Inconclusive decisions and error rates in forensic science.

In recent years, there has been discussion and controversy relating to the treatment of inconclusive decisions in forensic feature comparison disciplines when considering the reliability of examination methods and results. In this article, we offer a brief review of the various viewpoints and suggestions that have been recently put forth, followed by a solution that we believe addresses the treatment of inconclusive decisions. We consider the issues in the context of method conformance and method performance as two distinct concepts, both of which are necessary for the determination of reliability. Method conformance relates to an assessment of whether the outcome of a method is the result of the analyst's adherence to the procedures that define the method. Method performance reflects the capacity of a method to discriminate between different propositions of interest (e.g., mated and non-mated comparisons). We then discuss implications of these issues for the forensic science community.

Bactericidal activity and mechanism of action of AZD5847, a novel oxazolidinone for treatment of tuberculosis.

Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.

A dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects.

AIM: The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin. METHODS: The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo. RESULTS: Changes in glucose from baseline (mean +/- s.d.) at 140 min (2 h postprandial) were 94.84 +/- 22.3, 79.45 +/- 43.00, 70.68 +/- 35.71, 63.47 +/- 42.75 and 53.06 +/- 47.27 mg/dL, respectively, and exhibited linear dose-response. The insulin C(max) values were found to be 50.8 +/- 26.0 mU/L for placebo, 100.3 +/- 66.7 with 10 mg IN-105, 177.69 +/- 150.3 with 15 mg IN-105, 246.2 +/- 245.2 with 20 mg IN-105 and 352.5 +/- 279.3 mU/L with 30 mg of IN-105. CONCLUSIONS: IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.

Evaluating subject-treatment interaction when comparing two treatments.

Clinical and other studies that evaluate the effect of a treatment relative to a control often focus on estimating a mean treatment effect; however, the mean treatment effect may be misleading when the effect of the treatment varies widely across subjects. Methods are proposed to evaluate individual treatment heterogeneity (i.e., subject-treatment interaction) and its consequences in clinical experiments. The method of maximum likelihood is used to derive estimators and their properties. A bootstrap procedure that requires fewer assumptions is also presented as a small sample alternative to the maximum likelihood approach. It is shown that estimators for subject-treatment interaction are sensitive to an inestimable correlation parameter. This sensitivity is illustrated using some example data sets and using graphical plots. The practical consequence of subject-treatment interaction is that a proportion of the population may be not be responding to the treatment as indicated by the average treatment effect. Results obtained from the methods reported here can alert the practitioner to the possibility that individual treatment effects vary widely in the population and help to assess the potential consequences of this variation. Applications of the proposed procedures to clinical decision making, pharmacogenetic studies, and other contexts are discussed.

Unit-treatment interaction and its practical consequences.

Most statistical characterizations of a treatment effect focus on the average effect of the treatment over an entire population. However, average effects may provide inadequate information, sometimes misleading information, when a substantial unit-treatment interaction is present in the population. It is even possible that a nonnegligible proportion of the individuals in the population experience an unfavorable treatment effect even though the treatment might appear to be beneficial when considering population averages. This paper examines the extent to which information about unit-treatment interaction can be extracted using observed data from a two-treatment completely randomized experiment. A method for utilizing the information from an available covariate is proposed. Although unit-treatment interaction is a nonidentifiable quantity, we show that mathematical bounds for it can be estimated from observed data. These bounds lead to estimated bounds for the probability of an unfavorable treatment effect. Maximum likelihood estimators of the bounds and their corresponding large-sample distributions are given. The use of the estimated bounds is illustrated in a clinical trials data example.

An analysis of the yearly changes in sulfur concentrations at various national parks in the United States, 1980-1996.

An apparent increasing trend in the summer concentrations of particulate sulfur at Shenandoah (for the time period 1982-1995) and at Great Smoky Mountains (for the time period 1984-1995) has been pointed out by some researchers. Others have suggested that these increasing trends may be an analytical artifact resulting from the switch from the Stacked Filter Units (SFU) measurement system to the IMPROVE (Interagency Monitoring of Protected Visual Environments) measurement system that occurred during the winter of 1987. To obtain a better understanding of the effect of the protocol change, we investigate the changes in the seasonal averages of sulfur concentrations for successive pairs of years for the period 1980-1996 for about 20 national park sites in the United States. For the period 1980-1987, we use sulfur data from the old (SFU) database and for the period 1988-1996, we use the IMPROVE database. Changes from one year to the next similar to that between 1987 and 1988 occurred during other years and seasons suggesting that chance causes alone could perhaps explain it, the degree to which chance could have caused the changes was measured using the permutation test for matched. At the very least, additional information such as side by side readings using SFU and IMPROVE measurement methods, may be needed to better understand any systematic effect in the sulfur measurements that may be ascribable to the protocol change.

Trends in the extremes of sulfur concentration distributions.

Understanding the response of air quality parameters such as visibility to the implementation of new air quality regulations, population growth and redistribution, and federal land managing practices is essential to the evaluation of air quality management plans on air quality in federal Class I areas. For instance, the reduction of SO2 emissions from large single point sources should result in the decrease of extreme sulfate concentrations, while population growth in geographic areas outside of urban centers could cause a slow widespread increase of sulfate and organic concentrations. The change in federal land managing practice of increased prescribed fire on a year-round basis in lieu of large naturally occurring wild fires could have the same effect; that is, the frequency of high sulfur days increase and low sulfur days decrease as the result of the management practice. Therefore, it is of interest to examine the trends associated with the proportion of days during which the concentration of some aerosol species is above or below a certain threshold and decide whether this proportion of days is increasing or decreasing or shows a lack of trend. This is a direct indication of whether the quality of the environment is improving or worsening, or neither.

Sampling duration calculations.

Routine air quality monitoring produces filter samples that, when analyzed, yield the total amount of the aerosol present in the volume of air drawn by the pump in the monitoring device during the given sampling period. From this we obtain an average concentration of the aerosol for the given duration. The samples are therefore really aggregate samples. A natural question then is "what is the effect of the duration of aggregation on the accuracy and precision of the estimate of the quantity of interest?" The answer depends on a number of factors, such as the quantity that is being estimated: a mean, or an extreme value, or some other quantity; the nature of the measurement error--additive versus multiplicative; the costs of laboratory analyses, and so on. In this paper, we investigate these issues when the interest is in estimating the mean concentration of a specified aerosol species over a fixed time period. In particular, we propose a method for determining a sampling duration that will yield the "best estimate" of the mean concentration for a given cost whenever appropriate statistical assumptions hold.

Tolerance intervals for assessing individual bioequivalence.

Evaluation of equivalence of two formulations of a drug typically entails the comparison of average bioavailabilities. Recently, however, authors have become aware that this may be insufficient to assess individual bioequivalence, that is, interchangeability of formulations on an individual basis. This paper outlines a tolerance interval procedure to assess individual bioequivalence based on a model that includes a subject by formulation interaction. We give methods for several higher-order cross-over designs along with examples.

Human visual sensitivity to plumes with a Gaussian luminance distribution: experiments to develop an empirical probability of detection model.

This paper discusses results of a research project designed to develop an empirical model that could be used as a tool to predict human visual sensitivity to plumes. The resultant probability of detection algorithm (PROBDET) allows one to estimate the probability of a plume of known size, shape and contrast being detected visually. As a basis for the algorithm, a series of laboratory experiments using a high threshold signal detection procedure and computer generated images of plumes with Gaussian luminance distributions was conducted to measure human visual sensitivity to plumes. Results of the laboratory experiments are compared with results of contrast sensitivity experiments that examined visual sensitivity to stimuli with square and sine wave luminance distributions. An example of the PROBDET algorithm is presented to demonstrate its potential usefulness for assessing how probability of detection estimates change as plume size and contrast parameters vary. Since this research was designed to build on existing knowledge, a discussion of that knowledge and how it relates to the research conducted is also presented. The focus of this discussion is on the human visual system (HVS) and on how visual sensitivity is affected by factors such as the luminance of the stimulus and the surround, the luminance distribution of the stimulus, the size of the surround, and the size and spatial frequency characteristics of the stimulus.

Metal affinity protein precipitation: effects of mixing, protein concentration, and modifiers on protein fractionation.

Previous work by us and others has shown that mixing impacts apparent protein solubility in single protein precipitations. In this work, we probe the effects of contacting conditions on fractional precipitation behavior at the bench scale. We have chosen metal affinity precipitation as our model system; the kinetics of this mode of precipitation are very rapid and largely irreversible and, consequently, mixing conditions govern the extent of fractionation and purity of the product in such a process. Our experimental strategy involved a three-pronged approach to control the effects contacting conditions on precipitate yield, purity, and particle size distribution. First, we studied the impact of process variables that control precipitant concentrations in the reactor including impeller speed and precipitant addition rate. Second, we controlled the rate of precipitation by changing the initial protein concentration to alter the protein-protein collision rate. Third, we examined the role of the molecular-level kinetics of affinity precipitation by using modifiers that compete with surface moieties to bind the metal ion, thereby reducing its availability. Our model process and protein system consisted of zinc precipitations of mixtures of bovine serum albumin and bovine gamma-globulins, carried out at a nominal 1-L scale; glycine was examined as a modifier. Faster impeller speeds and lower precipitant addition rates increased the desired protein yields, decreased purities, and reduced average precipitate particle size. Higher initial protein concentrations were found to produce precipitates with higher yields, lower purities and diminished particle size. Experiments with glycine indicated that modifiers in the precipitant solution serve to increase product purity, decrease yield, and increase the average particle size in bench-scale precipitations.

Distribution of Brucella abortus in infected cattle.

Experimentally and naturally infected cattle were examined bacteriologically to determine the anatomical distribution of specimens yielding Brucella abortus. In 91 experimentally infected pregnant cows, examined 3 to 4.5 months after conjunctival challenge during pregnancy, the most frequently infected specimen was the mammary (syn. supramammary) lymph node. All experimentally infected cows could be identified from cultures of the mammary, mandibular (syn. submaxillary), medial iliac, caudal superficial cervical (syn. prescapular) lymph nodes and uterine caruncles, cotyledons or foetal tissues. Forty-six naturally infected cows were examined and again the most frequently infected specimen was the mammary lymph node. All naturally infected cows could be identified from cultures of the mammary, parotid, mandibular and subiliac (syn. prefemoral) lymph nodes. The distribution of infected specimens was somewhat different in heifers. In 61 naturally infected heifers the most frequently infected specimen was the mandibular lymph node but 8 other specimens would have been required to enable identification of all infected heifers. Specimens from 3 infected bulls were cultured and 11 of the 12 specimens examined were infected in at least one of the bulls. The most frequently infected tissues were the mandibular, caudal superficial cervical, subiliac and scrotal lymph nodes. The results suggest which specimens should be selected for culture, particularly when only a limited amount of effort can be expended.

An evaluation of a biphasic medium for the isolation of Brucella abortus from bovine tissues.

The isolation of virulent Brucella abortus from specimens taken from cattle was studied using culture in biphasic medium in which solid and liquid media were contained in the same flask and on solid medium in Petri plates. A total of 8638 specimens from 441 cattle, reactors to one or more of several serological tests or to an allergic test, were used. The specimens consisted of lymph nodes, udder, spleen, uterine caruncles, cotyledons, foetal tissues, foetal stomach contents and mammary secretions. Following maceration each specimen was inoculated into 2 flasks of biphasic medium one with 1 ml (Flask A) and the other with 2 ml (Flask B), and on to solid medium in one Petri plate. The biphasic medium and solid medium were shown to have equal ability to support the growth of B. abortus. The increased rate of detection in the biphasic medium was due to the increased volume of the inoculum used. Brucella were isolated from 1151 specimens. By direct plating on the solid medium 685 specimens were positive whereas Flask A positive for 961 specimens and Flask B for 1031 specimens. The success of the biphasic medium can be judged by the increase in the number of infected animals detected. Of the 150 infected cattle, both techniques identified 126 animals in common, 4 were identified only by the plate technique and 20 only by the biphasic technique. Culture on both solid medium and in biphasic medium is recommended for optimum results.

Differences between breeds of sheep in their responses to Bacteroides nodosus vaccines.

In a field experiment on irrigated pasture, sheep of several breeds were vaccinated twice, subcutaneously, in the upper neck, with Bacteroides nodosus vaccine containing either depiliated cells (DC vaccine), or whole, piliated cells (WC vaccine) and the responses were measured over the following 14 weeks. DC vaccine was as effective as WC vaccine in protecting against the development of foot-rot under conditions of moderate challenge, although the WC vaccine induced significantly higher pilus agglutinating antibody titres. Foot-rot developed in significantly more vaccinated Merinos (Peppin and Saxon strains) than in Romney Marsh, Dorset Horn or Border Leicester breeds. Agglutinating antibody titres after WC vaccination were significantly lower in the Peppin Merino than in the other sheep for the first 6 weeks, while after DC vaccination the titres remained elevated longer in the Border Leicester and Saxon Merino and were significantly higher from 6 weeks onwards. Reactions at the inoculation sites were generally larger in the British breeds than in the Merinos and among the former the reactions were largest, most numerous and most frequently discharged their contents in the Dorset Horn. Bodyweight gains in all vaccinated sheep were initially reduced, compared with controls, but the differences were no longer significant after the eighth week.

Intestinal obstruction due to schistosomiasis.

We have described a patient with intestinal obstruction caused by schistosomiasis but closely resembling colon carcinoma. The cause, demography, pathologic characteristics, and clinical management of the disease caused by Schistosoma mansoni are reviewed.

Assessment of a complement fixation test to detect Mycoplasma hyopneumoniae infection in pigs.

Serums from pigs slaughtered at abattoirs were tested for evidence of Mycoplasma hyopneumoniae infection using a complement fixation (CF) test which avoids the procomplementary effect of pig serum. To establish a diagnosis of enzootic pneumonia, the lungs from all sampled pigs were examined for pathological and histological changes consistent with the disease and cultures were made for mycoplasmas and bacteria. The study was carried out at Parkville and Bendigo 160 km apart at different times and all serums were tested at both laboratories. The results agreed closely. Thirty-six of 97 pigs at Parkville and 46 of 99 at Bendigo had enzootic pneumonia. About 80% were positive in the CF test. Sixteen per cent of porkers and 36% of baconers gave false negative reactors, that is, a negative test though lesions were present. About 18% to 36% gave false positive reactions but the level in the porkers in the Bendigo group was significantly higher (p less than 0.02). Possible explanations include, for the false negatives, loss of reactivity caused by circulating antigen and for the false positives, cross reacting antibody produced by another infection or failure to appreciate that lesions of EP were present in lungs because either they were not identified as such or they were not detected. The validity of any serological test for this disease cannot be established while there is a possibility that the present methods used for diagnosis, gross and microscopic examination and recovery of M. hyopneumoniae, fail to detect some infected animals. Other criteria may have to be adopted.

A statistical model and analysis for genetic and environmental effects in responses from twin-family studies.

A statistical model and analysis for genetic and environmental effects in twin-family data are presented. The model is used to derive expressions for phenotypic correlations of 22 essential pair relationships in twin-family units. The analysis proceeds in two steps. First, differential effects of sex, generation, and sex-zygosity of twin-family units and correlations due to cluster sampling are eliminated from correlation data. Then, estimates and tests of model parameters are calculated from the adjusted data. The theory and methods were developed for a Swedish twin-family study of many behaviors possibly related to the smoking habit. There, it is important to screen for behaviors that clearly are under genetic control and to assess relative influences of various biological and social environments on the development of all behaviors. Height data from the Swedish study are used to illustrate concepts and methods presented in this paper.