Biomedical subjects

Varghese George

Publications and source records attributed to Varghese George.

7 recordsLinked to original sources

PubMed2003

"Are we there yet?": Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits.

Although mathematical relationships can be proven by deductive logic, biological relationships can only be inferred from empirical observations. This is a distinct disadvantage for those of us who strive to identify the genes involved in complex diseases and quantitative traits. If causation cannot be proven, however, what does constitute sufficient evidence for causation? The philosopher Karl Popper said, "Our belief in a hypothesis can have no stronger basis than our repeated unsuccessful critical attempts to refute it." We believe that to establish causation, as scientists, we must make a serious attempt to refute our own hypotheses and to eliminate all known sources of bias before association becomes causation. In addition, we suggest that investigators must provide sufficient data and evidence of their unsuccessful efforts to find any confounding biases. In this editorial, we discuss what "causation" means in the context of complex diseases and quantitative traits, and we suggest guidelines for steps that may be taken to address possible confounders of association before polymorphisms may be called "causative."

Cystic Fibrosis↗

PubMed2003

Colon biopsies for evaluation of acute graft-versus-host disease (A-GVHD) in allogeneic bone marrow transplant patients.

BACKGROUND: Proper histomorphological interpretation of intestinal acute graft versus host disease (A-GVHD) associated with allogeneic bone marrow transplantation (BMT) is critical for clinical management. However, studies methodically evaluating different histomorphological features of A-GVHD are rare. METHODS: Colonic biopsies from 44 allogeneic BMT patients having biopsy-proven cutaneous A-GVHD were compared with colon biopsies from 48 negative controls. RESULTS: A-GVHD showed intra-cryptal apoptosis in 91% and pericryptal apoptosis in adjacent lamina propria in 70% (p < 0.002). Nonspecific apoptosis along the surface epithelium was observed in all groups with comparable frequency. The number of apoptotic cells in mucosa were approximately four times (5.3 per 10 HPF) the negative controls (p < 0.002) in A-GVHD group. 48% of cases with A-GVHD showed decreased number of lymphocytes in lamina propria. Some features, including intraepithelial lymphocytes in surface or crypt epithelium; and neutrophils, eosinophils, and edema in lamina propria, did not demonstrate significant difference in A-GVHD and negative controls. Pericryptal apoptosis, dilated crypts, irregular distribution of crypts, decreased lymphocytes, increased microvessel network, focal fibrosis, presence of muciphages, reactive changes in surface epithelium with mucin depletion, mucosal ulceration, and/or reduced mucosal thickness showed higher association with A-GVHD group. CONCLUSIONS: Intracyptal apoptosis is a reliable indicator of A-GVHD. Its diagnostic significance was improved if intracyptal apoptosis was associated with features which were observed more frequently in A-GVHD group as mentioned above.

Acute Disease↗

PubMed2003

Stochastic search variable selection for identifying multiple quantitative trait loci.

In this article, we utilize stochastic search variable selection methodology to develop a Bayesian method for identifying multiple quantitative trait loci (QTL) for complex traits in experimental designs. The proposed procedure entails embedding multiple regression in a hierarchical normal mixture model, where latent indicators for all markers are used to identify the multiple markers. The markers with significant effects can be identified as those with higher posterior probability included in the model. A simple and easy-to-use Gibbs sampler is employed to generate samples from the joint posterior distribution of all unknowns including the latent indicators, genetic effects for all markers, and other model parameters. The proposed method was evaluated using simulated data and illustrated using a real data set. The results demonstrate that the proposed method works well under typical situations of most QTL studies in terms of number of markers and marker density.

Bayes Theorem↗

PubMed2002

A Bayesian approach to the transmission/disequilibrium test for binary traits.

The transmission/disequilibrium test (TDT) for binary traits is a powerful method for detecting linkage between a marker locus and a trait locus in the presence of allelic association. The TDT uses information on the parent-to-offspring transmission status of the associated allele at the marker locus to assess linkage or association in the presence of the other, using one affected offspring from each set of parents. For testing for linkage in the presence of association, more than one offspring per family can be used. However, without incorporating the correlation structure among offspring, it is not possible to correctly assess the association in the presence of linkage. In this presentation, we propose a Bayesian TDT method as a complementary alternative to the classical approach. In the hypothesis testing setup, given two competing hypotheses, the Bayes factor can be used to weigh the evidence in favor of one of them, thus allowing us to decide between the two hypotheses using established criteria. We compare the proposed Bayesian TDT with a competing frequentist-testing method with respect to power and type I error validity. If we know the mode of inheritance of the disease, then the joint and marginal posterior distributions for the recombination fraction (theta) and disequilibrium coefficient (delta) can be obtained via standard MCMC methods, which lead naturally to Bayesian credible intervals for both parameters.

Alleles↗

PubMed2002

Subtenon's depot corticosteroid injections in patients with a history of corticosteroid-induced intraocular pressure elevation.

PURPOSE: To determine whether a history of intraocular pressure elevation from local corticosteroid administration could predict subsequent intraocular pressure elevation after posterior subtenon's corticosteroid injection. METHODS: A retrospective review was performed of 64 consecutive patients (64 eyes) receiving posterior subtenon's corticosteroid injection. Patients were categorized as either historical corticosteroid responders or nonresponders based on intraocular pressure response to topical corticosteroid drops in the same eye or to previous posterior subtenon's corticosteroid injection of the fellow eye. Historical responders were defined as having a relative intraocular pressure increase of 5 mm Hg and absolute intraocular pressure greater than 24 mm Hg with an anatomically open angle. Relative risk of intraocular pressure elevation was evaluated based on historical response and presenting diagnosis. RESULTS: Nine eyes were historical responders, and 55 eyes were historical nonresponders. A higher rate of recurrent intraocular pressure elevation developed in historical responder eyes (4 of 9, 44%) compared with nonresponders (7 of 55, 13%) after posterior subtenon's injection (P = .04, Fisher's test; P = .07, Kaplan-Meier analysis). Historical responders with uveitis were at significantly higher risk of intraocular pressure elevation than nonresponders without uveitis (hazard ratio = 10.8, P = .04, Cox proportional hazards). All but one eye that developed intraocular pressure elevation from posterior subtenon's injection was adequately controlled with topical antiglaucoma therapy. CONCLUSION: In nonglaucomatous eyes, a previous history of corticosteroid-induced intraocular pressure elevation is a relative, not absolute, contraindication to posterior subtenon's corticosteroid injection, because the risk of intraocular pressure elevation is not absolute, and because it can usually be well controlled with topical antiglaucoma therapy.

Adult↗

PubMedDate not supplied

Radium in Wisconsin drinking water: an analysis of osteosarcoma risk.

Epidemiological studies of radium dial painters have found an association between exposure to high-dose radium and bone cancers. However, only limited data exist on the relationship between low doses of radium, as are found in some drinking water sources, and osteosarcoma. The authors conducted a population-based case-control study to examine the association between exposure to radium in drinking water and the occurrence of osteosarcoma. Estimates of radium exposure and covariates used were based on subjects' residential ZIP codes. The median radium level was not significantly associated with osteosarcoma (odds ratio = .98; 95% confidence interval = .93, 1.04; p = .56). The authors found no evidence that radium, at current levels in Wisconsin drinking water, resulted in excess cases of osteosarcoma.

Adolescent↗

PubMedDate not supplied

A randomized, double-blind, controlled trial of vitamin C in the management of hypertension and lipids.

The effect of vitamin C on blood pressure is not well established. This is a randomized, double-blind control trial. Eligible patients were followed for 8 months. Patients were randomized to 500, 1000, or 2000 mg vitamin C. During each visit, a history including medication change was obtained and standardized blood pressure measurements were performed. A 1-week dietary diary was filled out before each visit. Multiple regression analysis and subsequent multiple comparisons were used for data analysis. Fifty-four patients satisfied our criteria and agreed to participate. Thirty-one patients (mean age, 62 +/- 2 years; 52% men, 90% whites) were randomized to the three doses of vitamin C. Overall compliance was 48 +/- 2%. Both mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased during the vitamin C supplementation phase [mean SBP dropped by 4.5 +/- 1.8 mm Hg (P <.05) and DBP by 2.8 +/- 1.2 mm Hg (P <.05)]. There was no difference between the three vitamin C groups (P =.48). This effect was significant for only 1 month of supplementation, but the trend persisted. There was no reported intolerance to vitamin C. There was no change in lipid levels after 6 months of treatment. Vitamin C supplementation lowers blood pressure in mildly hypertensive patients. There is no additional benefit for a higher dose than 500 mg daily. The effect of vitamin C is most likely to be only short term.

Antioxidants↗