No association between germline allele-specific expression of TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations.

BACKGROUND: Germline allele-specific expression (ASE) of the TGFBR1 gene has been reported as a strong risk factor for colorectal cancer (CRC) with an odds ratio close to 9. Considering the potential implications of the finding, we undertook the task of validating the initial results in this study. METHODS: Allele-specific expression was measured using the highly quantitative and robust technique of pyrosequencing. Individuals from two different populations were studied, one Caucasian-dominated and the other of Ashkenazi Jewish descent, with different sources of non-tumoral genetic material in each. RESULTS: Our results showed no statistically significant differences in the degree of ASE between CRC patients and controls, considering ASE as either a quantitative or a binary trait. Using defined cutoff values to categorise ASE, 1.0% of blood lymphocytes from informative Israeli cases (total n=96) were ASE positive (median 1.00; range 0.76-1.31) and 2.2% of informative matched controls (total n=90) were ASE positive (median 1.00; range 0.76-1.87). Likewise, normal mucosae from Spanish patients (median 1.03; range: 0.68-1.43; n=75) did not show significant differences in the degree of ASE when compared with the Israeli patients or controls. CONCLUSIONS: Taken together, these results suggest that ASE of TGFBR1 does not confer an increased risk of CRC.

Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype.

The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P=0.005; DZOase, P=0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P<0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a "level crossing" approach that includes intervening phenotypes in the study of complexly inherited disease.

Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype.

Paraoxonase (PON1) is tightly associated with high-density lipoprotein particles and is believed to contribute to the prevention of atherosclerosis by metabolizing oxidized lipids. PON1 also hydrolyses the bioactive oxon forms of organophosphorus pesticides such as parathion, diazinon and chlorpyrifos. Two common polymorphisms have been identified in the coding sequence of human PON1: L55M and R192Q. Several previous studies have found that the presence of the PON1R192 allele raises the risk of cardiovascular disease while others found no correlation. The studies, however, have focused on the genotype of PON1 and not the expression level of the protein. We found that the PON1 expression level in plasma, as determined by the rates of paraoxon and diazoxon hydrolysis, varies widely among individuals and within a genotype. Previous studies found that individuals having Met at PON155 have lower levels of both PON1 mRNA and activity. In this study, we determined the plasma activity levels of PON1 and examined the relationships between PON155 genotype and PON1 level. As with PON1192, we found considerable overlap in activity among the PON155 genotypes. Of the 317 individuals whose PON1 status was determined in this study, 48.9% were PON1Q192 homozygotes. Analysis of the PON1QQ192 population showed that while the average PON1 activity (diazoxon hydrolysis) was 12266 U/L for PON1LL55 and 7777 U/L for PON1MM55, a given PONMM55 individual could have more than twice the activity of a PON1LL55 individual. PON1 status, which includes PON1 level as well as PON1192 genotype, may be a better predictor for cardiovascular disease or organophosphate susceptibility than PON1 genotype alone.

Impact of family structure on the power of linkage tests using sib-pair methods.

This analysis sought to determine the impact of specific ascertainment criteria based upon nuclear family affectation structures. Specifically, we evaluated the predicted and observed proportion of alleles shared identical by descent conditional on the number of affected and unaffected siblings in a pedigree, and compared sib-pair method linkage results under two ascertainment schemes, random vs. selected ascertainment, for this simulated complex genetic disease. These results suggest that samples differing in the composition of affected and unaffected siblings in the family will differ in their power to detect linkage. An effect of sampling scheme on power to map using affected-sib-pair methods should be considered when a reported linkage is not found in another study population.

Experience-related differences in diagnosis from medical images displayed on monitors.

OBJECTIVE: To compare diagnostic accuracy using conventional versus monitor-displayed medical images in order to determine if years of experience as a board-certified clinician influences diagnostic performance in either modality. MATERIALS AND METHODS: In separate observer performance studies, six radiologists and six pathologists differing in years of experience viewed clinical images, once in the conventional modality (X-ray film or light microscopy) and once using a monitor display. Readers also were surveyed regarding their experience with digital/video display systems. RESULTS: In both studies, performance was similar for conventional and monitor modalities. For the conventional displays, there was a positive correlation between years of clinical experience and performance. For the monitor displays, however, there was a strong negative correlation between years of clinical experience and performance. Performance using the monitor displays correlated highly with experience using digital/video systems in general. CONCLUSION: More exposure to and use of monitor displays, such as recreational video games and computers, may influence positively the clinician-monitor display system interaction and improve diagnostic performance.

Human performance studies of the video microscopy component of a dynamic telepathology system.

Human performance studies were performed to evaluate the video microscopy component of a proposed dynamic telepathology system. Frozen sections from breast biopsies of 115 patients were evaluated by both conventional light microscopy and video microscopy by 6 pathologists. Receiver operator characteristic (ROC) curve studies showed nearly identical levels of discrimination between benign and malignant breast lesions for both viewing modalities. Viewing times were significantly greater (p < 0.001) for video microscopy but within a time frame that rendered the technology of potential value for pathology diagnostic applications. Large degrees of interobserver viewing time variability were found for light and video microscopy.

Telepathology. Long-distance diagnosis.

Telepathology is defined as the practice of pathology at a distance, by visualizing an image on a video monitor rather than viewing a specimen directly through a microscope. Components of a telepathology system include the following: (1) a workstation equipped with a high-resolution video camera attached to a remote-controlled light microscope; (2) a pathologist workstation incorporating controls for manipulating the robotic microscope as well as a high-resolution video monitor; and (3) a telecommunications link. Progress has been made in designing and constructing telepathology workstations and fully motorized, computer-controlled light microscopes suitable for telepathology. In addition, components such as video signal digital encoders and decoders that produce remarkably stable, high-color fidelity, and high-resolution images have been incorporated into the workstations. Resolution requirements for the video microscopy component of telepathology have been formally examined in receiver operator characteristic (ROC) curve analyses. Test-of-concept demonstrations have been completed with the use of geostationary satellites as the broadband communication linkages for 750-line resolution video. Potential benefits of telepathology include providing a means of conveniently delivering pathology services in real-time to remote sites or underserviced areas, time-sharing of pathologists' services by multiple institutions, and increasing accessibility to specialty pathologists.

Telepathology and the networking of pathology diagnostic services.

Telepathology is the practice of pathology over a long distance. Components of a telepathology system include the following: a remote-controlled light microscope attached to a high-resolution video camera; a pathologist workstation incorporating controls for manipulating the microscope and a high-resolution video monitor; and a telecommunications linkage. An immediate challenge is to establish the specifications for a telepathology system. Breast tissue has served as a model. Receiver operator characteristic curve studies show that the pathologist's ability to discriminate benign from malignant breast tumors is similar using either a conventional light microscope or a video monitor with approximately 1000 lines of resolution. The percentage of cases for which pathologists render an "equivocal" diagnosis is the same for the two modalities. Telepathology may be an effective way to provide on-line consultations in difficult cases and to provide hospitals in remote areas with immediate access to anatomic pathology services.