Showing papers by "Steven N. Goodman published in 2005"

Detection and quantification of mutations in the plasma of patients with colorectal tumors.

Abstract: The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.

Introduction to Bayesian methods I: measuring the strength of evidence.

Abstract: Bayesian inference is a formal method to combine evidence external to a study, represented by a prior probability curve, with the evidence generated by the study, represented by a likelihood function. Because Bayes theorem provides a proper way to measure and to combine study evidence, Bayesian methods can be viewed as a calculus of evidence, not just belief. In this introduction, we explore the properties and consequences of using the Bayesian measure of evidence, the Bayes factor (in its simplest form, the likelihood ratio). The Bayes factor compares the relative support given to two hypotheses by the data, in contrast to the P-value, which is calculated with reference only to the null hypothesis. This comparative property of the Bayes factor, combined with the need to explicitly predefine the alternative hypothesis, produces a different assessment of the strength of evidence against the null hypothesis than does the P-value, and it gives Bayesian procedures attractive frequency properties. However, the most important contribution of Bayesian methods is the way in which they affect both who participates in a scientific dialogue, and what is discussed. With the emphasis moved from "error rates" to evidence, content experts have an opportunity for their input to be meaningfully incorporated, making it easier for regulatory decisions to be made correctly.

A Bayesian approach to randomized controlled trials in children utilizing information from adults: the case of Guillain-Barre:

Abstract: Background Guillain-Barre syndrome (GBS) is a rare neurologic disease that occurs at all ages, causing a progressive, ascending paralysis that usually resolves over weeks or months. The disease app...

A review of the genus Scotophilus (Mammalia, Chiroptera, Vespertilionidae) on Madagascar, with the description of a new species

Abstract: Les chauves-souris du genre Scotophilus Leach, 1821 sont tres mal connues dans les iles de l'ouest de l'ocean Indien. S. borbonicus (E. Geoffroy, 1803) a ete decrit pour la premiere fois au debut du XIX e siecle a partir de deux specimens provenant de La Reunion. L'holotype a ete perdu et le lectotype est en tres mauvais etat, ce qui complique la determination des caracteres precis de ce taxon. S. borbonicus a ete signale a Madagascar, mais la documentation existante est peu claire. Tres peu d'informations sont disponibles sur l'espece endemique de Madagascar, S. robustus A. Milne-Edwards, 1881. Sur la base des decouvertes faites aussi bien avec de vieux specimens qu'avec ceux nouvellement collectes de Madagascar, nous reevaluons les limites des especes malgaches contenues dans ce genre. Trois especes de Scotophilus sont connues a Madagascar dont une est nouvelle pour la science et decrite ci-dessous. Cette nouvelle espece, S. tandrefana n. sp., se distingue des autres especes rencontrees a Madagascar et partout dans le monde par la couleur de son pelage et les mesures crâniennes et dentaires.

A new species of Eliurus Milne Edwards, 1885 (Rodentia: Nesomyinae) from the Réserve Spéciale d'Ankarana, northern Madagascar

Abstract: The nesomyine rodent Eliurus antsingy is presently known from disjunct limestone regions in the dry lowland forests of northern and western Madagascar. Previous studies of E. antsingy noted morphological varia- tion among isolated populations but recognized only a single species. Herein, we examine morphological and ge- netic variation within and among populations of E. antsingy with a particular focus on the taxonomic status of a population from the Reserve Speciale d'Ankarana in the extreme north of the island. Whereas morphometric ana- lysis cannot distinguish the Ankarana population from its nearest neighbor ~500 km to the south (Namoroka), both are morphologically distinguishable from a population of E. antsingy from the type locality (Bemaraha). In con- trast, genetic data reveal substantial interpopulation divergence among all three populations, and phylogenetic ana- lysis of these data indicates that the two morphologically similar forms do not form a clade. Based on these re- sults we recognize the population from the Reserve Speciale d'Ankarana as a new species but given the limitati- ons of current sampling, retain the other two populations as E. antsingy. Keywords. Eliurus, Nesomyinae, Rodentia, new species, Ankarana, Madagascar.

The methodologic ozone effect.

Abstract: rhe U.S. Environmental Protection Agency (EPA) has some nerve in the sense of scientific courage. That is a trait not often associated with government agencies, but the risk the EPA took in commissioning the 3 analyses published in this issue of the journall-3 must be recognized and applauded. The implications of this exercise go far beyond the question of the ozone mortality effect, the ostensible focus of these papers. In commissioning this examination in triplicate, the agency was testing not just the ozone mortality hypothesis, but the methods of science itself-methods the EPA and others have used to justify regulations in many areas. If these methods had failed this test, there would have been broad repercussions for the entire field of environmental risk assessment, not to mention the field of evidence synthesis. The results of this exercise will undoubtedly elicit a substantial sigh of relief in many quarters and perhaps an equal degree of consternation. The 3 groups used a wide diversity of methods and assumptions as outlined in Table 1. There were differences in the studies selected, the estimates used, the numbers abstracted, the confounders considered, the models used, the conversion factors applied, the subgroups investigated, and the alternatives explored. These many methodologic approaches could be contrasted and critiqued, but the bottom lines were remarkably consistent, within a fraction of a percent-a 0.8% increase in immediate mortality per 10-ppb increase in average daily ozone over the year, with most or all of this risk concentrated in the warmer months. However, behind the sigh of relief must be some discomfiture. Agreement aside, we are also given a glimpse of that Holy Grail-truth that looks somewhat different than suggested by the meta-analyses. The meta-analyses depended on published single-city analyses, each of which used different kinds of data, different analytic techniques, and different reporting-severely limiting the meta-analysts' ability to control for confound ing effects in a sophisticated and uniform manner. However, 2 of the meta-analyses threw in, as a bonus, a primary analysis of independent, multicity air-quality data, with the National Morbidity and Mortality Air Pollution Study (NMMAPS) representing the mother lode of such information: a longitudinal study of air quality in 95 U.S. cities over a 14-year period. Although the NMMAPS analysis' does not qualitatively contravene the meta analytic results, in that it still shows an ozone hazard, it does point strongly to a smaller effect-less than one third of the risk. Ito et a13 contrasted their meta-analysis with a reanalysis of primary air quality data from 7 U.S. cities. The weather-modeling approach closest to NMMAPS ("four-smoother") produced a point estimate approximately 40% lower than their meta-analysis. Both the NMMAPS and 7-city contrasts send a strong message that depending on published, single-estimate, single-site analyses is an invitation to bias. This is not the first time that such bias has been demonstrated,4'5 but it may be the

Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia.

Abstract: Purpose: Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia. Experimental Design: Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m 2 , day 8) and fludarabine (20 mg/m 2 , days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 × 10 6 IU/m 2 /d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo. Results: Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/μL (range, 97-3,776) pretreatment, 379 cells/μL (range, 54-2,599) at day 14, and 98 cells/μL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels. Conclusions: The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.

On health effects of ozone exposure and exposing the epidemiologic process : A meta-analysis of time-series studies of ozone and mortality with comparison to the national morbidity, mortality, and air pollution study. Commentary

Abstract: Background: Although many time-series studies of ozone and mortality have identified positive associations, others have yielded null or inconclusive results, making the results of these studies difficult to interpret. Methods: We performed a meta-analysis of 144 effect estimates from 39 time-series studies, and estimated pooled effects by lags, age groups, cause-specific mortality, and concentration metrics. We compared results with pooled estimates from the National Morbidity, Mortality, and Air Pollution Study (NMMAPS), a time-series study of 95 large U.S. urban centers from 1987 to 2000. Results: Both meta-analysis and NMMAPS results provided strong evidence of a short-term association between ozone and mortality, with larger effects for cardiovascular and respiratory mortality, the elderly, and current-day ozone exposure. In both analyses, results were insensitive to adjustment for particulate matter and model specifications. In the meta-analysis, a 10-ppb increase in daily ozone at single-day or 2-day average of lags 0, 1, or 2 days was associated with an 0.87% increase in total mortality (95% posterior interval = 0.55% to 1.18%), whereas the lag 0 NMMAPS estimate is 0.25% (0.12% to 0.39%). Several findings indicate possible publication bias: meta-analysis results were consistently larger than those from NMMAPS; meta-analysis pooled estimates at lags 0 or 1 were larger when only a single lag was reported than when estimates for multiple lags were reported; and heterogeneity of city-specific estimates in the meta-analysis were larger than with NMMAPS. Conclusions: This study provides evidence of short-term associations between ozone and mortality as well as evidence of publication bias.

On health effects of ozone exposure and exposing the epidemiologic process : Associations between ozone and daily mortality : Analysis and meta-analysis. Commentary

Abstract: Background: There is ample evidence that short-term ozone exposure is associated with transient decrements in lung functions and increased respiratory symptoms, but the short-term mortality effect of such exposures has not been established. Methods: We conducted a review and meta-analysis of short-term ozone mortality studies, identified unresolved issues, and conducted an additional time-series analysis for 7 U.S. cities (Chicago, Detroit, Houston, Minneapolis-St. Paul, New York City, Philadelphia, and St. Louis). Results: Our review found a combined estimate of 0.39% (95% confidence interval = 0.26-0.51%) per 10-ppb increase in 1-hour daily maximum ozone for the all-age nonaccidental cause/single pollutant model (43 studies). Adjusting for the funnel plot asymmetry resulted in a slightly reduced estimate (0.35%; 0.23-0.47%). In a subset for which particulate matter (PM) data were available (15 studies), the corresponding estimates were 0.40% (0.27-0.53%) for ozone alone and 0.37% (0.20-0.54%) with PM in model. The estimates for warm seasons were generally larger than those for cold seasons. Our additional time-series analysis found that including PM in the model did not substantially reduce the ozone risk estimates. However, the difference in the weather adjustment model could result in a 2-fold difference in risk estimates (eg, 0.24% to 0.49% in multicity combined estimates across alternative weather models for the ozone-only all-year case). Conclusions: Overall, the results suggest short-term associations between ozone and daily mortality in the majority of the cities, although the estimates appear to be heterogeneous across cities.