SEARCH · PubMed Health

Results for “Biomarker variability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources

PubMed2006

Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy.

Chronic liver diseases are very common worldwide, particularly those linked to viral hepatitis and to alcoholic and non-alcoholic fatty liver. Their natural history is variable and long-term evolution differs in individual patients. Optimised clinical management of compensated chronic liver diseases requires precise definition of the stage of liver fibrosis, the main determinant of prognosis and of most therapeutic decisions. Liver biopsy is the gold standard for assessment of hepatic fibrosis. However, it is invasive with possible complications, costly and prone to sampling errors. Many non-invasive markers of liver fibrosis have been recently proposed and assessed in the clinical setting as surrogates of liver biopsy. Direct markers are based on biochemical parameters directly linked to fibrogenesis while indirect markers use simple or more sophisticated parameters that correlate with liver fibrosis stages. Non-invasive markers of liver fibrosis have been tested in different forms of chronic liver disease and showed variable diagnostic performance, but accuracy rarely was above 75%-80%. Better results were obtained when markers were combined. On this line, we have recently proposed a set of algorithms that combine sequentially indirect non-invasive markers of liver fibrosis, reaching 90%-95% diagnostic accuracy with significant reduction in the need for liver biopsy. Based on available evidence, it can be anticipated that non-invasive markers of liver fibrosis and their combined use will soon become a most useful tool in the clinical management of many forms of chronic liver disease. However, their implementation is expected to reduce, but not to completely eliminate, the need for liver biopsy.

Algorithms↗

PubMed2001

Cytogenetic analysis of Greek farmers using the micronucleus assay in peripheral lymphocytes and buccal cells.

The potential cytogenetic damage associated with pesticide use in Greek agricultural workers was evaluated using micronuclei (MN) as biomarkers in lymphocytes of peripheral blood and exfoliated cells of the buccal mucosa. In addition, the effects of pesticide exposure and other variables on the cytokinesis block proliferation index (CBPI) in lymphocytes were also evaluated. Both the exposed and control individuals were selected from Nea Makri, a village near Athens (Greece). This location was selected for its high greenhouse density. Micronuclei were analysed in 50 agricultural workers exposed to pesticides (30 men and 20 women) and in 66 non-exposed individuals that constituted the control group (41 men and 25 women). The comparison between workers and controls did not reveal any statistical significant difference in the MN frequency for either lymphocytes or buccal cells. Nevertheless, the multiple regression analysis revealed that the age and the interaction between gender and the number of X-ray examinations during the last 3 years preceding the sampling increased the number of MN in lymphocytes. Moreover, the results of the negative binomial regression analysis suggested that the level of MN in buccal cells could be reduced by the intake of fish, whilst being increased by olive oil consumption. Regarding CBPI, the value found in the exposed group was lower than in controls, the difference being statistically significant. On the other hand, CBPI was inversely associated with both age and X-ray exposure.

Adult↗

PubMed2003

Effects of intermittent exposure to aflatoxin B1 on DNA and RNA adduct formation in rat liver: dose-response and temporal patterns.

We studied the effects of intermittent exposure to aflatoxin B1 (AFB1) on hepatic DNA and RNA adduct formation. Fisher-344 male rats were fed 0.01, 0.04, 0.4, or 1.6 ppm of AFB1 intermittently for 8, 12, 16, and 20 weeks, alternating with 4 weeks of dosing and 4 weeks of rest. Other groups of rats were fed 1.6 ppm of AFB1 continuously for 4, 8, 12, and 16 weeks. Control rats received AFB1-free NIH-31 meal diet. AFB1-DNA and -RNA adducts were measured by HPLC with fluorescence detection. The data are presented as total DNA or RNA adducts. The DNA and RNA adduct levels increased or decreased depending on the cycles of dosing and rest. Rats removed from treatment 1 month after 1 or 2 dosing cycles (8 and 16 weeks of intermittent exposure) showed approximately a twofold decrease in DNA adduct levels and a two- to elevenfold decrease in RNA adduct levels compared with rats euthanized immediately after the last dosing cycle (12 and 20 weeks of intermittent exposure). Our data indicate that DNA and RNA adducts increased linearly, from 0.01 ppm to 1.6 ppm of AFB1 after 12 and 20 weeks of intermittent treatment. A linear dose response was also apparent for DNA but not for RNA adducts after 8 and 16 weeks of treatment. As biomarkers of exposure, AFB1-RNA adducts were three to nine times more sensitive than AFB1-DNA adducts but showed greater variability. These results suggest that binding of AFB1 to hepatic DNA is a linear function of the dose, regardless of the way this is administered. The dose-response relationship for RNA adducts depends on the length of the no-dosing cycles and on the turnover rate of RNA.

Aflatoxin B1↗

PubMed2005

Evidence for restricted Vbeta usage in the leukemic phase of cutaneous T cell lymphoma.

Antibodies directed against the beta chain of the T cell receptor (anti-Vbeta antibodies) are useful to identify the Vbeta repertoire of T cells in various diseases and to quantify numbers of Vbeta-bearing T cells. The goals of this study were to identify Vbeta+ cases of leukemic phase cutaneous T cell lymphoma (CTCL) and to compare the percentage of positive calls with other measures of blood tumor burden, i.e., lymphocyte subsets with a CD4+CD7- and CD4+CD26- phenotype and Sezary cell counts. Thirty-three of 49 (67%) cases of leukemic CTCL reacted with an anti-Vbeta antibody. When combined with reports from the literature, the frequency of Vbeta5 (probably Vbeta5.1) usage was relatively high when compared with Vbeta2 that is also frequently expressed by normal CD4+ T cells. The percentage of Vbeta+ cells correlated to the percentage of CD4+CD7- and CD4+CD26- cells for cases in which the neoplastic cells were deficient in expression of CD7 and CD26, respectively, but not the Sezary cell count. We hypothesize that the increased Vbeta5.1 usage in CTCL may be the result of depletion of Vbeta2 and other Vbeta-bearing T cells by staphylococcal superantigens prior to neoplastic transformation, resulting in a relative increase in the frequency of Vbeta5.1 usage in CTCL.

Adult↗

PubMed1999

Radioimmunotherapy of human colon cancer xenografts using a dimeric single-chain Fv antibody construct.

Progress in the use of monoclonal antibodies (MAbs) for the treatment of solid tumors is limited by a number of factors, including poor penetration of the labeled IgG molecule into the tumors, their inability to reach the tumor in sufficient quantities without significant normal tissue toxicity, and the development of a human antimouse antibody response to the injected MAb. One possible way to alter the pharmacology of antibodies is via the use of smaller molecular weight antibody fragments called single-chain Fvs (scFvs). A divalent construct of MAb CC49, CC49 (scFv)2, composed of two noncovalently associated scFvs, was generated and shown to bind a tumor-associated antigen (TAG-72) epitope with a similar binding affinity to that of the murine IgG. The therapeutic potential of this construct after labeling with 131I was examined in athymic mice bearing established s.c. human colon carcinoma (LS-174T) xenografts. Treatment groups (n = 10) received a single dose of 131I-labeled CC49 (scFv)2 (500-2000 microCi) or 131I-labeled CC49 IgG (250 and 500 microCi). The group of mice treated with the lowest dose of 131I-(scFv)2 (500 microCi) showed statistically significant prolonged survival, compared with controls (P = 0.036). Complete tumor regression was observed in 20% of mice given 1500 microCi of labeled (scFv)2 and 30 and 60% of mice treated with 250 and 500 microCi of labeled IgG, respectively. In conclusion, the CC49 (scFv)2 construct provides a promising delivery vehicle for therapeutic applications.

Animals↗

PubMed1997

Staining of micronuclei in squamous epithelial cells of human oral mucosa.

OBJECTIVE: To evaluate the influence of methodologic variables, staining method and sampling, on the frequency of micronuclei scored in squamous epithelial cells of oral mucosa. Micronuclei were used as biomarkers of structural and numerical chromosome damage. STUDY DESIGN: Feulgen and Giemsa stain and fluorescent dyes Hoechst 33258 and propidium iodide were used for micronucleus staining. Cells were collected by either light or vigorous scraping of oral mucosa. RESULTS: Staining of micronuclei by Hoechst 33258 proved more handly, less time consuming and at least equally reliable to the more widely used Feulgen staining. Results with Giemsa stain and propidium iodide were unsatisfactory. Micronuclei were less frequent in superficial layers of the oral mucosa. CONCLUSION: Hoechst 33258 can be recommended for micronucleus staining in squamous epithelial cells of oral mucosa. Differences in scraping may affect the measurement of micronucleus frequency; scraping should therefore be carefully standardized in each laboratory.

Epithelial Cells↗

PubMed1999

Preliminary external quality assessment for the biological monitoring of carbon disulfide with urinary 2-thiothiazolidine-4-carboxylic acid.

Four laboratories have participated in an external quality control assessment for the determination of 2-thiothiazolidine-4-carboxylic acid (TTCA). TTCA is used as a biomarker for exposure to CS2. Thirteen different urine samples were analyzed by each laboratory. Ten of these were spiked with known amounts of TTCA, and had either a high or intermediate creatinine content. Two samples without any TTCA were used as controls and one sample was a pool of samples of urine from five employees occupationally exposed to CS2. The latter had unknown TTCA content. For each sample, TTCA and creatinine concentration were determined. The samples were supplied in three consecutive deliveries. Several samples were offered more than once. Thus, within-laboratory variability could be established for creatinine and TTCA determination and accuracy could be determined for TTCA analysis. Within-laboratory variability was low for all laboratories for creatinine, although laboratory D seemed to have a slight downward bias. Accuracy for TTCA was good for all laboratories. No significant mean deviation from the expected TTCA value was encountered. There does not seem to be any clear influence of the TTCA concentration level of the samples on the accuracy and within-laboratory variability. Two of the four laboratories (A and C) showed lower within-laboratory variability than the other two for TTCA, although coefficients of variation between replicated samples are high for these two laboratories as well. The laboratory giving the best accuracy, gave the highest within-laboratory variability. A non-systematic, random error is probably the source of this. The results of this preliminary study indicate that analysis of TTCA, although regarded as an established biomarker, can give biases and thus negatively interfere with inferred dose-effect or dose-response relationships in occupational epidemiology.

Bias↗

PubMed2005

Unexpectedly high prevalence of alcohol use among pregnant Swedish women: failed detection by antenatal care and simple tools that improve detection.

OBJECTIVE: We examined the use of alcohol during early pregnancy in urban Swedish women, the ability of Swedish antenatal care to identify alcohol-related risk pregnancies and the utility of some potential tools for improving its performance. METHOD: Women attending regular antenatal care were randomized to regular assessment only (control, n = 156) or intensified screening (intervention, n = 147). In the intervention group, alcohol use was determined using the Timeline Followback (TLFB) interview, alcohol use habits with the Alcohol Use Disorder Inventory Test (AUDIT), and biomarkers for alcohol use were analyzed. Data were typically obtained in pregnancy week 12. RESULTS: In the intervention group as a whole, average absolute alcohol consumption during the first 6 weeks of pregnancy was low but highly variable (mean [SD] = 24.9 [50.5] g/week; 4.8 [6.0] episodes for the entire 6 week period); 22 women (15%) drank at levels exceeding 70 g/week during any 2 or more weeks and/or in a heavy episodic drinking pattern, 60 g/episode, on 2 or more episodes. The AUDIT had a moderate sensitivity (54%) to identify these subjects. Biomarkers identified subjects with somatic illness rather than high alcohol consumption. In the control group, only 4 (3%) were identified as using alcohol, indicating a probable underestimation of alcohol use by regular antenatal screening procedures (p = .0001). CONCLUSIONS: An unexpected proportion of pregnant women in urban Sweden consume alcohol at levels likely to produce adverse effects. Regular antenatal care did not identify most of these risk pregnancies. The TLFB identified pregnant women with risk use of alcohol during pregnancy who were only partly identified by analyzing prepregnancy alcohol use patterns with the AUDIT. Elevated laboratory markers likely indicated somatic illness rather than harmful drinking.

Adult↗

PubMed2006

Defective maturation of dendritic cells in common variable immunodeficiency.

Monocyte-derived dendritic cells (MdDCs) from many patients with common variable immunodeficiency (CVID) have been shown recently to have reduced expression of surface molecules associated with maturity. Using flow cytometry and confocal microscopy, we now show that this is due to a partial failure to fix Class II DR molecules on the surface during procedures that induce full maturation in vitro in cells from normal subjects. Major histocompatibility complex (MHC) class I, CD86 and CD83 expression were expressed normally, but CD40 was reduced. These abnormalities are unlikely to be due to prior in vivo exposure of monocytes to lipopolysaccharide (LPS), as addition of LPS to monocytes from normal subjects in vitro caused a different pattern of changes. CVID MdDCs retained Class II DR in the cytoplasm during maturation, showed increased internalization of cross-linked Class II DR surface molecules and were unable to polarize DR within a lipid raft at contact sites with autologous lymphocytes. These cells retained some features of monocytes, such as the ability to phagocytose large numbers of fixed yeast and fluorescent carboxylated microspheres and expression of surface CD14. These abnormalities, if reflected in vivo, could compromise antigen presentation and may be a fundamental defect in the mechanism of the antibody deficiency in a substantial subset of CVID patients.

Adult↗

PubMed2002

Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker.

Human kallikrein 6 protein is a newly discovered human kallikrein. We determined the amount of human kallikrein 6 in extracts of 182 ovarian tumours and correlated specific activity (ng hK6 mg(-1) total protein) with clinicopathological variables documented at the time of surgical excision and with outcome (progression free survival, overall survival) monitored over a median interval of 62 months. Thirty per cent of the tumours were positive for human kallikrein 6 (>35 ng hK6 mg(-1) total protein). Human kallikrein 6-specific immunohistochemical staining of four ovarian tissues that included benign, borderline and malignant lesions indicated a cytoplasmic location of human kallikrein 6 in tumour cells of epithelial origin, although the intensity of staining was variable. Tumour human kallikrein 6 (ng hK6 mg(-1) total protein) was higher in late stage disease, serous histotype, residual tumour >1 cm and suboptimal debulking (>1 cm) (P<0.05). Univariate analysis revealed that patients with tumour human kallikrein 6 positive specific activity were more likely to suffer progressive disease and to die (hazard ratio 1.71 (P=0.015) and 1.88 (P=0.022), respectively). Survival curves demonstrated the same (P=0.013 and 0.019, respectively). Multivariate analysis revealed that human kallikrein 6 positivity was retained as an independent prognostic variable in several subgroups of patients, namely those with (low) grade I and II tumours (hazard ratio progression free survival 4.3 (P=0.027) and overall survival 4.1 (P=0.023)) and those with optimal debulking (hazard ratio progression free survival 3.8 (P=0.019) and overall survival 5.6 (P=0.011)). We conclude that tumour kallikrein 6 protein levels have utility as an independent adverse prognostic marker in a subgroup of ovarian cancer patients with otherwise apparently good prognosis.

Adult↗

PubMed2006

Utility of a new model to diagnose an alcohol basis for steatohepatitis.

BACKGROUND & AIMS: Distinguishing an alcohol basis from a nonalcoholic basis for the clinical and histologic spectrum of steatohepatitic liver disease is difficult because of unreliability of alcohol consumption history. Unfortunately, various biomarkers have had limited utility in distinguishing alcoholic liver disease (ALD) from nonalcoholic fatty liver disease (NAFLD). Thus, the aim of our study was to create and validate a model to diagnose ALD in patients with steatohepatitis. METHODS: A cross-sectional cohort study was performed at the Mayo Clinic, Rochester, Minnesota, to create a model using multivariable logistic regression analysis. This model was validated in 3 independent data sets comprising patients of varying severity of steatohepatitis spanning over 10 years. RESULTS: Logistic regression identified mean corpuscular volume, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, body mass index, and gender as the most important variables that separated patients with ALD from NAFLD. These variables were used to generate the ALD/NAFLD Index (ANI), with ANI of greater than zero incrementally favoring ALD and ANI of less than zero incrementally favoring a diagnosis of NAFLD, thus making ALD unlikely. ANI had a c-statistic of 0.989 in the derivation sample, and 0.974, 0.989, 0.767 in the 3 validation samples. ANI performance characteristics were significantly better than several conventional and recently proposed biomarkers used to differentiate ALD from NAFLD, including the histopathologic marker protein tyrosine phosphatase 1b, AST/ALT ratio, gamma-glutamyl transferase, and carbohydrate-deficient transferrin. CONCLUSIONS: ANI, derived from easily available objective variables, accurately differentiates ALD from NAFLD in hospitalized, ambulatory, and pretransplantation patients and compares favorably with other traditional and proposed biomarkers.

Adult↗

PubMed2006

Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture.

Corneal diseases are some of the most prevalent causes of blindness worldwide. While the most common treatment for corneal blindness is the transplantation of cadaver corneas, expanded limbal stem cells are finding recent application. Unknown, however, is the identity of the actual repopulating stem cell fraction utilized in both treatments and the critical factors governing successful engraftment and repopulation. In order to localize potential stem cell populations in vivo, we have immunohistochemically mapped a battery of candidate stem and progenitor cell markers including c-Kit and other growth factor receptors, nuclear markers including DeltaNp63, as well as adhesion factors across the cornea and distal sclera. Cell populations that differentially and specifically stained for some of these markers include the basal and superficial limbal/conjunctival epithelium and scattered cells within the substantia propria of the bulbar conjunctiva. We have also determined that the culture of differentiated cornea epithelial cells as dissociated and explant cultures induces the expression of several markers previously characterized as candidate limbal stem cell markers. This study provides a foundation to explore candidate corneal stem cell populations. As well, we show that expression of traditional stem cell markers may not be reliable indicator of stem cell content during limbal stem cell expansion in vitro and could contribute to the variable success rates of corneal stem cell transplantation.

Adult↗

PubMed2006

KIF14 mRNA expression is a predictor of grade and outcome in breast cancer.

Gain of chromosome 1q is a hallmark of breast cancer, and likely reflects oncogene amplification. We previously identified mitotic kinesin KIF14 (kinesin family member 14) as an overexpressed candidate oncogene in the 1q31.3-1q32.1 minimal region of genomic gain in breast cancer cell lines. KIF14 also showed high expression in other cancers, notably an association with survival in lung tumors. We now report KIF14 expression in 99 primary breast tumors and 10 normal breast controls. Measured by real-time RT-PCR, KIF14 was overexpressed 10-fold on average in tumors relative to normals (t test p = 0.000054); expression increased with grade (ANOVA p = 0.000006). Infiltrating ductal carcinomas had higher KIF14 levels than lobular (p = 0.017), and estrogen receptor (ER) negative tumors had higher KIF14 levels than ER positive tumors (t test p = 0.030). KIF14 expression correlated positively with Ki-67 mRNA level (Spearman r = 0.692, p = 0.000001), fraction of positive nodes (r = 0.227, p = 0.024) and percent invasive cells (r = 0.360, p = 0.0002), and negatively with percent fatty stroma (r = -0.258, p = 0.010) and percent normal epithelium (r = -0.291, p = 0.003). KIF14 expression is thus tumor-specific and increased in more aggressive tumors. Indeed, KIF14 expression predicted overall survival (univariate Cox p = 0.010), with an odds ratio of 3.60 (1.37-9.48), in 50 tumors with available outcome data. KIF14 overexpression also predicted decreased disease-free survival (log-rank p = 0.049). These findings are the first evidence of association between expression of a mitotic kinesin and prognostic variables in breast cancer.

Adult↗

PubMed2005

The effects of serial intravascular transfusions in ascitic/hydropic RhD-alloimmunized fetuses.

OBJECTIVE: To evaluate the effects of serial intravascular transfusions on RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion by measuring multiple hematological/biochemical blood variables. METHODS: Thirty-one singleton pregnancies were referred for management of RhD alloimmunization. Seven fetuses had hydrops on presentation and were transfused immediately. The remainder underwent weekly ultrasound examinations, and fetal blood sampling and transfusion were performed on development of ascites. In the 104 samples collected overall from the 31 fetuses, glucose, uric acid, urea, creatinine, total protein, total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, lactic dehydrogenase, amylase, pseudocholinesterase (PCHE), creatine kinase, triglycerides and cholesterol were measured and compared with a reference range for non-anemic fetuses. RESULTS: The median gestational age at first transfusion was 26 (range, 18-34) weeks. There were three fetal losses after the first transfusion, two of which were due to procedure-related complications; one further loss occurred. At the first transfusion fetal hematocrit, pO2, total protein, PCHE, creatinine and urea concentrations were significantly decreased compared to reference data, while total and direct bilirubin, AST, ALT, amylase, triglyceride and uric acid concentrations were increased. In all surviving fetuses ascites/hydrops had disappeared by the second transfusion. Fetal pO2, total protein, AST, ALT and PCHE concentrations had normalized by the third transfusion. Correction of fetal anemia did not affect the other variables. CONCLUSIONS: RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion had a survival rate of 87%. Alterations of several biochemical fetal blood indices are present at the first sampling/transfusion, but most variables normalize with intravascular transfusions.

Ascites↗

PubMed2000

Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in Hodgkin's disease, the milan cancer institute experience.

Alterated cytokine secretion may play a role in determining Hodgkin's disease-related immunosuppression. The aim of this study was to analyze the clinical significance of interleukin-10 (IL-10) serum levels in 73 chemotherapy-naive patients with Hodgkin's disease. We evaluated the relationship between pretreatment circulating values of IL-10 and both the clinical characteristics of the disease as well as the prognosis in terms of freedom from progression and overall survival. Abnormally high pre-treatment serum levels (mean+/-standard error: 26.79+/-13.24 pg/ml) were detected in 33/73 (45%) patients. The percentage of patients with enhanced IL-10 secretion was significantly higher in the presence of advanced disease (56% vs 32%, P<0.03), systemic symptoms (57% vs 34%, P<0.04) and more than 3 involved sites (61% vs 36%, P<0.03). The high basal levels of IL-10 negatively influenced long-term results: at 8-years freedom from progression (FFP) and overall survival (OS) for patients with IL-10>6 pg/ml vs</=6 pg/ml were 69% and 76% vs 97. 5% and 95%, respectively. The multivariate analysis confirmed the prognostic value of IL-10 basal serum levels (FFP, P=0.0001; OS, P=0. 06). Our study suggests that high pre-treatment circulating levels of IL-10 are associated with a poor prognosis, irrespective of other common prognostic variables.

Adolescent↗

PubMed2006

Relation of C-reactive protein and tumor necrosis factor-alpha to ambulatory blood pressure variability in healthy adults.

Elevated blood pressure (BP) variability has been linked to an increased risk for adverse cardiovascular events, but the biologic factors that promote elevated BP variability are not entirely understood. This cross-sectional study examined whether inflammatory factors might be associated with elevated BP variability during 24-hour ambulatory BP monitoring. Subjects were 140 healthy, normotensive adults. Inflammatory markers included C-reactive protein (CRP) and tumor necrosis factor-alpha. BP variability was calculated as the within-subject SD of BP values obtained during the daytime, nighttime, and 24-hour periods. In linear regression models that were adjusted for mean BP and other factors, CRP quartiles were positively associated with daytime systolic BP variability; for subjects in the lowest to highest CRP quartiles, the mean within-subject SDs of daytime systolic BP were 9.31, 9.62, 10.55, and 11.17, respectively (p for linear trend = 0.001). CRP showed similar positive associations with nighttime and 24-hour systolic BP variability. In contrast, tumor necrosis factor-alpha was not independently associated with systolic BP variability during any of the time periods. With respect to diastolic BP variability, significant positive associations were found between CRP and diastolic BP variability during all time periods and between tumor necrosis factor-alpha and daytime diastolic BP variability. In conclusion, there are positive associations between markers of inflammation and BP variability in healthy, normotensive adults, suggesting that inflammation may be 1 of the factors that promotes increased BP variability.

Adult↗

PubMed2006

Shrinkage estimation method for mapping multiple quantitative trait loci.

In this article, shrinkage estimation method for multiple-marker analysis and for mapping multiple quantitative trait loci (QTL) was reviewed. For multiple-marker analysis, Xu (Genetics, 2003, 163:789-801) developed a Bayesian shrinkage estimation (BSE) method. The key to the success of this method is to allow each marker effect have its own variance parameter, which in turn has its own prior distribution so that the variance can be estimated from the data. Under this hierarchical model, a large number of markers can be handled although most of them may have negligible effects. Under epistatic genetic model, however, the running time is very long. To overcome this problem, a novel method of incorporating the idea described above into maximum likelihood, known as penalized likelihood method, was proposed. A simulated study showed that this method can handle a model with multiple effects, which are ten times larger than the sample size. For multiple QTL analysis, two modified versions for the BSE method were introduced: one is the fixed-interval method and another is the variable-interval method. The former deals with markers with intermediate density, and the latter can handle markers with extremely high density as well as model with epistatic effects. For the detection of epistatic effects, penalized likelihood method and the variable-interval approach of the BSE method are available.

Bayes Theorem↗

PubMed1992

Cell proliferation of transitional cell bladder tumours determined by PCNA/cyclin immunostaining and its prognostic value.

Cell proliferation of transitional cell bladder cancer (TCC) was determined by PCNA (proliferating cell nuclear antigen)/cyclin immunostaining in 178 TCCs and the results were related to established prognostic factors, progression and survival during a mean follow-up period of 10 years. The fraction of PCNA/cyclin positive nuclei was related to T-category (P = 0.008), papillary status, WHO grade, DNA ploidy, S phase fraction, M/V index (volume corrected mitotic index) and AgNORs (silver stained nucleolar organiser regions) (for all P less than 0.001). TCCs presenting with pelvic lymph node metastasis at diagnosis had a significantly higher growth fraction than the tumours confined to the bladder wall (P less than 0.001). The fraction of PCNA/cyclin positive nuclei predicted progression in T-, N- and M-categories (P less than 0.001). In Ta-T1 tumours high fraction of PCNA/cyclin positive nuclei predicted metastasis (P = 0.019). In survival analysis the fraction of PCNA/cyclin positive nuclei predicted survival in the entire cohort (P less than 0.001) and in Ta-T1 tumours (P = 0.0005). In a multivariate survival analysis the fraction of PCNA/cyclin positive nuclei showed independent predictive value in the entire cohort (P = 0.046), in papillary tumours (P = 0.006) and in Ta-T1 tumours (P = 0.015). The results show that the growth fraction as determined by PCNA/cyclin immunostaining is a significant prognostic variable in TCC.

Analysis of Variance↗