Exposure to ambient temperature and heat index in relation to DNA methylation age: A population-based study in Taiwan.

BACKGROUND: Climate change caused an increase in ambient temperature in the past decades. Exposure to high ambient temperature could result in biological aging, but relevant studies in a warm environment were lacking. We aimed to study the exposure effects of ambient temperature and heat index (HI) in relation to age acceleration in Taiwan, a subtropical island in Asia. METHODS: The study included 2,084 participants from Taiwan Biobank. Daily temperature and relative humidity data were collected from weather monitoring stations. Individual residential exposure was estimated by ordinary kriging. Moving averages of ambient temperature and HI from 1 to 180 days prior to enrollment were calculated to estimate the exposure effects in multiple time periods. Age acceleration was defined as the difference between DNA methylation age and chronological age. DNA methylation age was calculated by the Horvath's, Hannum's, Weidner's, ELOVL2, FHL2, phenotypic (Pheno), Skin & blood, and GrimAge2 (Grim2) DNA methylation age algorithms. Multivariable linear regression models, generalized additive models (GAMs), and distributed lag non-linear models (DLNMs) were conducted to estimate the effects of ambient temperature and HI exposures in relation to age acceleration. RESULTS: Exposure to high ambient temperature and HI were associated with increased age acceleration, and the associations were stronger in prolonged exposure. The heat stress days with maximum HI in caution (80-90°F), extreme caution (90-103°F), danger (103-124°F), and extreme danger (>124°F) were also associated with increased age acceleration, especially in the extreme danger days. Each extreme danger day was associated with 571.38 (95 % CI: 42.63-1100.13), 528.02 (95 % CI: 36.16-1019.87), 43.9 (95 % CI: 0.28-87.52), 16.82 (95 % CI: 2.36-31.28) and 15.52 (95 % CI: 2.17-28.88) days increase in the Horvath's, Hannum's, Weidner's, Pheno, and Skin & blood age acceleration, respectively. CONCLUSION: High ambient temperature and HI may accelerate biological aging.

Immunometabolic features of natural killer cells are associated with infection outcomes in critical illness.

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness.

Model-based hypothesis tests for the causal mediation of semi-competing risks.

Analyzing the causal mediation of semi-competing risks has become important in medical research. Semi-competing risks refers to a scenario wherein an intermediate event may be censored by a primary event but not vice versa. Causal mediation analyses decompose the effect of an exposure on the primary outcome into an indirect (mediation) effect: an effect mediated through a mediator, and a direct effect: an effect not through the mediator. Here we proposed a model-based testing procedure to examine the indirect effect of the exposure on the primary event through the intermediate event. Under the counterfactual outcome framework, we defined a causal mediation effect using counting process. To assess statistical evidence for the mediation effect, we proposed two tests: an intersection-union test (IUT) and a weighted log-rank test (WLR). The test statistic was developed from a semi-parametric estimator of the mediation effect using a Cox proportional hazards model for the primary event and a series of logistic regression models for the intermediate event. We built a connection between the IUT and WLR. Asymptotic properties of the two tests were derived, and the IUT was determined to be a size [Formula: see text] test and statistically more powerful than the WLR. In numerical simulations, both the model-based IUT and WLR can properly adjust for confounding covariates, and the Type I error rates of the proposed methods are well protected, with the IUT being more powerful than the WLR. Our methods demonstrate the strongly significant effects of hepatitis B or C on the risk of liver cancer mediated through liver cirrhosis incidence in a prospective cohort study. The proposed method is also applicable to surrogate endpoint analyses in clinical trials.

Exposure to PM2.5 Metal Constituents and Liver Cancer Risk in REVEAL-HBV.

BACKGROUND: Ambient particulate matter is classified as a human Class 1 carcinogen, and recent studies found a positive relationship between fine particulate matter (PM2.5) and liver cancer. Nevertheless, little is known about which specific metal constituent contributes to the development of liver cancer. OBJECTIVE: To evaluate the association of long-term exposure to metal constituents in PM2.5 with the risk of liver cancer using a Taiwanese cohort study. METHODS: A total of 13,511 Taiwanese participants were recruited from the REVEAL-HBV in 1991-1992. Participants' long-term exposure to eight metal constituents (Ba, Cu, Mn, Sb, Zn, Pb, Ni, and Cd) in PM2.5 was based on ambient measurement in 2002-2006 followed by a land-use regression model for spatial interpolation. We ascertained newly developed liver cancer (ie, hepatocellular carcinoma [HCC]) through data linkage with the Taiwan Cancer Registry and national health death certification in 1991-2014. A Cox proportional hazards model was utilized to assess the association between exposure to PM2.5 metal component and HCC. RESULTS: We identified 322 newly developed HCC with a median follow-up of 23.1 years. Long-term exposure to PM2.5 Cu was positively associated with a risk of liver cancer. The adjusted hazard ratio (HR) was 1.13 (95% confidence interval [CI], 1.02-1.25; P = 0.023) with one unit increment on Cu normalized by PM2.5 mass concentration in the logarithmic scale. The PM2.5 Cu-HCC association remained statistically significant with adjustment for co-exposures to other metal constituents in PM2.5. CONCLUSION: Our findings suggest PM2.5 containing Cu may attribute to the association of PM2.5 exposure with liver cancer.

Genome-wide multimediator analyses using the generalized Berk-Jones statistics with the composite test.

MOTIVATION: Mediation analysis is performed to evaluate the effects of a hypothetical causal mechanism that marks the progression from an exposure, through mediators, to an outcome. In the age of high-throughput technologies, it has become routine to assess numerous potential mechanisms at the genome or proteome scales. Alongside this, the necessity to address issues related to multiple testing has also arisen. In a sparse scenario where only a few genes or proteins are causally involved, conventional methods for assessing mediation effects lose statistical power because the composite null distribution behind this experiment cannot be attained. The power loss hence decreases the true mechanisms identified after multiple testing corrections. To fairly delineate a uniform distribution under the composite null, Huang (Genome-wide analyses of sparse mediation effects under composite null hypotheses. Ann Appl Stat 2019a;13:60-84; AoAS) proposed the composite test to provide adjusted P-values for single-mediator analyses. RESULTS: Our contribution is to extend the method to multimediator analyses, which are commonly encountered in genomic studies and also flexible to various biological interests. Using the generalized Berk-Jones statistics with the composite test, we proposed a multivariate approach that favors dense and diverse mediation effects, a decorrelation approach that favors sparse and consistent effects, and a hybrid approach that captures the edges of both approaches. Our analysis suite has been implemented as an R package MACtest. The utility is demonstrated by analyzing the lung adenocarcinoma datasets from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. We further investigate the genes and networks whose expression may be regulated by smoking-induced epigenetic aberrations. AVAILABILITY AND IMPLEMENTATION: An R package MACtest is available on https://github.com/roqe/MACtest.

Unified semicompeting risks analysis of hepatitis natural history through mediation modeling.

Natural history of hepatitis B or C is comprised of multiple milestones such as liver cirrhosis and liver cancer. To fully characterize its natural course, semicompeting risks represent a common problem where liver cirrhosis and liver cancer are both of interest, but only the former may be censored by the latter. Copula, frailty and multistate models serve as well-established analytics for semicompeting risks. Here, we cast the semicompeting risks in a mediation framework, with liver cirrhosis as a mediator and liver cancer as an outcome. We define the indirect and direct effects as the effects of an exposure on the liver cancer incidence mediated and not mediated through liver cirrhosis, respectively. With the estimands derived as conditional probabilities, we derive respective expressions under the copula, frailty, and multistate models. Next, we propose estimators based on nonparametric maximum likelihood or U-statistics and establish their asymptotic results. Numerical studies demonstrate that the efficiency of copula models leads to potential bias due to model misspecification. Moreover, the robustness of frailty models is accompanied by a loss in efficiency, and multistate models balance the efficiency and robustness. We demonstrate the utility of the proposed methods by a hepatitis study, showing that hepatitis B and C lead to a higher incidence of liver cancer by increasing liver cirrhosis incidence. Thus, mediation modeling provides a unified framework that accommodates various semicompeting risks models.

Corrigendum: Systolic blood pressure as the mediator of the effect of early menarche on the risk of coronary artery disease: A Mendelian randomization study.

[This corrects the article DOI: 10.3389/fcvm.2022.1023355.].

Mediation and instrumental variable analyses for vaccine-induced antibody titer against influenza B.

OBJECTIVE: Immune correlate analyses for vaccine trials have been applied to investigate associations of vaccine efficacy and surrogate markers such as vaccine-induced antibodies. However, the role of antibody as a surrogate marker in predicting the outcome can vary by time, and surrogate-outcome confounding may have resulted in bias even in randomized trials. We provide a framework for surrogate marker assessment to address the aforementioned issues. STUDY DESIGN AND SETTING: We reanalyzed the vaccine randomized trial for influenza B. We conducted a mediation analysis that enables estimation of vaccine efficacy, mediation effects and proportion of mediation on disease probabilities at various follow-up times. We proposed instrumental variable (IV) analyses with randomized vaccination as an IV accounting for potential unmeasured confounding. RESULTS: The mediation effect of vaccine efficacy by hemagglutination inhibition (HAI) titer was significantly protective at 181 days after vaccination: 63.2% [95% confidence interval, (CI) = (39.9%, 82.0%)], and HAI titer explained 61.1% [95% CI = (36.7%, 96.2%)] of the protective effect of vaccination. CONCLUSIONS: Most of vaccine efficacy is mediated by HAI titer, particularly in children 10 years and older. Our contribution is to provide causal analytics for the role of surrogate marker with weaker assumptions regarding surrogate-disease causation.

Hypertension as a Novel Link for Shared Heritability in Age at Menarche and Cardiometabolic Traits.

CONTEXT: Extremely early age at menarche, also called precocious puberty, has been associated with various cardiometabolic traits, but their shared heritability remains unclear. OBJECTIVES: This work aimed to identify new shared genetic variants and their pathways for age at menarche and cardiometabolic traits and to investigate the influence of central precocious puberty on childhood cardiometabolic traits. METHODS: Using the conjunction false discovery rate method, this study analyzed genome-wide association study data from the menarche-cardiometabolic traits among 59 655 females of Taiwanese ancestry and systemically investigated pleiotropy between age at menarche and cardiometabolic traits. To support the novel hypertension link, we used the Taiwan Puberty Longitudinal Study (TPLS) to investigate the influence of precocious puberty on childhood cardiometabolic traits. RESULTS: We discovered 27 novel loci, with an overlap between age at menarche and cardiometabolic traits, including body fat and blood pressure. Among the novel genes discovered, SEC16B, CSK, CYP1A1, FTO, and USB1 are within a protein interaction network with known cardiometabolic genes, including traits for obesity and hypertension. These loci were confirmed through demonstration of significant changes in the methylation or expression levels of neighboring genes. Moreover, the TPLS provided evidence regarding a 2-fold higher risk of early-onset hypertension that occurred in girls with central precocious puberty. CONCLUSION: Our study highlights the usefulness of cross-trait analyses for identifying shared etiology between age at menarche and cardiometabolic traits, especially early-onset hypertension. The menarche-related loci may contribute to early-onset hypertension through endocrinological pathways.

Associations of polygenic risks, depression, and obesity-related traits in Taiwan Biobank.

BACKGROUND: The comorbidity of obesity and major depressive disorder (MDD) may be attributable to a bidirectional relationship and shared genetic influence. We aimed to examine the polygenic associations between obesity and MDD and to characterize their corresponding impacts on the obesity mechanism. METHODS: Genome-wide genotyping was available in 106,604 unrelated individuals from Taiwan Biobank. Polygenic risk score (PRS) for body mass index (BMI) and MDD was derived to evaluate their effects on obesity-related traits. Stratified analyses were performed for the modified effect of depression on the polygenic associations. RESULTS: The MDD PRS was positively associated with waistline (beta in per SD increase in PRS = 0.12), hipline (beta = 0.08), waist-hip ratio (WHR) (beta = 0.05), body fat rate (beta = 0.08), BMI (beta = 0.05), overweight (OR = 1.02 for BMI ≥ 25), and obesity (OR = 1.05 for BMI ≥ 30). For the synergism between depression and BMI PRS, the presence of active depression symptoms defined by the PHQ-4 (p for interaction < 0.05 for waistline, WHR, and BMI) was more salient than lifetime MDD. LIMITATIONS: Limitations include recall bias for MDD due to a retrospective self-reporting questionnaire, a low response rate of the PHQ-4 for evaluating active psychological symptoms, and limited generalizability to non-Taiwanese ancestries. CONCLUSIONS: The shared genetic etiology of obesity and depression was demonstrated. The amplified effect of BMI polygenic effect on obesity for individuals with active depressive symptoms was also characterized. The study may be helpful for designing public health interventions to reduce the disease burden caused by obesity and depression.

Mediators linking obesity to childhood asthma.

BACKGROUND: Obesity and asthma are highly associated, but the mechanisms underlying the association remain unknown. We examined five mediators linking obesity with childhood asthma: (1) pulmonary function impairment, (2) airway inflammation, (3) physical fitness, (4) sleep-disordered breathing (SDB), and (5) early puberty. METHODS: A Mendelian randomization (MR) study with mediation analysis of data obtained from 5965 children as part of the Taiwan Children Health Study. Observational analysis, MR two-stage least-squares method, and MR sensitivity analysis were carried out to investigate each causal pathway. Prospective cohort analyses were used to strengthen the findings. RESULTS: The increased asthma risk associated with obesity was found to be mostly mediated through impaired pulmonary function, low physical fitness, and early puberty. In the MR analysis, body mass index was negatively associated with FEV1/FVC and physical fitness index (ß = -2.17 and -0.71; 95% CI, -3.92 to -0.42 and -1.30 to -0.13, respectively) and positively associated with early puberty (OR, 1.09; 95% CI, 1.02-1.17). High FEV1/FVC and physical fitness index reduced asthma risk (OR, 0.98 and 0.93; 95% CI, 0.97-0.99 and 0.88-0.98, respectively), whereas SDB and early puberty increased the risk of asthma (OR, 1.03 and 1.22; 95% CI, 1.01-1.05 and 1.05-1.42, respectively). Temporal causality was strengthened in prospective cohort analyses. The three main mediators were low physical fitness, impaired pulmonary function, and early puberty, with mediation proportions of 73.76%, 61.63%, and 27.66%, respectively. CONCLUSIONS: Interventions promoting physical fitness and pulmonary function might effectively reduce obesity-induced asthma risk.

Mechanism and modeling of human disease-associated near-exon intronic variants that perturb RNA splicing.

It is estimated that 10%-30% of disease-associated genetic variants affect splicing. Splicing variants may generate deleteriously altered gene product and are potential therapeutic targets. However, systematic diagnosis or prediction of splicing variants is yet to be established, especially for the near-exon intronic splice region. The major challenge lies in the redundant and ill-defined branch sites and other splicing motifs therein. Here, we carried out unbiased massively parallel splicing assays on 5,307 disease-associated variants that overlapped with branch sites and collected 5,884 variants across the 5' splice region. We found that strong splice sites and exonic features preserve splicing from intronic sequence variation. Whereas the splice-altering mechanism of the 3' intronic variants is complex, that of the 5' is mainly splice-site destruction. Statistical learning combined with these molecular features allows precise prediction of altered splicing from an intronic variant. This statistical model provides the identity and ranking of biological features that determine splicing, which serves as transferable knowledge and out-performs the benchmarking predictive tool. Moreover, we demonstrated that intronic splicing variants may associate with disease risks in the human population. Our study elucidates the mechanism of splicing response of intronic variants, which classify disease-associated splicing variants for the promise of precision medicine.

Effectiveness of entecavir vs tenofovir disoproxil fumarate for functional cure of chronic hepatitis B in an international cohort.

INTRODUCTION: Both entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line therapies for chronic hepatitis B (CHB), but their comparative effectiveness with regards to hepatitis B surface antigen (HBsAg) seroclearance remains unclear. METHODS: This international multicenter cohort study enrolled 7697 treatment-naïve CHB patients (median age 50 years; male 66.75%) initiated on either ETV (n = 5430) or TDF (n = 2267) without baseline malignancy or immunosuppression from 23 centers across 10 countries or regions. Patients were observed for HBsAg seroclearance until death, loss to follow-up, or treatment discontinuation or switching. The incidences of HBsAg seroclearance were adjusted for competing mortality and compared between ETV and TDF cohorts with inverse probability of treatment weighting (IPTW) and also by multivariable regression analysis. RESULTS: The study population was followed up for a median duration of 56.1 months with 36,929 11 person-years of observation. HBsAg seroclearance occurred in 70 ETV-treated and 21 TDF-treated patients, yielding 8-year cumulative incidence of 1.69% (95% confidence interval [CI] 1.32-2.17) for ETV and 1.34% (95% CI 0.85-2.10%), for TDF (p = 0.58). In the IPTW analysis with the two study cohorts more balanced in background covariates, the age-adjusted hazard ratio (HR) of TDF versus ETV for HBsAg seroclearance was 0.91 (95% CI 0.50-1.64; p = 0.75). Furthermore, there was no significant difference between the two medications in the multivariable competing risk regression model (adjusted sub-distributional HR 0.92 for TDF vs. ETV; 95% CI 0.56-1.53; p = 0.76). CONCLUSIONS: ETV and TDF did not differ significantly in the incidence of HBsAg seroclearance, which rarely occurred with either regimen.

Assisted Reproductive Technology and Risk of Childhood Cancers.

Importance: The number of children born through the use of assisted reproductive technology (ART) has been increasing. These children may have higher risks for epigenetic alteration and adverse perinatal outcomes, which may be associated with childhood cancers. Objective: To determine the associations between different modes of conception and childhood cancers and potential mediation by preterm birth and low birth weight. Design, Setting, and Participants: This nationwide, population-based cohort study included registry data from 2 308 016 eligible parents-child triads in Taiwan from January 1, 2004, to December 31, 2017. A total of 1880 children with incident childhood cancer were identified. Data were analyzed between September 1, 2020, and June 30, 2022. Exposure: Mode of conception, defined as (1) natural conception, (2) subfertility and non-ART (ie, infertility diagnosis but no ART-facilitated conception), or (3) ART (ie, infertility diagnosis and ART-facilitated conception). Main Outcomes and Measures: Diagnosis of childhood cancer according to the International Classification of Childhood Cancers, Third Edition. Results: The mean (SD) paternal and maternal ages were 33.28 (5.07) and 30.83 (4.56) years, respectively. Of the 2 308 016 children, 52.06% were boys, 8.16% were born preterm, and 7.38% had low birth weight. During 14.9 million person-years of follow-up (median, 6 years [IQR, 3-10 years]), ART conception was associated with an increased risk of any type of childhood cancers compared with natural conception (hazard ratio, 1.58; 95% CI, 1.17-2.12) and subfertility with non-ART conception (hazard ratio, 1.42; 95% CI, 1.04-1.95). The increased cancer risk of children conceived with ART was mainly owing to leukemia and hepatic tumor. The increased cancer risk associated with ART conception was not mediated by preterm birth or low birth weight. Conclusions and Relevance: In this cohort study, children conceived via ART had a higher risk of childhood cancers than those conceived naturally and those born to parents with an infertility diagnosis did not use ART. The increased risk could not be explained by preterm birth or low birth weight.

Path-specific effects in the presence of a survival outcome and causally ordered multiple mediators with application to genomic data.

Causal multimediation analysis (i.e. the causal mediation analysis with multiple mediators) is critical for understanding the effectiveness of interventions, especially in medical research. Deriving the path-specific effects of exposure on the outcome through a set of mediators can provide detail about the causal mechanism of interest However, existing models are usually restricted to partial decomposition, which can only be used to evaluate the cumulative effect of several paths. In genetics studies, partial decomposition fails to reflect the real causal effects mediated by genes, especially in complex gene regulatory networks. Moreover, because of the lack of a generalized identification procedure, the current multimediation analysis cannot be applied to the estimation of path-specific effects for any number of mediators. In this study, we derive the interventional analogs of path-specific effect for complete decomposition to address the difficulty of nonidentifiability. On the basis of two survival models of the outcome, we derive the generalized analytic forms for interventional analogs of path-specific effects by assuming the normal distributions of mediators. We apply the new methodology to investigate the causal mechanism of signature genes in lung cancer based on the cell cycle pathway, and the results clarify the gene pathway in cancer.

Associations between prenatal exposure to perfluoroalkyl substances, hypomethylation of MEST imprinted gene and birth outcomes.

Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted ß range: -1.56, -2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was -93.2 (95% CI = -170.5, -17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.

Why does mode of conception affect early breastfeeding outcomes? A retrospective cohort study.

INTRODUCTION: It is uncertain whether Assisted Reproductive Technology (ART) is associated with an increased risk of poor breastfeeding outcomes and what could be possible mechanisms. This study aimed to examine the effect of mode of conception on breastfeeding outcomes during the first two months postpartum and identify the potential mediating pathways for this relationship. METHODS: A retrospective cohort study was conducted in a sample of 3,565 women with live births. Participants were classified by mode of conception as follows: fertile women who conceived naturally (fertile women; n = 2,857), women with infertility who conceived naturally (sub-fertile women; n = 483), and women with infertility who conceived through ART (women with infertility; n = 310). The infant-feeding patterns were assessed with four-time points before two months postpartum. Binary and multinomial logistic regression and causal mediation analyses were performed. RESULTS: The rates of breastfeeding initiation and discontinuation across modes of conception were similar. However, infertile and sub-fertile women had 37% (95% CI 1.02, 1.83) and 56% (95% CI 1.06, 2.27) increased risks of introducing formula before the first week postpartum, respectively, and 35% (95% CI 1.01, 1.82) and 52% (95% CI 1.04, 2.24) higher risks of exclusive breastfeeding for less than one week, respectively, compared to fertile women. The relationships were mainly mediated through multiple gestation and admission to neonatal/pediatric intensive care units (NICU/PICU; proportions of mediation were over 50%). The effects of mode of conception on breastfeeding outcomes became not significant in cases of singleton birth. CONCLUSIONS: Sub-fertile women and women with infertility intended to breastfeed but experienced higher perinatal risks in the early postpartum period. Multiple gestation and admission to NICU/PICU forced them to introduce formula earlier than preferred, thus leading to a shorter duration of exclusive breastfeeding. Single embryo transfer policy and breastfeeding support in NICU/PICU could help those women achieve positive early breastfeeding outcomes.

Familial aggregation and shared genetic loading for major psychiatric disorders and type 2 diabetes.

AIMS/HYPOTHESIS: Psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BPD), are highly comorbid with type 2 diabetes. However, the mechanisms underlying such comorbidity are understudied. This study explored the familial aggregation of common psychiatric disorders and type 2 diabetes by testing family history association, and investigated the shared genetic loading between them by testing the polygenic risk score (PRS) association. METHODS: A total of 105,184 participants were recruited from the Taiwan Biobank, and genome-wide genotyping data were available for 95,238 participants. The Psychiatric Genomics Consortium-derived PRS for SCZ, MDD and BPD was calculated. Logistic regression was used to estimate the OR with CIs between a family history of SCZ/MDD/BPD and a family history of type 2 diabetes, and between the PRS and the risk of type 2 diabetes. RESULTS: A family history of type 2 diabetes was associated with a family history of SCZ (OR 1.23, 95% CI 1.08, 1.40), MDD (OR 1.19, 95% CI 1.13, 1.26) and BPD (OR 1.26, 95% CI 1.15, 1.39). Compared with paternal type 2 diabetes, maternal type 2 diabetes was associated with a higher risk of a family history of SCZ. SCZ PRS was negatively associated with type 2 diabetes in women (OR 0.92, 95% CI 0.88, 0.97), but not in men; the effect of SCZ PRS reduced after adjusting for BMI. MDD PRS was positively associated with type 2 diabetes (OR 1.04, 95% CI 1.00, 1.07); the effect of MDD PRS reduced after adjusting for BMI or smoking. BPD PRS was not associated with type 2 diabetes. CONCLUSIONS/INTERPRETATION: The comorbidity of type 2 diabetes with psychiatric disorders may be explained by shared familial factors. The shared polygenic loading between MDD and type 2 diabetes implies not only pleiotropy but also a shared genetic aetiology for the mechanism behind the comorbidity. The negative correlation between polygenic loading for SCZ and type 2 diabetes implies the role of environmental factors.

Hypothesis test for causal mediation of time-to-event mediator and outcome.

Hepatitis B has been a well-documented risk factor of liver cancer and mortality. To what extent hepatitis B affects mortality through increasing liver cancer incidence is of research interest and remains to be studied. We formulate the research question as a hypothesis testing problem of causal mediation where both the mediator and the outcome are time-to-event variables. The problem is closely related to semicompeting risks because time to the intermediate event may be censored by an occurrence of the outcome. We propose two hypothesis testing methods: a weighted log-rank test (WLR) and an intersection-union test (IUT). A test statistic of the WLR is constructed by adapting a nonparametric estimator of the mediation effect; however, the test may be conservative regarding its Type I Error rate. To address this, we further propose the IUT, the test statistic of which is constructed under the composite null hypothesis. Asymptotic properties of the two tests are studied, showing that the IUT is a size α test with better statistical power than the WLR. The theoretical properties are supported by extensive simulation studies under finite samples. Applying the proposed methods to the motivating hepatitis study, both WLR and IUT provided strong evidence that hepatitis B had a significant mediation effect on mortality via liver cancer incidence.

Serum soluble programmed cell death 1 levels predict spontaneous functional cure in inactive carriers with chronic hepatitis B.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroclearance is the most important milestone indicating favourable clinical outcomes in patients with chronic hepatitis B (CHB). However, it is difficult to achieve due to the impaired HBV-specific immunity, such as programmed cell death 1 (PD-1)-associated T cell exhaustion. We assessed soluble PD-1 (sPD-1) as a novel seromarker for predicting spontaneous HBsAg loss. METHODS: Serial serum levels of sPD-1 were evaluated in 1046 untreated hepatitis B e antigen (HBeAg)-seronegative individuals who had achieved undetectable serum HBV DNA. Multiple regression analyses were applied to assess associations among baseline and subsequent sPD-1 levels, HBsAg decline during follow-up, and spontaneous HBsAg seroclearance. RESULTS: A total of 390 individuals achieved spontaneous HBsAg seroclearance during 6464.4 person-years of follow-up. Baseline sPD-1 levels were inversely associated with baseline HBsAg levels (qHBsAg) as well as a greater decline in qHBsAg during follow-up. Incidence rates of HBsAg seroclearance were 11.5, 61.7, 96.7 and 151.0 per 1000 person-years for sPD-1 levels of ≥4000, 536-3999, 125-535 and <125 pg/mL, respectively (Ptrend  < 0.0001). Compared with baseline sPD-1 levels ≥4000 pg/mL, the rate ratio (95% CI) of HBsAg seroclearance was 2.1 (1.1-3.9), 3.0 (1.6-5.5) and 5.1 (2.8-9.5), for baseline sPD-1 levels of 536-3999, 125-535 and <125 pg/mL, respectively, after adjustment for sex, age and serum alanine aminotransferase and HBsAg levels. CONCLUSION: sPD-1 level is a novel marker which independently predicts spontaneous HBsAg seroclearance of HBeAg-negative inactive CHB patients with undetectable HBV DNA. (word count: 234, <250).