Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Combining fecal immunochemical testing and questionnaire-based risk assessment in selecting participants for colonoscopy screening in the Chinese National Colorectal Cancer Screening Programs: A population-based cohort study.

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.

Development, validation, and evaluation of a risk assessment tool for personalized screening of gastric cancer in Chinese populations.

BACKGROUND: Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. METHODS: In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40-75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20-80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. RESULTS: The GCRS using 11 questionnaire-based variables demonstrated a Harrell's C-index of 0.754 (95% CI, 0.745-0.762) and 0.736 (95% CI, 0.710-0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. CONCLUSIONS: The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

A trans-omics assessment of gene-gene interaction in early-stage NSCLC.

Epigenome-wide gene-gene (G × G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans-omics analysis, which had significant (P ≤ 0.05) epigenetic cis-regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (ßinteraction  = 0.018, P = 1.87 × 10-12 ), which mapped to RELA × HLA-G (ßinteraction  = 0.218, P = 8.82 × 10-11 ) and cg08872738 × cg27077312 (ßinteraction  = -0.010, P = 1.16 × 10-11 ), which mapped to TUBA1B × TOMM40 (ßinteraction =-0.250, P = 3.83 × 10-10 ). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.

Risk Assessment for Longitudinal Trajectories of Modifiable Lifestyle Factors on Chronic Kidney Disease Burden in China: A Population-based Study.

BACKGROUND: Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from noncommunicable diseases. We aimed to examine the longitudinal trajectories in risk factors, estimate their impact on CKD burden in China from 1991 to 2011, and project trends in the next 20 years. METHODS: We used data from a cohort of the China Health and Nutrition Survey and applied the comparative risk assessment method to estimate the number of CKD events attributable to all non-optimal levels of each risk factors. RESULTS: In 2011, current smoking was the leading individual attributable factor for CKD burden in China responsible for 7.9 (95% confidence interval [CI], 7.5-8.3) million CKD cases with a population-attributable fraction of 8.7% (95% CI, 6.0-11.6), while the rates of smoking have reduced and may have mitigated the increase in CKD. High triglyceride (TG) and high systolic blood pressure (SBP) were the leading metabolic risk factors responsible for 6.8 (95% CI, 6.4-7.1) million and 5.8 (95% CI, 5.5-6.1) million CKD-attributable cases, respectively. Additionally, the number of CKD cases associated with high body mass index (BMI), high diastolic blood pressure (DBP), high plasma glucose, and low high-density lipoprotein cholesterol (HDL-C) was 5.4 (95% CI, 5.1-5.6), 3.9 (95% CI, 3.7-4.1), 3.0 (95% CI, 2.8-3.1) and 2.6 (95% CI, 2.5-2.8) million, respectively. CONCLUSION: Current smoking, high TG, and high SBP were the top three risk factors that contributed to CKD burden in China. Increased BMI, DBP, plasma glucose, and decreased HDL-C were also associated with the increase in CKD burden.

Risk assessment models for genetic risk predictors of lung cancer using two-stage replication for Asian and European populations.

In the past ten years, great successes have been accumulated by taking advantage of both candidate-gene studies and genome-wide association studies. However, limited studies were available to systematically evaluate the genetic effects for lung cancer risk with large-scale and different ethnic populations. We systematically reviewed relevant literatures and filtered out 241 important genetic variants identified in 124 articles. A two-stage case-control study within specific subgroups was performed to assess the effects [Training set: 2,331 cases vs. 3,077 controls (Chinese population); testing set: 1,937 cases vs. 1,984 controls (European population)]. Variable selection and model development were used LASSO penalized regression and genetic risk score (GRS) system. Further change in area under the receiver operator characteristic curves (AUC) made by the epidemiologic model with and without GRS was used to compare predictions. It kept 38 genetic variants in our study and the ratios of lung cancer risk for subjects in the upper quartile GRS was three times higher compared to that in the low quartile (odds ratio: 4.64, 95% CI: 3.87-5.56). In addition, we found that adding genetic predictors to smoking risk factor-only model improved lung cancer predictive value greatly: AUC, 0.610 versus 0.697 (P < 0.001). Similar performance was derived in European population and the combined two data sets. Our findings suggested that genetic predictors could improve the predictive ability of risk model for lung cancer and highlighted the application among different populations, indicating that the lung cancer risk assessment model will be a promising tool for high risk population screening and prediction.

Comprehensive assessment showed no associations of variants at the SLC10A1 locus with susceptibility to persistent HBV infection among Southern Chinese.

The sodium taurocholate cotransporting polypeptide (NTCP) encoded by SLC10A1 was recently demonstrated to be a functional receptor for hepatitis B virus (HBV). The role of SLC10A1 polymorphisms, particularly the Ser267Phe variant (rs2296651) in exon 4, has been frequently investigated in regard to risk of persistent HBV infection. However, these investigations have generated conflicting results. To examine whether common genetic variation at the SLC10A1 locus is associated with risk of persistent HBV infection, haplotype-tagging and imputed single nucleotide polymorphisms (SNPs) were assessed in two case-control sample sets, totally including 2,550 cases (persistently HBV infected subjects, PIs) and 2,124 controls (spontaneously recovered subjects, SRs) of Southern Chinese ancestry. To test whether rare or subpolymorphic SLC10A1 variants are associated with disease risk, the gene's exons in 244 cases were sequenced. Overall, we found neither SNPs nor haplotypes of SLC10A1 showed significant association in the two sample sets. Furthermore, no significant associations of rare variants or copy number variation covering SLC10A1 were observed. Finally, expression quantitative trait locus analyses revealed that SNPs potentially affecting SLC10A1 expression also showed no significant associations. We conclude that genetic variation at the SLC10A1 locus is not likely a major risk factor of persistent HBV infection among Southern Chinese.

Risk assessment model for invasive breast cancer in Hong Kong women.

No risk assessment tool is available for identifying high risk population of breast cancer (BCa) in Hong Kong. A case-control study including 918 BCa cases and 923 controls was used to develop the risk assessment model among Hong Kong Chinese women.Each participant received an in-depth interview to obtain their lifestyle and environmental risk factors. Least absolute shrinkage and selection operator (LASSO) selection model was used to select the optimal risk factors (LASSO-model). A risk score system was constructed to evaluate the cumulative effects of selected factors. Bootstrap simulation was used to test the internal validation of the model. Model performance was evaluated by receiver-operator characteristic curves and the area under the curve (AUC).Age, number of parity, number of BCa cases in 1st-degree relatives, exposure to light at night, and sleep quality were the common risk factors for all women. Alcohol drinking was included for premenopausal women; body mass index, age at menarche, age at 1st give birth, breast feeding, using of oral contraceptive, hormone replacement treatment, and history of benign breast diseases were included for postmenopausal women. The AUCs were 0.640 (95% CI, 0.598-0.681) and 0.655 (95% CI, 0.621-0.653) for pre- and postmenopausal women, respectively. Further subgroup evaluation revealed that the model performance was better for women aged 50 to 70 years or ER-positive.This BCa risk assessment tool in Hong Kong Chinese women based on LASSO selection is promising, which shows a slightly higher discriminative accuracy than those developed in other populations.

Prediction models and risk assessment for silicosis using a retrospective cohort study among workers exposed to silica in China.

This study aims to develop a prognostic risk prediction model for the development of silicosis among workers exposed to silica dust in China. The prediction model was performed by using retrospective cohort of 3,492 workers exposed to silica in an iron ore, with 33 years of follow-up. We developed a risk score system using a linear combination of the predictors weighted by the LASSO penalized Cox regression coefficients. The model's predictive accuracy was evaluated using time-dependent ROC curves. Six predictors were selected into the final prediction model (age at entry of the cohort, mean concentration of respirable silica, net years of dust exposure, smoking, illiteracy, and no. of jobs). We classified workers into three risk groups according to the quartile (Q1, Q3) of risk score; 203 (23.28%) incident silicosis cases were derived from the high risk group (risk score ≥ 5.91), whilst only 4 (0.46%) cases were from the low risk group (risk score < 3.97). The score system was regarded as accurate given the range of AUCs (83-96%). This study developed a unique score system with a good internal validity, which provides scientific guidance to the clinicians to identify high-risk workers, thus has important cost efficient implications.

Population aging and migrant workers: bottlenecks in tuberculosis control in rural China.

BACKGROUND: Tuberculosis is a serious global health problem. Its paradigms are shifting through time, especially in rapidly developing countries such as China. Health providers in China are at the forefront of the battle against tuberculosis; however, there are few empirical studies on health providers' perspectives on the challenges they face in tuberculosis control at the county level in China. This study was conducted among health providers to explore their experiences with tuberculosis control in order to identify bottlenecks and emerging challenges in controlling tuberculosis in rural China. METHODS: A qualitative approach was used. Semi-structured, in-depth interviews were conducted with 17 health providers working in various positions within the health system of one rural county (ZJG) of China. Data were analyzed based on thematic content analysis using MAXQDA 10 qualitative data analysis software. RESULTS: Health providers reported several problems in tuberculosis control in ZJG county. Migrant workers and the elderly were repeatedly documented as the main obstacles in effective tuberculosis control in the county. At a personal level, doctors showed their frustration with the lack of new drugs for treating tuberculosis patients, and their opinions varied regarding incentives for referring patients. CONCLUSION: The results suggest that several problems still remain for controlling tuberculosis in rural China. Tuberculosis control efforts need to make reaching the most vulnerable populations a priority and encourage local health providers to adopt innovative practices in the local context based on national guidelines to achieve the best results. Considerable changes in China's National Tuberculosis Control Program are needed to tackle these emerging challenges faced by health workers at the county level.

Prognostic assessment of apoptotic gene polymorphisms in non-small cell lung cancer in Chinese.

Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P < 0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P = 0.003; CASP9 rs4645981: P = 0.007 and FAS rs1800682: P = 0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR = 0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR = 0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR = 0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.

Breast cancer risk assessment with five independent genetic variants and two risk factors in Chinese women.

INTRODUCTION: Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese. METHODS: In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth). RESULTS: Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting (AUC: 0.637, 95% CI: 0.619 to 0.655; sensitivity = 62.16%, specificity = 60.03%) (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676) (sensitivity = 61.98%, specificity = 60.26%) was obtained for the combination of five marker SNPs, age at menarche and age at first live birth. CONCLUSIONS: This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment.

Weighted Markov chains for forecasting and analysis in Incidence of infectious diseases in jiangsu Province, China.

This paper first applies the sequential cluster method to set up the classification standard of infectious disease incidence state based on the fact that there are many uncertainty characteristics in the incidence course. Then the paper presents a weighted Markov chain, a method which is used to predict the future incidence state. This method assumes the standardized self-coefficients as weights based on the special characteristics of infectious disease incidence being a dependent stochastic variable. It also analyzes the characteristics of infectious diseases incidence via the Markov chain Monte Carlo method to make the long-term benefit of decision optimal. Our method is successfully validated using existing incidents data of infectious diseases in Jiangsu Province. In summation, this paper proposes ways to improve the accuracy of the weighted Markov chain, specifically in the field of infection epidemiology.

[Estimation of gene-environment interaction regarding partial case-control study with missing data on gene information of the controls].

OBJECTIVE: To discuss the estimation on gene-environment interaction in partial case-control studies when gene information of the controls was partly missing. METHODS: The results of hot deck multiple imputation and listwise deletion analysis were compared when missing data was generated using Monte Carlo method in Stata 9.0. RESULTS: Coefficients of environment effect, gene effect and gene-environment interaction were respectively estimated by means of hot deck multiple imputation and listwise deletion when approaching to those complete data with missing part less than 50 percent. Both estimated variances of the two methods were increasing with the increased proportion of missing data, but the estimated variance of hot deck multiple imputation was smaller than the one with listwise deletion in each proportion. CONCLUSION: Hot deck imputation could be adopted to make full use of existing information to estimate gene-environment interaction in the partial case-control study when missing proportion of gene data of controls was less than 50 percent so as to increase the precision of the estimation.