244 research outputs found
Detection of Differentially Expressed Gene Sets in a Partially Paired Microarray Data Set
No full textPartially paired data sets often occur in microarray experiments (Kim et al., 2005; Liu, Liang and Jang, 2006). Discussions of testing with partially paired data are found in the literature (Lin and Stivers 1974; Ekbohm, 1976; Bhoj, 1978). Bhoj (1978) initially proposed a test statistic that uses a convex combination of paired and unpaired t statistics. Kim et al. (2005) later proposed the t3 statistic, which is a linear combination of paired and unpaired t statistics, and then used it to detect differentially expressed (DE) genes in colorectal cancer (CRC) cDNA microarray data. In this paper, we extend Kim et al.’s t3 statistic to the Hotelling’s T2 type statistic Tp for detecting DE gene sets of size p. We employ Efron’s empirical null principle to incorporate inter-gene correlation in the estimation of the false discovery rate. Then, the proposed Tp statistic is applied to Kim et al’s CRC data to detect the DE gene sets of sizes p=2 and p=3. Our results show that for small p, particularly for p=2 and marginally for p=3, the proposed Tp statistic compliments the univariate procedure by detecting additional DE genes that were undetected in the univariate test procedure. We also conduct a simulation study to demonstrate that Efron’s empirical null principle is robust to the departure from the normal assumption.
The Effect of PDSS2, a Component of the Coenzyme Q Biosynthetic Pathway, on Murine Oocyte Embryo Development
No full textFemale reproductive capacity dramatically declines with age. Decrease in oocyte number and quality is primarily responsible for this phenomenon. However, although multiple theories of reproductive aging have been proposed, the exact cause of oocyte quality decline remains unclear. One factor that seems to contribute is the reduced availability of coenzyme Q (coQ), a component of the mitochondrial respiratory chain, as it has been previously shown that both transcript and protein expression of various coQ biosynthetic enzymes decrease in aged murine oocytes. To further explore the impact of coQ deficiency on female fertility, we generated a mouse line harbouring an oocyte-specific deletion of Pdss2 and sought to fully characterize its phenotypes.
Pdss2-deficient females recapitulated many hallmarks of reproductive aging, such as low ovulation rates and inability to produce litters. Embryonic health was also drastically reduced, and most Pdss2-deficient embryos arrested at the 2-to 4-cell stage during in vitro development. Highlighting the importance of coQ and Pdss2 in the maintenance of mitochondrial health, oocytes and 2-cell embryos from Pdss2-deficient females had compromised mitochondrial function and decreased mitochondrial endowment. Furthermore, Pdss2-deficient 2-cell embryos failed to undergo maternal-to-zygotic transition (MZT) during early embryogenesis, displaying aberrant epigenetic landscapes and accumulation of maternal factors. They also displayed aberrant mTOR signaling, as was previously observed in somatic tissue of Pdss2 mutant mice.
To ameliorate symptoms of oocyte-specific Pdss2 deficiency, in vivo coQ supplementation was provided via drinking water, as well as another mitochondrial bioenergetic, pyrroloquinoline quinone (PQQ). Interestingly, PQQ supplementation was able to increase the proportion of d3.5 Pdss2-deficient embryos at the morula/blastocyst stage and litter production rates of Pdss2-deficient females, although coQ could not. We found PQQ can improve oocyte and embryo mitochondrial function, but it is not yet clear why PQQ is a more effective treatment than coQ. Further understanding of the impact of PDSS2 and PQQ on the developmental capacity of oocytes and early embryos will help elucidate the pathogenesis underlying oocyte aging and contribute to development of effective assisted reproductive techniques.Ph.D.2025-06-26 00:00:0
Expansion of CD45RA−FOXP3++ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation
No full textAbstract Objectives Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). Methods Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. Results Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non‐tolerant group). The CD45RA−FOXP3++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non‐tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA−FOXP3++ Treg cells to CD45RA−FOXP3+ cells indicated good discrimination between the tolerant and non‐tolerant groups. Conclusion Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT
Statistical issues in mapping genetic determinants for expression level polymorphisms
No full textUnraveling the underlying mechanism of inheritance for complex traits has been of great interest to the scientific community for many years. Complex traits are typically controlled by multiple genes that are organized into networks and may behave differently under varying environmental conditions. With advances in technologies, namely microarray technology, it is now possible to comprehensively dissect complex traits at a molecular level by identifying genetic determinants of expression level polymorphism (ELP; the quantified variation in mRNA transcripts by way of microarray technology), and thus provides a systems biological way to investigate gene networks. To date, the identification of ELP determinants has been pursued via existing statistical methods for association mapping and/or quantitative trait locus (QTL) mapping. Although these analytical methodologies address many important statistical issues ( e.g., sample size and replication), they fail to deal with the unification of QTL mapping and microarray technology for the purpose of molecularly dissecting a complex trait. A framework for designing, understanding, and analyzing ELP experiments is proposed with focus on three major components: experimental design; genetic mapping or locating of ELP determinants; and the construction of gene regulatory networks. A novel multivariate mixture linear model (MMLM) with mixed effects is proposed in an interval mapping setting for the purpose of mapping genetic determinants of ELPs. The performance of existing QTL methods and the proposed MMLM method is investigated using both simulated and real data. Practical recommendations for future ELP studies are given, and suggestions regarding the incorporation of ELP mapping results to gene network construction are made
Associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans
No full textBACKGROUND/OBJECTIVES: Korea is quickly becoming an aged society. Dementia is also becoming a vital public health problem in Korea. Cognitive impairment as a pre-stage of dementia shares most risk factors for dementia. The aim of the present study was to determine associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans.SUBJECTS/METHODS: In this cross-sectional study, a total of 230 participants aged 60-79 years from Yangpyeong cohort were included. Cognitive function was assessed by the Korean version of the Mini-Mental State Examination for Dementia Screening. The logistic multivariable regression model was applied to determine the effect of serum vitamins A, C, and E on the risk of cognitive impairment.RESULTS: There was no significant association between the risk of cognitive impairment and serum levels of vitamin A and vitamin C. There was a significant odd ratio when the second tertile group of beta-gamma tocopherol level was compared to the first tertile group [odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.14-0.98, P for trend = 0.051]. In subgroup analyses, there were significant negative associations between beta-gamma tocopherol level and the risk of cognitive impairment in men (OR = 0.17, 95% CI = 0.03-0.87, P for trend = 0.028), non-drinkers or former drinkers (OR = 0.13, 95% CI = 0.02-0.66, P for trend = 0.025), and non-smokers or former smokers (OR = 0.27, 95% CI = 0.09-0.82, P for trend = 0.017).CONCLUSION: Serum beta-gamma tocopherol levels tended to be inversely associated with the risk of cognitive impairment. Further prospective large-scaled studies are needed to examine this association.This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012R1A1A1041792)
Evaluating adherence to recommended diets among cancer patients
No full textWe examined dietary and health-related behaviors among Korean cancer patients in the fourth Korean National Health and Nutrition Examination Survey. To compare the dietary and health-related behaviors among cancer patients, patients who had recovered from cancer, and those who had never had cancer, we obtained odds ratio (OR)s and 95% confidence interval (CI)s for the adherence to American Institute for Cancer Research (AICR) recommendations or a Dietary Approaches to Stop Hypertension (DASH)-style diet using the multivariate polytomous logistic regression. A total of 103 cancer patients, 139 patients who had recovered from cancer, and 7,963 participants who had never had cancer were included. Patients who had ever been diagnosed with cancer were more likely to follow AICR recommendations or a DASH-style diet compared to those who had never had cancer. Compared to bottom tertile of the AICR adherence score, ORs (95% CIs) in the top tertile were 3.19 (1.86-5.46) for patients who recovered from cancer and 3.34 (1.81-6.17) for cancer patients. For a DASH-style diet, we found an OR of 2.26 (95% CI 1.28-3.99) for patients who recovered from cancer and an OR of 1.60 (95% CI 0.89-2.89) for cancer patients, comparing top to bottom tertiles. We also found that the degree of adherence among cancer patients was stronger among ever smokers than never smokers. Korean patients who had ever been diagnosed with cancer showed higher adherence to diets designed to prevent cancer or high blood pressure than those who had never had cancer. Our observations warrant further prospective studies to evaluate the association of adherence to a healthy diet with survival and quality of life among Asian cancer patients.N
AI-assisted Analysis to Facilitate Detection of Humeral Lesions on Chest Radiographs
No full textPurpose: To develop an artificial intelligence (AI) system for humeral tumor detection on chest radiographs (CRs) and evaluate the impact on reader performance. Materials and Methods: In this retrospective study, 14 709 CRs (January 2000 to December 2021) were collected from 13 468 patients, including CT -proven normal ( n = 13 116) and humeral tumor ( n = 1593) cases. The data were divided into training and test groups. A novel training method called false -positive activation area reduction (FPAR) was introduced to enhance the diagnostic performance by focusing on the humeral region. The AI program and 10 radiologists were assessed using holdout test set 1, wherein the radiologists were tested twice (with and without AI test results). The performance of the AI system was evaluated using holdout test set 2, comprising 10 497 normal images. Receiver operating characteristic analyses were conducted for evaluating model performance. Results: FPAR application in the AI program improved its performance compared with a conventional model based on the area under the receiver operating characteristic curve (0.87 vs 0.82, P = .04). The proposed AI system also demonstrated improved tumor localization accuracy (80% vs 57%, P < .001). In holdout test set 2, the proposed AI system exhibited a false -positive rate of 2%. AI assistance improved the radiologists' sensitivity, specificity, and accuracy by 8.9%, 1.2%, and 3.5%, respectively ( P < .05 for all). Conclusion: The proposed AI tool incorporating FPAR improved humeral tumor detection on CRs and reduced false -positive results in tumor visualization. It may serve as a supportive diagnostic tool to alert radiologists about humeral abnormalities.Y
Comparison of the long-term efficacy and safety of generic Tacrobell with original tacrolimus (Prograf) in kidney transplant recipients
No full textSeung Yeon Son,1 Hye Ryoun Jang,1 Jung Eun Lee,1 Heejin Yoo,2 Kyunga Kim,2,3 Jae Berm Park,4 Sung Joo Kim,4 Ha Young Oh,1 Wooseong Huh1 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, 3Department of Digital Health, SAIHST, 4Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Abstract: This study aimed to evaluate the long-term efficacy and safety of a generic tacrolimus (Tacrobell [TCB]) compared to the original tacrolimus (Prograf [PGF]) in kidney transplant recipients. In this retrospective observational study, we analyzed the data from 444 patients who took TCB as a first-line immunosuppressive drug and 245 patients who took PGF. The 5-year graft survival rate was 92% for patients in the PGF group and 97% for patients in the TCB group, respectively. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval [CI] limit of the hazard ratio [HR]<1.2) for TCB compared to PGF (HR: 0.58; 95% CI: 0–1.14). The 5-year patient survival rate was 96% for patients in the PGF group and 97% for patients in the TCB group. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval limit of the HR<2.0) for TCB compared to PGF (HR: 0.83; 95% CI: 0–1.95). The 5-year acute rejection-free graft survival rate was not significantly different between the groups (TCB 67%, PGF 68.8%; P=0.6286). The incidence of adverse events including adverse cardiovascular or cerebrovascular events, malignancies, new-onset diabetes after transplantation, and infection events did not differ significantly between the two groups. We conclude that TCB is a comparable alternative to the original tacrolimus as a first-line immunosuppressive drug. Producers of generics should support further study of their products after approval to assure physicians of their efficacy and safety. Keywords: kidney transplant, generic, tacrolimu
Genome-wide search for genetic modulators in gene regulatory pathways: Weighted window-based peak identification algorithm
No full textAbstractGenome-wide gene expression and genotype data have been integratively analyzed in expression quantitative trait loci (eQTL) studies to elucidate the genetics of gene transcription. Most eQTL analyses have focused on identifying polymorphic genetic variants that influence the expression levels of individual genes, and such analyses may have limitations in explaining gene regulatory pathways that are likely to involve multiple genes and their genetic and/or non-genetic modulators. We have developed a novel two-step method for identifying potential genetic modulators of transcription processes for multiple genes in a biological pathway. We proposed a new weighted window-based peak identification algorithm to improve the detection of genetic modulators for individual genes and employed a Poisson-based test to search for master genetic modulators of multiple genes. Here, we have illustrated this two-step approach by analyzing the gene expression data in the Centre d'Etude du Polymorphisme Humain (CEPH) lymphoblast cells and single nucleotide polymorphism chip data
- …
