Browsing by Author "Luo, Sheng"

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Open Access
A Bayesian approach for individual-level drug benefit-risk assessment.
(Statistics in medicine, 2019-07) Li, Kan; Luo, Sheng; Yuan, Sammy; Mt-Isa, Shahrul
In existing benefit-risk assessment (BRA) methods, benefit and risk criteria are usually identified and defined separately based on aggregated clinical data and therefore ignore the individual-level differences as well as the association among the criteria. We proposed a Bayesian multicriteria decision-making method for BRA of drugs using individual-level data. We used a multidimensional latent trait model to account for the heterogeneity of treatment effects with latent variables introducing the dependencies among outcomes. We then applied the stochastic multicriteria acceptability analysis approach for BRA incorporating imprecise and heterogeneous patient preference information. We adopted an efficient Markov chain Monte Carlo algorithm when implementing the proposed method. We applied our method to a case study to illustrate how individual-level benefit-risk profiles could inform decision-making.
Open Access
A few remarks on 'Statistical distribution of the difference of two proportions' by Nadarajah and Kotz, Statistics in Medicine 2007; 26(18):3518-3523.
(Statistics in medicine, 2011-07) Chen, Yong; Luo, Sheng
Open Access
A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers.
(Carcinogenesis, 2021-10-13) Qian, Danwen; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Walsh, Kyle M; Huang, Jiaoti; Li, Chuan-Yuan; Wei, Qingyi
ATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect in cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P=5.27×10 -7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis.
Open Access
A prognostic model of Alzheimer's disease relying on multiple longitudinal measures and time-to-event data.
(Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018-05) Li, Kan; O'Brien, Richard; Lutz, Michael; Luo, Sheng; Alzheimer's Disease Neuroimaging Initiative
INTRODUCTION:Characterizing progression in Alzheimer's disease is critically important for early detection and targeted treatment. The objective was to develop a prognostic model, based on multivariate longitudinal markers, for predicting progression-free survival in patients with mild cognitive impairment. METHODS:The information contained in multiple longitudinal markers was extracted using multivariate functional principal components analysis and used as predictors in the Cox regression models. Cross-validation was used for selecting the best model based on Alzheimer's Disease Neuroimaging Initiative-1. External validation was conducted on Alzheimer's Disease Neuroimaging Initiative-2. RESULTS:Model comparison yielded a prognostic index computed as the weighted combination of historical information of five neurocognitive longitudinal markers that are routinely collected in observational studies. The comprehensive validity analysis provided solid evidence of the usefulness of the model for predicting Alzheimer's disease progression. DISCUSSION:The prognostic model was improved by incorporating multiple longitudinal markers. It is useful for monitoring disease and identifying patients for clinical trial recruitment.
Open Access
A systematic assessment and optimization of photon-counting CT for lung density quantifications.
(Medical physics, 2024-02) Sotoudeh-Paima, Saman; Segars, W Paul; Ghosh, Dhrubajyoti; Luo, Sheng; Samei, Ehsan; Abadi, Ehsan
Background
Photon-counting computed tomography (PCCT) has recently emerged into clinical use; however, its optimum imaging protocols and added benefits remains unknown in terms of providing more accurate lung density quantification compared to energy-integrating computed tomography (EICT) scanners.
Purpose
To systematically assess the performance of a clinical PCCT scanner for lung density quantifications and compare it against EICT.
Methods
This cross-sectional study involved a retrospective analysis of subjects scanned (August-December 2021) using a clinical PCCT system. The influence of altering reconstruction parameters was studied (reconstruction kernel, pixel size, slice thickness). A virtual CT dataset of anthropomorphic virtual subjects was acquired to demonstrate the correspondence of findings to clinical dataset, and to perform systematic imaging experiments, not possible using human subjects. The virtual subjects were imaged using a validated, scanner-specific CT simulator of a PCCT and two EICT (defined as EICT A and B) scanners. The images were evaluated using mean absolute error (MAE) of lung and emphysema density against their corresponding ground truth.
Results
Clinical and virtual PCCT datasets showed similar trends, with sharper kernels and smaller voxel sizes increasing percentage of low-attenuation areas below -950 HU (LAA-950) by up to 15.7 ± 6.9% and 11.8 ± 5.5%, respectively. Under the conditions studied, higher doses, thinner slices, smaller pixel sizes, iterative reconstructions, and quantitative kernels with medium sharpness resulted in lower lung MAE values. While using these settings for PCCT, changes in the dose level (13 to 1.3 mGy), slice thickness (0.4 to 1.5 mm), pixel size (0.49 to 0.98 mm), reconstruction technique (70 keV-VMI to wFBP), and kernel (Qr48 to Qr60) increased lung MAE by 15.3 ± 2.0, 1.4 ± 0.6, 2.2 ± 0.3, 4.2 ± 0.8, and 9.1 ± 1.6 HU, respectively. At the optimum settings identified per scanner, PCCT images exhibited lower lung and emphysema MAE than those of EICT scanners (by 2.6 ± 1.0 and 9.6 ± 3.4 HU, compared to EICT A, and by 4.8 ± 0.8 and 7.4 ± 2.3 HU, compared to EICT B). The accuracy of lung density measurements was correlated with subjects' mean lung density (p < 0.05), measured by PCCT at optimum setting under the conditions studied.
Conclusion
Photon-counting CT demonstrated superior performance in density quantifications, with its influences of imaging parameters in line with energy-integrating CT scanners. The technology offers improvement in lung quantifications, thus demonstrating potential toward more objective assessment of respiratory conditions.
Open Access
A Unified Framework for Evidence-Based Diagnostic Criteria Programs in Movement Disorders.
(Movement disorders : official journal of the Movement Disorder Society, 2023-07) Mestre, Tiago A; Fabbri, Margherita; Luo, Sheng; Stebbins, Glenn T; Goetz, Christopher G; Sampaio, Cristina
Open Access
Adjuvant Chemotherapy Versus Observation Following Resection for Patients With Nonmetastatic Poorly Differentiated Colorectal Neuroendocrine Carcinomas.
(Annals of surgery, 2019-08-30) Mao, Rui; Li, Kan; Cai, Jian-Qiang; Luo, Sheng; Turner, Megan; Blazer, Dan; Zhao, Hong
OBJECTIVE:The aim of this study was to determine whether adjuvant chemotherapy (AC) provides a survival benefit in patients with nonmetastatic poorly differentiated colorectal neuroendocrine carcinomas (CRNECs) following resection. BACKGROUND:There is little evidence to support the association between use of AC and improved overall survival (OS) in patients with CRNECs. METHODS:Patients with resected non-metastatic CRNECs were identified in the National Cancer Database (2004-2014). Inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS of patients in different treatment groups. RESULTS:A total of 806 patients diagnosed between 2004 and 2014 met the study entry criteria. Of these, 394 patients (48.9%) received AC. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation [57.4 (interquartile range, IQR, 14.8-153.8) vs 38.2 (IQR, 10.4-125.4) months; P = 0.007]. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.64-0.84; P < 0.001]. The results were consistent across subgroups stratified by pathologic T stage, pathologic N stage, and surgical margin status. Subgroup analysis according to tumor location demonstrated improved OS in the adjuvant therapy cohort among patients with left-sided neuroendocrine carcinomas (HR, 0.55; 95% CI, 0.44-0.68), but not in those with right-sided disease (HR, 0.89; 95% CI, 0.74-1.07). CONCLUSIONS:Patients with nonmetastatic CRNECs may derive survival benefit from AC. These findings support current guidelines recommending AC in patients with poorly differentiated neuroendocrine carcinomas in the colon and rectum. Efforts in education and adherence to national guidelines for NECs are needed.
Open Access
Adverse Events of Immune Checkpoint Inhibitor-Based Therapies for Unresectable Hepatocellular Carcinoma in Prospective Clinical Trials: A Systematic Review and Meta-analysis
(Liver Cancer) Zhang, Yizhou; Wang, Minghao; Chen, Qichen; Deng, Yiqiao; Chen, Jinghua; Dai, Yimin; Luo, Sheng; Xu, Jianming; Zhao, Hong; Cai, Jianqiang
Introduction: To investigate the incidence and spectrum of adverse events in unresectable hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs) or ICI-based combinations. Methods: The study protocol was prospectively registered on PROSPERO (CRD42022319255). We searched PubMed, EMBASE, and the Cochrane Library for published clinical trials from database inception to April 22, 2022. Studies that included at least one group of unresectable HCC patients treated with ICIs or ICI-based combinations and reported the incidence or spectrum of treatment-related adverse events (trAEs) or immune-related adverse events (irAEs) were eligible. The incidence and spectra of all-grade and grade ≥3 trAEs were the primary outcomes. The profiles of irAEs, the incidence of trAEs leading to treatment discontinuation, and treatment-related mortalities were additional outcomes. We applied random-effects models to pool the incidence and spectra of adverse events. Subgroup analyses and meta-regression were performed. Results: The literature search identified 2464 records. Twenty studies (4146 participants with HCC) met the eligibility criteria. The pooled incidences of all-grade trAEs, grade ≥3 trAEs, all-grade irAEs, and grade≥3 irAEs were 80.1% (95% CI 73.8-85.2), 35.4% (95% CI 27.2-44.6), 31.1% (95% CI 21.0-43.5), and 6.6% (95% CI 3.6-11.8), respectively. ICIs plus oral targeted agents (all-grade OR=17.07, 95% CI 6.05-48.16, P<0.001; grade ≥3 OR=9.35, 95% CI 4.53-19.29, P<0.001) and ICIs plus intravenous targeted agents (all-grade OR=4.91, 95% CI 1.80-13.42, P=0.003; grade ≥3 OR=4.21, 95% CI 1.42-12.48, P=0.012) were associated with increased trAEs compared with monotherapy. The all-grade trAEs with the highest pooled incidences were reactive capillary endothelial proliferation (49.2%, 95% CI 26.3-72.3), neutropenia (34.6%, 95% CI 17.1-57.5), and proteinuria (32.8%, 95% CI 19.8-49.2). The grade ≥3 trAEs with highest pooled incidences were hypertension (11.1%, 95% CI 4.0-29.0), neutropenia (10.5%, 95% CI 7.0-15.4), and aspartate aminotransferase increased (7.7%, 95% CI 6.3-9.4). The pooled incidence of trAEs leading to treatment discontinuation was 8.0% (95% CI 6.0-10.5), and the overall incidence of treatment-related mortalities was 1.1%. Conclusions: This study comprehensively summarized the incidence and spectrum of trAEs in unresectable HCC patients receiving ICIs or ICI-based combinations in clinical trials. The results from this study will provide a useful reference to guide clinical practice.
Open Access
AN INTEGRATIVE MODELING FRAMEWORK FOR MULTIVARIATE LONGITUDINAL CLINICAL DATA
(2024) Choi, Dongrak
This dissertation is centered on the development of innovative statistical methodologies specifically tailored to address the complex nature of multivariate data associated with Parkinson's disease (PD). PD is known to manifest impairments across both behavioral and cognitive domains, and as of now, there are no available disease-modifying treatments. Consequently, researchers typically gather a diverse array of data types, encompassing binary, continuous, categorical outcomes, and time-to-event data, in order to gain a comprehensive understanding of the multifaceted aspects of this disorder. Furthermore, due to the long follow-up of PD studies, the occurrence of intermittent missing data is a common challenge, which can introduce bias into the analysis. In this dissertation, we introduce novel approaches for jointly modeling multivariate longitudinal outcomes and time-to-event data using functional latent trait models and generalized multivariate functional mixed models to deal with different types of data. Additionally, we present a method for the detection and handling of missing data patterns through the utilization of joint modeling techniques.
Open Access
Analysis of antepartum obstetric triage utilization at 24 weeks and beyond
(AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2021-02) Ren, Xuehan; Jelovsek, Eric; Luo, Sheng; Hughes, Brenna L; Reiff, Emily
Open Access
APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.
(Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020-04) Deng, Wei; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wei, Qingyi
BACKGROUND:Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear. METHODS:We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies. We used multivariate Cox proportional hazards regression and expression quantitative trait loci analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used the Kaplan-Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs. RESULTS:We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C, and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with worse survival (P trend < 0.0001). In addition, both APOB rs1801701T
Open Access
Application of Longitudinal Item Response Theory Models to Modeling Parkinson's Disease Progression.
(CPT: pharmacometrics & systems pharmacology, 2022-07-27) Zou, Haotian; Aggarwal, Varun; Stebbins, Glenn T; Müller, Martijn LTM; Cedarbaum, Jesse M; Pedata, Anne; Stephenson, Diane; Simuni, Tanya; Luo, Sheng
The Movement Disorder Society revised version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts 2 and 3 reflect patient-reported functional impact and clinician-reported severity of motor signs of Parkinson's disease (PD), respectively. Total scores are common clinical outcomes but may obscure important time-based changes in items. We aim to analyze longitudinal disease progression based on MDS-UPRDS Parts 2 and 3 item-level responses over time and as functions of Hoehn & Yahr (H&Y) stages 1 and 2 for subjects with early PD. The longitudinal IRT modeling is a novel statistical method addressing limitations in traditional linear regression approaches such as ignoring varying item sensitivities and the sum score balancing out improvements and declines. We utilized a harmonized dataset consisting of six studies with 3,573 early PD subjects and 14,904 visits, and mean follow-up time of 2.5 year (±1.57). We applied both a unidimensional (each Part separately) and multidimensional (both Parts combined) longitudinal item response theory (IRT) models. We assessed the progression rates for both parts, anchored to baseline Hoehn & Yahr (H&Y) stages 1 and 2. Both the uni- and multidimensional longitudinal IRT models indicate significant worsening time effects in both Parts 2 and 3. Baseline H&Y stage 2 was associated with significantly higher baseline severities, but slower progression rates in both parts, as compared with stage 1. Patients with baseline H&Y stage 1 demonstrated slower progression in Part 2 severity compared to Part 3, while patients with baseline H&Y stage 2 progressed faster in Part 2 than Part 3. The multidimensional model had a superior fit compared to the unidimensional models and it had excellent model performance.
Open Access
Appropriate dose of regorafenib based on body weight of colorectal cancer patients: a retrospective cohort study.
(BMC Cancer, 2023-12-21) Nakashima, Masayuki; Li, Kan; Chen, Qichen; de Silva, Sajith; Li, Hal; Kawakami, Koji; Wei, Qingyi; Luo, Sheng; Zhao, Hong
PURPOSE: Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. METHODS: We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. RESULTS: We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 - 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 - 1.37). CONCLUSION: The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.
Open Access
Assessing tilavonemab efficacy in early Alzheimer's disease via longitudinal item response theory modeling
(Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2024-04) Zhou, Xiaoxiao; Zou, Haotian; Lutz, Michael W; Arbeev, Konstantin; Akushevich, Igor; Yashin, Anatoli; Welsh-Bohmer, Kathleen A; Luo, Sheng
AbstractINTRODUCTIONAlzheimer's disease (AD) is a neurodegenerative disorder characterized by declines in cognitive and functional severities. This research utilized the Clinical Dementia Rating (CDR) to assess the influence of tilavonemab on these deteriorations.METHODSLongitudinal Item Response Theory (IRT) models were employed to analyze CDR domains in early‐stage AD patients. Both unidimensional and multidimensional models were contrasted to elucidate the trajectories of cognitive and functional severities.RESULTSWe observed significant temporal increases in both cognitive and functional severities, with the cognitive severity deteriorating at a quicker rate. Tilavonemab did not demonstrate a statistically significant effect on the progression in either severity. Furthermore, a significant positive association was identified between the baselines and progression rates of both severities.DISCUSSIONWhile tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories.Highlights Utilized longitudinal Item Response Theory (IRT) models to analyze the Clinical Dementia Rating (CDR) domains in early‐stage Alzheimer's disease (AD) patients, comparing unidimensional and multidimensional models. Observed significant temporal increases in both cognitive and functional severities, with cognitive severity deteriorating at a faster rate, while tilavonemab showed no statistically significant effect on either domain's progression. Found a significant positive association between the baseline severities and their progression rates, indicating interconnected progression patterns of cognitive and functional declines in AD. Introduced the application of multidimensional longitudinal IRT models to provide a comprehensive perspective on the trajectories of cognitive and functional severities in early AD, suggesting new avenues for future research including the inclusion of time‐dependent random effects and data‐driven IRT models.
Open Access
Association and Trends in Medicare Denials and Utilization for Brain CT: Indirect Impacts by Targeted Policy Intervention?
(Current problems in diagnostic radiology, 2022-07-30) French, Robert J; Hirsch, Joshua; Hemingway, Jennifer; Hughes, Danny R; Lerebours, Reginald; Luo, Sheng; Allen, Brian C; Duszak, Richard; Rosman, David A
Twenty-five years of annual Medicare Physician/Supplier Procedure Summary (PSPS) Master File data were used to assess trends in normalized volume and claim denial rates for brain computerized tomography. Alongside growth in utilization of brain computerized tomography (services, denial rates, fell from 1999-2005 and with relatively leveled growth and less denial rate volatility thereafter. More recent trends in denial rates may be related to policy interventions initially aimed at cost and volume reduction.
Open Access
Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer's Disease.
(Journal of Alzheimer's disease : JAD, 2021-10-13) Liu, Hongliang; Lutz, Michael; Luo, Sheng; Alzheimer’s Disease Neuroimaging Initiative
Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer's disease (AD). In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, se = 0.061, p = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, se = 0.037, p = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PIB and AV45), but decreased hippocampus and entorhinal cortex volumes (p < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ 42 (beta = 0.056, SE = 0.026, p = 0.036). Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI.
Open Access
Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival.
(Annals of translational medicine, 2021-03) Wang, Haijiao; Liu, Hongliang; Dai, Wei; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Li, Xin; Yue, Ying; Nan, Hongmei; Wei, Qingyi
Background
Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM).
Methods
We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS).
Results
Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs (TMEM135 rs567403 C>G and PEX5 rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the TMEM135 rs567403 GG and PEX5 rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively.
Conclusions
Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.
Open Access
Association of genetic variants of FBXO32 and FOXO6 in the FOXO pathway with breast cancer risk.
(Molecular carcinogenesis, 2021-07) Wang, Haijiao; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Akinyemiju, Tomi; Hwang, Shelley; Yue, Ying; Wei, Qingyi
Forkhead box class O (FOXO) transcription factors play a pivotal role in regulating a variety of biological processes, including organismal development, cell signaling, cell metabolism, and tumorigenesis. Therefore, we hypothesize that genetic variants in FOXO pathway genes are associated with breast cancer (BC) risk. To test this hypothesis, we conducted a large meta-analysis using 14 published genome-wide association study (GWAS) data sets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study. We assessed associations between 5214 (365 genotyped in DRIVE and 4849 imputed) common single-nucleotide polymorphisms (SNPs) in 55 FOXO pathway genes and BC risk. After multiple comparison corrections by the Bayesian false-discovery probability method, we found five SNPs to be significantly associated with BC risk. In stepwise multivariate logistic regression analysis with adjustment for age, principal components, and previously published SNPs in the same data set, three independent SNPs (i.e., FBXO32 rs10093411 A>G, FOXO6 rs61229336 C>T, and FBXO32 rs62521280 C>T) remained to be significantly associated with BC risk (p = 0.0008, 0.0011, and 0.0017, respectively). Additional expression quantitative trait loci analysis revealed that the FBXO32 rs62521280 T allele was associated with decreased messenger RNA (mRNA) expression levels in breast tissue, while the FOXO6 rs61229336 T allele was found to be associated with decreased mRNA expression levels in the whole blood cells. Once replicated by other investigators, these genetic variants may serve as new biomarkers for BC risk.
Open Access
Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.
(Cancer medicine, 2020-11-16) Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Moorman, Patricia G; Walsh, Kyle M; Li, Wei; Wei, Qingyi
Because the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.
Open Access
Associations of novel variants in PIK3C3, INSR and MAP3K4 of the ATM pathway genes with pancreatic cancer risk.
(American journal of cancer research, 2020-01) Zhao, Ling-Ling; Liu, Hong-Liang; Luo, Sheng; Walsh, Kyle M; Li, Wei; Wei, Qingyi
The ATM serine/threonine kinase (ATM) pathway plays important roles in pancreatic cancer (PanC) development and progression, but the roles of genetic variants of the genes in this pathway in the etiology of PanC are unknown. In the present study, we assessed associations between 31,499 single nucleotide polymorphisms (SNPs) in 198 ATM pathway-related genes and PanC risk using genotyping data from two previously published PanC genome-wide association studies (GWASs) of 15,423 subjects of European ancestry. In multivariable logistic regression analysis, we identified three novel independent SNPs to be significantly associated with PanC risk [PIK3C3 rs76692125 G>A: odds ratio (OR)=1.26, 95% confidence interval (CI)=1.12-1.43 and P=2.07×10-4, INSR rs11668724 G>A: OR=0.89, 95% CI=0.84-0.94 and P=4.21×10-5 and MAP3K4 rs13207108 C>T: OR=0.83, 95% CI=0.75-0.92, P=2.26×10-4]. The combined analysis of these three SNPs exhibited an increased PanC risk in a dose-response manner as the number of unfavorable genotypes increased (P trend<0.0001). The risk-associated rs76692125 A allele was correlated with decreased PIK3C3 mRNA expression levels, while the protective-associated rs11668724 A allele was correlated with increased INSR mRNA expression levels, but additional mechanistic studies of these SNPs are warranted. Once validated, these SNPs may serve as biomarkers for PanC risk in populations of European ancestry.

Browsing by Author "Luo, Sheng"

Background

Purpose

Methods

Results

Conclusion

Background

Methods

Results

Conclusions