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PubMed2002

Population mixing and leukaemia in young people around the La Hague nuclear waste reprocessing plant.

In order to investigate for an association between population mixing and the occurrence of leukaemia in young people (less than 25 years), a geographical study was conducted, for the years 1979 to 1998, in Nord Cotentin (France). This area experienced between the years 1978 and 1992 a major influx of workers for the construction of a nuclear power station and a new nuclear waste reprocessing unit. A population mixing index was defined on the basis of the number of workers born outside the French department of 'La Manche' and living in each 'commune', the basic geographical unit under study. The analyses were done with indirect standardisation and Poisson regression model allowing or not for extra-Poisson variation. Urban 'communes' were considered as the reference population. The Incidence Rate Ratio was 2.7 in rural 'communes' belonging to the highest tertile of population mixing (95% Bayesian credible interval, 95%BCI=1.2-5.9). A positive trend was observed among rural strata with increasing population mixing index (IRR for trend=1.4, 95%BCI=1.1-1.8). The risk became stronger for Acute Lymphoblastic Leukaemia in children 1-6 years old in the highest tertile of population mixing (IRR=5.5, 95%BCI=1.4-23.3). These findings provide further support for a possible infective basis of childhood leukaemia.

Adolescent↗
PubMed1990

Cardiovascular screening in Army personnel over age 40 in the State of Hawaii.

A cardiovascular screening protocol was applied prospectively to 1,900 soldiers over 40 years of age to identify individuals with latent coronary artery disease. Primary screening included a cardiovascular history, physical examination, electrocardiogram, serum cholesterol and serum glucose determinations, and calculated Framingham risk index. Seven hundred ninety-six individuals required secondary screening, consisting of stress testing and cardiac fluoroscopy. The screening process led to coronary angiography in 43 individuals; of these, 17 had obstructive coronary artery disease, ten had nonobstructive coronary artery disease, and 16 had normal coronary arteries. Application of primary screening before exercise testing increased the posttest probability of obstructive coronary artery disease to 50% in the individuals with a positive treadmill test. This is four times the expected value of 11% calculated using Bayes' theorem. The combination of a positive treadmill test and the finding of coronary artery calcification on fluoroscopy was an excellent predictor of obstructive coronary artery disease.

Adult↗
PubMed1997

Models for diagnosing chest pain: is CART helpful?

The use of classification and regression tree (CART) methodology is explored for the diagnosis of patients complaining of anterior chest pain. The results are compared with those previously obtained using correspondence analysis and independent Bayes classification. The technique is shown to be of potential value for identifying important indicators and cutpoints for continuous variables, although the overall classification performance was rather disappointing. Suggestions are made for extensions to the methodology to make it more suitable for clinical practice.

Age Factors↗
PubMed2005

BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.

BACKGROUND: BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. METHODS: In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. RESULTS: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939. CONCLUSIONS: Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.

Administration, Oral↗
PubMed1984

Bayes' theorem--a review.

Formal probability analysis based on Bayes' theorem greatly enhances the diagnostic capabilities of exercise testing in the detection of coronary artery disease. The pretest characteristics of a patient must be considered along with the test results in arriving at a post-test probability of disease. The essential concepts of probability analysis have broad applications in the entire field of medicine.

Adult↗
PubMed1992

Presymptomatic diagnosis of von Hippel-Lindau disease with flanking DNA markers.

Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by the development of retinal, cerebellar, and spinal haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. We have investigated the usefulness of currently available DNA markers for the presymptomatic diagnosis of VHL disease. In the first part of this investigation, genetic linkage data from two previously published studies were updated and reanalysed to provide accurate estimates of sex specific recombination fractions and to confirm that there is no evidence of locus heterogeneity. In the second part of this study, 14 families containing 23 asymptomatic subjects at 50% prior risk of VHL disease were investigated with closely linked DNA markers (RAF1, D3S18, D3S732). Seventeen subjects were informative with one or more markers, six of whom were informative at markers flanking the VHL disease gene. By combining age related and DNA based risk information the carrier risk for 11 subjects was reduced to < 2%.

Adolescent↗
PubMed2005

Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation.

Identification of tissue-specific gene regulatory networks can yield insights into the molecular basis of a tissue's development, function and pathology. Here, we present a computational approach designed to identify potential regulatory target genes of photoreceptor cell-specific transcription factors (TFs). The approach is based on the hypothesis that genes related to the retina in terms of expression, disease and/or function are more likely to be the targets of retina-specific TFs than other genes. A list of genes that are preferentially expressed in retina was obtained by integrating expressed sequence tag, SAGE and microarray datasets. The regulatory targets of retina-specific TFs are enriched in this set of retina-related genes. A Bayesian approach was employed to integrate information about binding site location relative to a gene's transcription start site. Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted. To experimentally assess the validity of the bioinformatic predictions, mobility shift, transient transfection and chromatin immunoprecipitation assays were performed with five predicted CRX targets, and the results were suggestive of CRX regulation in 5/5, 3/5 and 4/5 cases, respectively. Together, these experiments strongly suggest that RP1, GUCY2D, ABCA4 are novel targets of CRX.

Animals↗
PubMed2005

Inhibition of NF-kappaB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines.

Multidrug resistance (MDR) is the main reason for failure of cancer therapy with resistance to apoptosis being one of the mechanisms involved. Constitutive NF-kappaB activity has been detected in many tumors contributing to oncogenesis and tumor survival whereas inhibition of NF-kappaB activity has proved to enhance cell death induced by chemotherapeutic agents. Consequently, the use of BAY 11-7082, an irreversible inhibitor of IkappaB-alpha phosphorylation, could be beneficial in the treatment of certain tumors. Although there are several reports which demonstrate a transient activation of NF-kappaB by cytotoxic drugs, little is known about the role of NF-kappaB activation in the development of a chemoresistant phenotype in leukemic cells. In this study, we analyzed the relationship between NF-kappaB and the survival of murine leukemic drug resistant cell lines. The modulation of this transcription factor by BAY 11-7082 and the chemotherapeutic agents vincristine and doxorubicin was evaluated. The effect of BAY 11-7082 on the expression of genes containing NF-kappaB-binding sites was also studied. We found that the cell lines LBR-V160 and LBR-D160 (resistant to vincristine and doxorubicin, respectively) presented higher constitutive NF-kappaB activity than the sensitive LBR- and the active complex contained both p50 and p65 subunits. BAY 11-7082 (3.5 microM) inhibited constitutive NF-kappaB activity in the three cell lines whereas the anticancer agents did not. Treatment with BAY 11-7082 induced a higher percentage of apoptosis in LBR-V160 and LBR-D160 than in LBR-. Cells treated with BAY 11-7082 displayed modulation of NF-kappaB-inducible genes such as IL-10, IL-15, TNF-alpha and TGF-beta. Taken together, these data suggest that suppression of constitutive NF-kappaB activity by BAY 11-7082 may be a useful treatment for MDR leukemias.

Animals↗
PubMed1982

The determination of the post-test likelihood for coronary disease using Bayes Theorem.

This report describes a method of using Bayes Theorem for determining the post-test likelihood for coronary disease from the exercise test. The pre-test likelihood is determined from the age, sex, and type of chest pain. Discriminant analysis of the amount of S-T depression, maximum pressure rate product and sex of the patient is then used to determine the sensitivity and specificity of the patient's exercise test for coronary artery disease. The post-test likelihood for coronary artery disease can then be calculated using Bayes Theorem. The discriminant function was estimated from a training set of 174 patients. This was then applied to 113 new patients who had both exercise tests and coronary arteriograms. In this new set, 47 patients had a post-test likelihood of 90% or greater for coronary disease. Only one of these patients had normal coronary arteriograms, a predictive accuracy of 98%. Of the 25 patients with a post-test likelihood of 10% or less for coronary disease, four had multivessel disease and four had single vessel disease. The predictive accuracy for the absence of coronary disease was 68%. The predictive accuracy for the exclusion of multivessel disease was 84%. Eight of 10 patients with left main disease had a post-test likelihood for coronary disease of greater than 90%.

Age Factors↗
PubMed2005

Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects.

OBJECTIVES: There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939--a novel, oral, direct Factor Xa (FXa) inhibitor--were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. METHODS: Healthy male subjects (aged 20-45 years, body mass index 18.6-31.4 kg/m(2)) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3-7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. RESULTS: There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C(max, norm)) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3-4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose. CONCLUSIONS: BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.

Administration, Oral↗
PubMed1986

Estimating the probability of malignancy in solitary pulmonary nodules. A Bayesian approach.

Decisions about managing solitary pulmonary nodules often involve estimates of the likelihood that the nodule is malignant. We used Bayes' theorem to devise a simple scheme for estimating the likelihood that a solitary pulmonary nodule is malignant based on the diameter of the nodule, the patient's age and history of cigarette smoking, and data on the overall prevalence of malignancy in solitary nodules. This method may improve the accuracy of estimating the likelihood of malignancy for individual patients with solitary pulmonary nodules.

Age Factors↗
PubMed2002

The Ontario Family Medicine Residents Cohort Study: factors affecting residents' decisions to practise obstetrics.

BACKGROUND: The number of family physicians practising obstetrics in Canada is declining. On the assumption that factors related to the obstetrics training of family medicine residents may be influencing this trend, we conducted a cohort study of residents' stated intentions with regard to practising obstetrics, their educational experiences and their subsequent obstetric practice. METHODS: We followed a cohort consisting of all residents who enrolled in family medicine residency programs in Ontario in 1994 and 1995. The data, collected by mail-in survey at entry to, during and 2 years after completion of the 2-year training programs, consisted of residents' characteristics, stated plans during residency to practise obstetrics, obstetric experiences during training, attitudes and opinions related to obstetrics, and actual practice 2 years after completion of residency. We used logistic regression to determine the factors influencing whether a family physician practises obstetrics after graduation. RESULTS: Of the 498 residents who started programs in 1994 and 1995, 480 were eligible for inclusion, although not all of those eligible responded to the various surveys. At entry into the residency programs, 216 (52%; 95% confidence interval [CI] 47-57%) of the 411 respondents expressed an intention to practise obstetrics. By the end of residency, the proportion intending to practise obstetrics had fallen to 17% (95% CI 13-22%; 46 of 274 respondents), and only 16% (95% CI 12% to 20%) were actually practising intrapartum obstetrics (i.e., delivering babies) 2 years later. The proportions of residents in the 7 Ontario family medicine programs who were actually practising obstetrics 2 years later ranged from 2% of those from the University of Western Ontario to 38% of those from Thunder Bay. Three factors were independently associated with practising intrapartum obstetrics 2 years after completing residency: intention at the end of residency to practise intrapartum obstetrics (odds ratio [OR] 11.7, 95% CI 3.1-44.7, p = 0.001), not having the opinion that intrapartum care is too disruptive of personal life (OR 9.1, 95% CI 1.5-55.5, p = 0.02) and practising in a community of 15 000 or fewer people (OR 6.0, 95% CI 1.8-19.4, p = 0.003). INTERPRETATION: Residents who have positive attitudes toward obstetrics at the end of their training and who intend at that time to perform deliveries are more likely to be doing so 2 years later, especially if they practise in communities of 15,000 or fewer people.

Career Choice↗
PubMed1997

A device to predict lower third molar eruption.

This study was designed to create a transparent device to be superimposed on a panoramic tomogram taken of a patient at age 20 years to make predictions of future eruption or impaction of lower third molars. The device was developed from data on 40 lower third molars initially retained at age 20 years; one half of these remained impacted, and the other half of them erupted by age 26 years. Tracings were made from panoramic tomograms taken at age 20 years. The critical point for prediction in the overlay was the intersection of a horizontal reference line and the anterior border of the ascending ramus. To estimate this critical separation line, Bayes' Decision Theory was used. The sum of false negatives and false positives was least at a distance of 14.5 mm from the distal surface of the second molar. Mesial from this point, the probability of impaction was 76%; distal from this point, the probability of eruption was 72%. Tested against 35 initially unerupted lower third molars, the predictions made by the device and the actual clinical findings were in conformity in relation to 97% of the test teeth. It could thus be concluded that the method was simple to use and may prove a good addition for predicting lower third molar development.

Adult↗
PubMed2005

[The impact of socioeconomic status in the estimation of non-adult dental age].

The aim of this study is to observe the possible impact of socioeconomic level on stages of macroscopic dental development. The sample consists of 456 children from European origin, aged 3.5 to 16 years (242 girls and 214 boys). We apply a radiographic method of non-adult dental age estimation based on Bayes' theorem. Both socioeconomic level and geographic origin of grandparents are given in a questionnaire devised by the first author. First, results obtained with the Bayesian dependent method (BD method) are compared to those obtained with a more commonly used method of dental age estimation based on Correspondence Analysis and linear Regression (CAR method). Second, two approaches are proposed in order to test potential relationships between socioeconomic level and stages of macroscopic dental development. Both are based on observed shifts between dental age and chronological age with regard to socioeconomic level. Results obtained with the BD method are better, in terms of quality, than those obtained with the CAR method. We observed no influence of socioeconomic level on stages of macroscopic dental development.

Adolescent↗
PubMed2006

Desmoid tumors -- a characterization of patients seen at Mayo Clinic 1976-1999.

Desmoid tumors occur with high frequency in individuals with Familial Adenomatous Polyposis (FAP). Because of this, individuals developing desmoid tumors may be referred for genetic risk assessment. Determining whether a person has a FAP-related desmoid tumor or a sporadic desmoid can be challenging. We sought to characterize the patients who were seen at our institution to determine if there were clinical differences in presentation between FAP-associated and sporadic desmoid tumors. We searched the Mayo Clinic-modified H-ICDA (Hospital adaptation of the International Classification of Diseases) diagnostic codes for all diagnoses of desmoid tumors in patients seen between 1976 and 1999. Charts were reviewed to determine accuracy of diagnosis, age when seen, gender, site of tumor, and presence of polyposis. A total of 454 patients (174 males and 280 females) met the search criterion. Of the 447 patients on whom all data was obtained, 70 had FAP and 377 had no evidence of FAP. The female/male ratio for FAP cases was 1.12 compared to female/male ratio of 1.71 for non-FAP cases. (P=0.17). Location of development of desmoid tumors was correlated with but not specific for distinguishing FAP from non-FAP desmoids. Abdominal desmoids comprised the majority of FAP desmoids and extra-abdominal desmoids comprised the majority of non-FAP desmoids (P<0.001) but age was not a discriminating factor. Using Bayesian analysis, we demonstrate how these findings can assist genetic professionals in their evaluation of patients with desmoid tumors by providing prior probabilities of FAP based upon clinical presentation.

Adenomatous Polyposis Coli↗
PubMed1983

Polychlorinated biphenyl pollution from shipbuilding in Nagasaki Bay, Japan.

Polychlorinated biphenyl (PCB) pollution from shipbuilding in Nagasaki Bay, Japan, was discussed by determining PCB concentrations in sediment, in water, and in biological samples. PCBs were detected in all samples, in which much higher concentrations, more than 10 micrograms/g, were found in three sediment samples where located near the shipyard drains. In general, PCB concentrations in sediments and organisms tended to increase toward the inner part of this bay. PCB isomer and congener compositions in organisms as well as sediments were composed mainly of higher chlorinated biphenyls and almost similar to Kanechlor 500 and 600 products (chlorine content 54 and 60%, respectively) that have been used for ship paints. These results strongly suggest that the shipbuilding is primarily responsible for the PCB pollution in Nagasaki Bay. Bioaccumulation factors of PCBs were different among the organisms according to their trophic levels. This might be a result of the predominant PCB transfer through the food chain in organisms and the discharge of bioaccumulative PCBs as higher chlorinated biphenyls from shipyards. These observations imply that the PCB pollution from shipbuilding would continue for a long time due to the accumulative characteristics of PCBs used for ship paints and the further discharge by scraping the stale paints in shipyards.

Animals↗
PubMed2001

Recent trends and future projections of lymphoid neoplasms--a Bayesian age-period-cohort analysis.

OBJECTIVES: A steady increase in incidence of lymphoid neoplasms has been reported, especially for non-Hodgkin's lymphoma (NHL). Using high-quality incidence data from 1973-1992 in nine population-based cancer registries (Alberta, Bombay, Denmark, Israel, New Zealand, Osaka, Oxford, Slovenia, Utah), we have examined past increases in specific lymphoid neoplasms. Further, by using a Bayesian age-period-cohort approach, we have calculated 5-, 10- and 15-year projections for each group of lymphoid neoplasms. RESULTS: NHL incidence increased in all centers by an average of 77% in men and 66% in women between 1973 and 1992. Fifteen-year projections of these rates to 2003-2007 indicate that they will increase by an average of 55% among men and 79% among women. High projected incidence rates above 15/100,000 in men and 10/100,000 in women are expected in Alberta, Denmark, Israel, New Zealand, Oxford, and Utah by 2003-2007. The one notable exception was among men from Osaka, where no increase was projected. Modest increases in leukemia and multiple myeloma rates were observed in most of the nine registries with further projected increases by 2007. Projected incidence rates of Hodgkin's disease indicated little change. CONCLUSION: Increases in NHL rates are occurring worldwide and provide no evidence of peaking. A key assumption in the projected rates is that the effect of environmental agents determining the trends during 1973-1992 will remain stable during the subsequent projection period.

Age Factors↗