Institute of Statistical Science, Academia Sinica

Few genome-wide association studies have examined genetic variants associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV, and the long-term impact of these variants remains uncertain. This multi-stage study analyzed adults >30 years old who were seronegative for HBsAg and anti-HCV. In the genome-wide association study discovery phase, 765 HCC cases and 9,949 controls were analyzed for 308,693 SNPs, with significant SNPs confirmed in community-based (171 HCC cases, 684 controls) and hospital-based (470 HCC cases, 5,460 controls) validation sets. A cohort of 67,909 participants, followed from 2012 to 2021, was used to evaluate the long-term HCC risk associated with these variants. Ten SNPs in PNPLA3/SAMM50 were significantly associated with HCC risk (p <1.62 × 10-7) and were in high linkage disequilibrium. Three SNPs (rs738409, rs2281135, rs2235776) were replicated and demonstrated strong associations with HCC, independent of steatosis. Over 267,238 person-years of follow-up, 32 new HCC cases occurred, with elevated risks observed in individuals homozygous for the risk genotypes: GG (rs738409), AA (rs2281135), and TT (rs2235776). The adjusted hazard ratios (95% CI) were 3.37 (1.32-8.63), 2.80 (1.06-7.37), and 2.64 (0.91-7.66), respectively. In allelic models, carriers of the risk allele had higher HCC risk, with adjusted hazard ratios (95% CI) of 1.88 (1.14-3.10) for rs738409, 1.68 (1.02-2.78) for rs2281135, and 1.61 (0.98-2.67) for rs2235776. This study identified PNPLA3/SAMM50 variants significantly associated with long-term HCC risk in individuals without viral hepatitis. These findings highlight their potential utility as biomarkers for HCC risk stratification and underscore the need for further research into underlying mechanisms. Variants in the PNPLA3/SAMM50 locus were significantly associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV. The stepwise increase in HCC risk with higher numbers of risk alleles suggests their potential utility as biomarkers to identify high-risk individuals without a history of chronic hepatitis B or C virus infection. These findings provide a foundation for genetic risk stratification and precision prevention strategies in populations where non-viral etiologies of HCC are becoming increasingly important.

Gastric cancer, with disproportionately higher incidence in East Asia, arises from complex host-microbiome-environment interactions beyond Helicobacter pylori (HP) infection. However, the molecular architecture linking environmental carcinogens, microbial succession and host response remains unclear. To delineate multifactorial aetiologies and clinically actionable subtypes/biomarkers of gastric cancer through integrative proteogenomic, microbial and environmental exposure profiling. We established a multiomics atlas of paired tumour, adjacent mucosa tissues and blood from 154 treatment-naïve Taiwanese patients, integrating whole-exome sequencing, RNA-seq, proteome and phosphoproteome profiling with carcinogen signatures, HP status, microbiome composition and refined anatomical mapping. Cell-based functional assays tested carcinogen effects. Microbial subtype was assessed in an independent cohort. A polycyclic-aromatic-hydrocarbon signature, dibenz[a,h]acridine, emerged as a high-risk exposure promoting invasion, immune suppression and poor survival, significantly exceeding nitrosamine-linked risk in this cohort. Multilayer integration defined three initiation ecologies: HP-driven inflammatory, non-HP microbiome-enriched immune-silent and HP-free microbially depleted states. Among HP-negative tumours, a Streptococcus-enriched subtype associated with tight-junction (CLDN18.2/ZO-1/OCLN) disruption and epithelial-mesenchymal transition, whereas a subset of clinically aggressive cases retained CLDN18.2-high epithelial-stable subtype for therapeutic accessibility. An independent cohort revealed gastric juice-derived Streptococcus anginosus abundance inversely correlated with tight-junction proteins. Anatomical mapping reveals location-specific, sex-specific, subtype-specific oncogenic networks and kinase activity, including CDK4 activation in clinical biomarker-negative tumours. Decision-tree models combining exposure and proteome-immune states refined recurrence and survival prediction beyond stage. This proteogenomic framework defines exposure-informed and microbiome-informed gastric cancer subtypes, providing a molecular schema for patient stratification, prevention and actionable therapeutic vulnerabilities.

In this article, we develop comprehensive frequency domain methods for estimating and inferring the second-order structure of spatial point processes. The main element here is on utilizing the discrete Fourier transform (DFT) of the point pattern and its tapered counterpart. Under second-order stationarity, we show that both the DFTs and the tapered DFTs are asymptotically jointly independent Gaussian even when the DFTs share the same limiting frequencies. Based on these results, we establish an α-mixing central limit theorem for a statistic formulated as a quadratic form of the tapered DFT. As applications, we derive the asymptotic distribution of the kernel spectral density estimator and establish a frequency domain inferential method for parametric stationary point processes. For the latter, the resulting model parameter estimator is computationally tractable and yields meaningful interpretations even in the case of model misspecification. We investigate the finite sample performance of our estimator through simulations, considering scenarios of both correctly specified and misspecified models.

Traditional Chinese Medicine (TCM) is extensively utilized in Asian societies and has shown potential benefits in improving survival rates of patient with specific diseases and anti-aging effects. However, its impact on life expectancy of general population remains relatively unexplored. This study aimed to investigate the impact of TCM utilization on mortality risk and life expectancy in Taiwan. A nationwide longitudinal cohort study was conducted using data from the Taiwan National Health Interview Survey linked with the National Health Insurance Research Database. Cox proportional hazard models were used to calculate the risk of all-cause mortality between frequent TCM users (≥20% of outpatient visits) and non-frequent users (<20%). A rolling extrapolation algorithm was used to estimate lifetime survival functions, and inverse probability of treatment weighting was integrated to adjust for confounding variables. The study included 12,176 participants (1,596 frequent TCM users and 10,580 non-frequent TCM users) aged ≥55 years, with a median follow-up duration of 10.49 years. After adjustment for confounding factors, frequent TCM users had a longer life expectancy compared to non-frequent TCM users, with a difference of 1.37 years (95% CI: 0.22-3.32). Higher TCM utilization was associated with reduced mortality risk (HR: 0.89, 95% CI: 0.80-0.99). Results remained consistent across dose-response analysis and time-dependent exposure models. This study suggests that higher TCM utilization is associated with longer life expectancy and lower mortality risk among older adults in Taiwan. Further studies are warranted to clarify potential mechanisms and to explore how TCM utilization may complement conventional healthcare in addressing the needs of aging populations.

BackgroundPrevious research has focused on the relationship between excessive daytime sleepiness (EDS) and the risk of developing dementia. However, limited evidence investigates the effects of EDS on domain‐specific cognitive functions or the associations between various sleepiness situations from the Epworth Sleepiness Scale (ESS) and cognitive performance. This study aims to examine the relationships between EDS, different ESS sleepiness situations, and cognitive function in community‐dwelling older adults.MethodThis study (2015‐2022) included 377 non‐demented older adults from the Taiwan Initiative for Geriatric Epidemiological Research, with biennial follow‐up since 2011. Cognitive function was assessed repeatedly using the Taiwanese version of the Montreal Cognitive Assessment for global cognition and neuropsychological tests for domain‐specific cognition, including memory, attention, executive function, and language. EDS was measured by the ESS at baseline (2015‐2017) with a total score of 24 and a cutoff point of 11. The presence of a specific ESS sleepiness situation was defined as participants scoring 1 on any individual ESS situation. A generalized linear mixed model was applied to investigate the associations between EDS and cognitive performance.ResultParticipants had a mean age of 75.7 and 55.2% of women. We found that one unit increment of baseline ESS score at baseline was associated with poorer performance of memory (β: ‐0.03, 95% CI: ‐0.05, ‐0.001) but associated with better performance of executive functions (β: 0.01, 95% CI: 0.0005, 0.03) over time. Regarding specific ESS sleepiness situations, over time, dozing while lying down to rest was associated with poorer global cognition (β: ‐0.21, 95% CI: ‐0.37, ‐0.06), and dozing when sitting and talking to someone was associated with poorer memory (β: ‐0.32, 95% CI: ‐0.50, ‐0.13). Conversely, dozing while sitting and reading, watching television, sitting quietly after a meal without alcohol, or as a passenger in a car for an hour or more without stopping was associated with better executive function (β: 0.06 to 0.16) over time. No significant association was found between the existence of EDS and cognition over time.ConclusionEDS and specific sleepiness situations demonstrated mixed associations with cognition, including poor performance of global cognition and memory but improved performance of executive function over time.

BackgroundPrevious studies have suggested that obstructive sleep apnea (OSA) may be related to cognitive function. However, the effect of snoring, as the most prominent characteristic of OSA, on cognitive function has not been fully explored. This study aimed to investigate the effect of snoring on cognitive function based on a seven‐year cohort study.MethodThis cohort study (2015‐2022) using data from the Taiwan Initiatives for Geriatric Epidemiological Research collected at baseline (2015‐2017), involving 440 older adults aged 65 or older, with two follow‐up surveys conducted biennially. Cognitive function, including global cognition and specific domains (memory, attention, executive function, and language), was assessed at baseline and two follow‐ups using the Taiwanese version of the Montreal Cognitive Assessment and a battery of neuropsychological tests, respectively. The existence of snoring was obtained from the Pittsburgh Sleep Quality Index questionnaire, including both self‐reports and partner assessments at baseline. A generalized linear mixed model was employed to examine the association between snoring and cognitive performance, adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, depressive symptoms, alcohol consumption, practice effect, and follow‐up years. We further stratified the associations above by sex and age.ResultThe mean age of this population is 75.7 at baseline and 55.4% were women. We found that body mass index, and sex significantly differed by the existence of snoring. Snoring was not associated with global or domain‐specific cognition. However, after stratification by sex, we found that, among men, baseline snoring was associated with the poor performance of global cognition over time (MoCA‐T, β = ‐0.33, 95% confidence interval=‐0.60, ‐0.05). In addition, snoring was associated with poor memory at baseline ( β = ‐0.50, 95% confidence interval=‐0.95, ‐0.05). In those aged >74 years, snoring‐time interaction was significantly linked to a decline in global cognition (MoCA‐T, β = ‐0.39, 95% CI = ‐0.70, ‐0.08).ConclusionThis study found that snoring had a significant detrimental effect on global cognition and memory in men but with an improvement in attention for women over time. Future research is warranted to investigate the sex differences and underlying mechanisms for the association of snoring with cognitive function.

Larger mean corpuscular volume (MCV) may indicate impaired oxygen and nutrient delivery to the brain, and could be associated with cognitive impairment, yet longitudinal evidence remains limited. This study investigated this association in community-dwelling older adults. This prospective cohort study (2011-2022) was from the Taiwan Initiative for Geriatric Epidemiological Research at baseline with four biennial follow-ups. Global cognition was assessed longitudinally using the Montreal Cognitive Assessment, Taiwanese version, and domain-specific cognition via a battery of neuropsychiatric tests. Red cell distribution width (RDW), hemoglobin, platelet, and vitamin B12 were also collected. Generalized linear mixed models were utilized to analyze the association between baseline MCV and cognition adjusting for covariates. A total of 530 non-demented participants (mean age 72.7±5.3 years, range 65-89; 247 men and 283 women) were included. MCV was non-linearly associated with cognition. Larger baseline MCV (>93.0fL) was significantly associated with poor memory (immediate free recall, delayed free recall, and delayed theme recall: βˆ=-0.028 to -0.041) and attention (digit span forward: βˆ=-0.028) over time, particularly in those with high platelet counts (> 230×103/μL), high hemoglobin, and in men. A significant interaction between MCV and age on global cognition (pinteraction=0.04) was observed. Elevated baseline MCV was associated with poor cognition, especially in memory and attention domains, over time. Future longitudinal studies are warranted to confirm this temporal relationship.

BackgroundNon-high-density lipoprotein cholesterol (non-HDL-C) is a key cardiovascular risk factor, yet its optimal range in healthy individuals remains unclear.MethodsThis study analyzed data from 134,343 adults aged 40–79 in the MJ Health Check-up Cohort in Taiwan (2000–2017). Participants with prior cardiovascular disease or extreme/incomplete BMI data (≥50 kg/m2) were excluded. Covariates included lifestyle, blood pressure, and diet. All-cause mortality was assessed using Cox proportional hazards models.ResultsThe mean age was 51.8 years, and 47.3 % were male. Most participants (62.7 %) had a BMI of 18.5–25. The average non-HDL-C level was 146.8 mg/dL. A U-shaped association was observed between non-HDL-C levels and all-cause mortality. Compared with the reference group (160–179 mg/dL), non-HDL-C levels of <100, 100–119, 120–139, and ≥200 mg/dL were linked to elevated mortality risk, with hazard ratios (HR) of 1.42 (95 % CI: 1.31–1.54), 1.19 (1.11–1.27), 1.11 (1.04–1.18), and 1.11 (1.03–1.20), respectively. The highest risk was noted in the 40–49 age group with non-HDL-C ≥200 mg/dL, particularly among females (HR 1.72, 95 % CI: 1.15–2.58). However, no significant increase in risk was observed for the same category in older age groups.ConclusionsA non-HDL-C range of 160–179 mg/dL was associated with the lowest all-cause mortality among healthy Taiwanese adults. Both lower and higher levels were linked to increased mortality risk, highlighting the importance of maintaining moderate non-HDL-C levels to support longevity and overall health.

Chronic respiratory diseases, particularly chronic obstructive pulmonary disease (COPD), are the eighth leading cause of death in Taiwan. Although COPD management has advanced in the previous two decades, mortality trends remain unclear. The present study analysed COPD mortality rates in Taiwan from 2002 to 2022. COPD mortality and population data were obtained from Taiwan's National Health Statistics and the Ministry of the Interior's Demographic Yearbook. For comparison, global COPD mortality data were sourced from the WHO mortality database. A joinpoint analysis was conducted to assess trends in age-specific and age-standardised mortality rates across sex, region or country. From 2002 to 2022, Taiwan had 100 147 deaths attributed to COPD. The age-standardised mortality rate decreased with an annual average percentage change (AAPC) of -3.79%, which was more pronounced in women (AAPC: -4.28%) than in men (AAPC: -3.79%). The largest decline occurred from 2016 to 2022, with an AAPC of -7.70%. Most COPD-related deaths occurred among older individuals, with significant reductions in mortality rates observed among men aged ≥60 years and among women aged ≥50 years. A downward trend in COPD mortality rates was noted in most counties from 2016 to 2022, although patterns varied. The overall COPD mortality rate has declined in most countries since 2002, including Taiwan, which ranks third in Asia in terms of reductions in COPD mortality rates during this period. From 2002 to 2022, COPD mortality rates in Taiwan declined considerably across sexes and regions, although patterns varied. In Asia, Taiwan's reduction in the rate of COPD mortality ranks third behind those of the Republic of Korea and Singapore. The reductions observed in COPD mortality rates in Taiwan may be attributable to tobacco control initiatives and nationwide COPD care programmes.