk factors and systolic blood pressure in the Tohoku Medical Megabank Community-based Cohort Study (23,446 men and 38,921 women aged ≥20 years). A model adjusted for age, body mass index, smoking status, drinking status, estimated daily salt intake, potassium excretion, (or urinary sodium-to-potassium ratio), gamma-glutamyl transferase, physical activity, education level, status of damage to homes during the Great East Japan Earthquake, and residential areas was used. The average age and systolic blood pressure were 62.5 (10.3) years for men and 59.6 (11.3) years for women, 128.9 (16.7) mmHg for men and 124.7 (17.5) mmHg for women, respectively. Body mass index estimated daily salt intake, urinary sodium-to-potassium ratio and gamma-glutamyl transferase levels were positively associated with systolic blood pressure. Compared with never-drinkers, current drinkers who consumed 23-45 g/day and ≥46.0 g/day had significantly increased systolic blood pressure. Conversely, current smokers (1-10 cigarettes/day and 11-20 cigarettes/day) were inversely associated with systolic blood pressure compared to never-smokers. Overall, systolic blood pressure was associated with gamma-glutamyl transferase and hypertension risk factors, including body mass index, alcohol consumption, estimated daily salt intake, urinary sodium-to-potassium ratio, and potassium excretion. Our findings support the notion that lifestyle modifications should be attempted to prevent hypertension.

The association between depressive symptoms and masked hypertension in participants with normotension measured at research center.

Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study.

AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

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.

Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study.

BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.

Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background.

The Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study (TMM Brain MRI Study) was established to collect multimodal information through neuroimaging and neuropsychological assessments to evaluate the cognitive function and mental health of residents who experienced the Great East Japan Earthquake (GEJE) and associated tsunami. The study also aimed to promote advances in personalized healthcare and medicine related to mental health and cognitive function among the general population. We recruited participants for the first (baseline) survey starting in July 2014, enrolling individuals who were participating in either the TMM Community-Based Cohort Study (TMM CommCohort Study) or the TMM Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). We collected multiple magnetic resonance imaging (MRI) sequences, including 3D T1-weighted sequences, magnetic resonance angiography (MRA), diffusion tensor imaging (DTI), pseudo-continuous arterial spin labeling (pCASL), and three-dimensional fluid-attenuated inversion recovery (FLAIR) sequences. To assess neuropsychological status, we used both questionnaire- and interview-based rating scales. The former assessments included the Tri-axial Coping Scale, Impact of Event Scale in Japanese, Profile of Mood States, and 15-item Depression, Anxiety, and Stress Scale, whereas the latter assessments included the Mini-Mental State Examination, Japanese version. A total of 12,164 individuals were recruited for the first (baseline) survey, including those unable to complete all assessments. In parallel, we returned the MRI results to the participants and subsequently shared the MRI data through the TMM Biobank. At present, the second (first follow-up) survey of the study started in October 2019 is underway. In this study, we established a large and comprehensive database that included robust neuroimaging data as well as psychological and cognitive assessment data. In combination with genomic and omics data already contained in the TMM Biobank database, these data could provide new insights into the relationships of pathological processes with neuropsychological disorders, including age-related cognitive impairment.

Association of Central Blood Pressure and Carotid Intima Media Thickness with New-Onset Hypertension in People with High Normal Blood Pressure.

AIM: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. METHODS: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP ＜90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. RESULTS: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5±0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p＜0.001). Subgroup analysis according to age (＜60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. CONCLUSIONS: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

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.

Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression.

AIM: Previous studies based on a relatively limited number of subjects have indicated potential associations between plasma cytokine concentrations in perinatal women and postpartum depression (PPD). This report aimed to examine alterations in cytokine levels during pregnancy and after delivery by measuring nine cytokines in prenatal and postnatal plasma samples in a large cohort. METHODS: A nested, case-control study was conducted using plasma samples from 247 women with PPD (Edinburgh Postnatal Depression Scale: EPDS ≥9) and 243 age-matched control (EPDS ≤2) women from among perinatal women who participated in the Tohoku Medical Megabank three-generation cohort. Concentrations of nine plasma cytokines (IFN-γ, IL-1ß, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, and TNF-α) in plasma collected at the time of enrollment during pregnancy and 1 month after delivery were determined using an immunoassay kit. RESULTS: Cross-sectional comparisons of cytokine levels during pregnancy and after delivery indicated that the PPD group maintained significantly lower plasma IL-4 levels during pregnancy and after delivery than the control group, and that plasma IL-4 levels decreased significantly during pregnancy regardless of PPD status. Plasma IL-10 levels were significantly higher during pregnancy than after delivery only among healthy controls, and plasma IL-10 levels were significantly higher in the control group than in the PPD group. Moreover, IFN-γ, IL-6, IL-12p40, and TNF-α levels were significantly lower during pregnancy compared with after delivery regardless of PPD status. CONCLUSIONS: These results suggest a potential protective effect of the anti-inflammatory cytokines IL-4 and IL-10 during pregnancy against the development of PPD.

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.

Effect of Nicotinamide Mononucleotide Concentration in Human Milk on Neurodevelopmental Outcome: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

(1) Background: Breast milk is the only source of nutrition for breastfed infants, but few studies have examined the relationship between breast milk micronutrients and infant neurodevelopmental outcome in exclusively breastfed infants. The aim of this study was to characterize the association between nicotinamide adenine dinucleotide (NAD)-related compounds in the breast milk of Japanese subjects and infant neurodevelopmental outcome. (2) Methods: A total of 150 mother-child pairs were randomly selected from the three-generation cohort of the Tohoku Medical Megabank in Japan. Infants were exclusively breastfed for up to 6 months. Breast milk was collected at 1 month postpartum, and the quantity of NAD-related substances in the breast milk was quantified. The mothers also completed developmental questionnaires at 6, 12, and 24 months. The relationship between the concentration of NAD-related substances in breast milk and developmental indicators was evaluated via ordinal logistic regression analysis. (3) Results: Nicotinamide mononucleotide (NMN) was quantified as the major NAD precursor in breast milk. The median amount of NMN in the breast milk was 9.2 µM. The NMN concentration in breast milk was the only NAD-related substance in breast milk that showed a significant positive correlation with neurodevelopmental outcome in infants at 24 months. (4) Conclusions: The results suggest that NMN in human milk may be an important nutrient for early childhood development.

Plasma metabolic disturbances during pregnancy and postpartum in women with depression.

Examining plasma metabolic profiling during pregnancy and postpartum could help clinicians understand the risk factors for postpartum depression (PPD) development. This analysis targeted paired plasma metabolites in mid-late gestational and 1 month postpartum periods in women with (n = 209) or without (n = 222) PPD. Gas chromatogram-mass spectrometry was used to analyze plasma metabolites at these two time points. Among the 170 objected plasma metabolites, principal component analysis distinguished pregnancy and postpartum metabolites but failed to discriminate women with and without PPD. Compared to women without PPD, those with PPD exhibited 37 metabolites with disparate changes during pregnancy and the 1-month postpartum period and an enriched citrate cycle. Machine learning and multivariate statistical analysis identified two or three compounds that could be potential biomarkers for PPD prediction during pregnancy. Our findings suggest metabolic disturbances in women with depression and may help to elucidate metabolic processes associated with PPD development.

Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study.

Purpose: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data. Design: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs). Participants: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined. Methods: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis. Main Outcome Measures: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages. Results: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci. Conclusions: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

Visualization of estimated prevalence of CES-D positivity accounting for background factors and AIS scores.

Development of methods for population screening is necessary to improve the efficiency of secondary prevention of diseases. Until now, a common cutoff has been used for all people in the data set. However, if big data for health information can be used to modify individual cutoffs according to background factors, it may avoid wasting medical resources. Here we show that the estimated prevalence of the Center for Epidemiologic Studies Depression Scale positivity can be visualized by a heatmap using background factors from epidemiological big data and scores from the Athens Insomnia Scale. We also show that cutoffs based on the estimated prevalence can be used to decrease the number of people screened without decreasing the number of prevalent cases detected. Since this method can be applied to the screening of different outcomes, we believe our work can contribute to the development of efficient screening methods for various diseases.