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Estimating possible fraud in coal mine operators' samples of respirable dust.

Coal mine operators are required to sample miners' exposure to respirable dust on a regular basis. A method has been developed for screening all operator samples for detecting possible instances of fraud. This method relies on the occurrence of very low concentration (VLC = 0.1 mg/m3) samples more frequently than expected. The number of underground mine sections from which 50% or more of all samples for FY 1990 were VLC (VLC-50 sections) was compared to the expected number, which was estimated by assuming that the occurrence of VLC samples could be described with a binomial probability distribution. Out of 1983 continuous mining sections, there were 147 VLC-50 sections vs. 7.3 expected (O/E = 20.1). Moreover, these 147 sections occurred more frequently than expected among small as opposed to large mines. For sections using conventional mining methods, 19 of 175 were VLC-50 vs. 0.9 expected (O/E = 20.8). There was one VLC-50 longwall section vs. 0.003 expected. For 99 bituminous and anthracite hand-loading sections the observed number of VLC-50 sections was 65 vs. 78 expected (O/E = 0.8). It is suggested that, except for hand-loading and longwall sections, sampling programs should be investigated at mines with VLC-50 sections.

Coal↗

Field performance measurements of half-facepiece respirators: developing probability estimates to evaluate the adequacy of an APF of 10.

To evaluate the protection provided by negative-pressure, half-facepiece respirators, ambient and in-facepiece samples were collected on workers in foundry, aircraft-painting, and steel-manufacturing operations. Protection was assessed by workplace protection factors (WPF). The appropriateness of the assigned protection factor (APF) for half-facepiece respirators was evaluated with a new approach using the WPF data from these and other studies previously published. The new approach utilizes binomial statistics based on the number of successes (no overexposure) and failures (overexposure) and is illustrated with a graphical representation of WPF data. With this consideration of the data, the probability of overexposure occurring during a wearing period for workers wearing the half-facepiece respirators represented by the studies referenced here was 0.5%, with a 95% confidence interval of 0.01 to 2.7%. If 50% in-facepiece sampling errors are considered, the probability of overexposure was 2.9%, with a 95% confidence interval of 1.1 to 6.3%. The authors believe the current APF of 10 for half-facepiece respirators is appropriate.

Air Pollutants, Occupational↗

Some results on combinations of two binary screening tests.

When two medical screening tests for a disease exist, it may be appealing to combine them to increase screening accuracy. Combination of two valid screening tests, where each independently has screening performance, can increase the overall disease screening performance. Some results are obtained when two binary screening tests are combined according to the Boolean Any+ strategy, as defined by Maguire (1). These results are useful and provide investigators of two screening tests a sense of what to expect of the performance of the two tests when combined. This then may be followed by a clinical trial that directly demonstrates the benefit of the combined test.

Binomial Distribution↗

Noninferiority testing in crossover trials with correlated binary outcomes and small event proportions with applications to the analysis of condom failure data.

Regulatory agencies may require demonstrating a new therapy or device as noninferior to an existing method. For example, a new condom type must demonstrate noninferiority to existing latex condoms before consideration as an equivalent method of pregnancy prevention. Studies designed to assess condom effectiveness typically measure experimental and standard condom failure in a crossover trial, resulting in unbalanced correlated binary outcomes with low event proportions. We used simulations to evaluate the test size of a simple population average approach to noninferiority testing with the small event proportions, intracluster correlations, and sample sizes frequently found in condom studies. Results emphasize the importance of considering test accuracy when designing any study.

Binomial Distribution↗

Clinical equivalence.

When the classical approach of testing the null hypothesis of equality is used and the results are not statistically significant, formal conclusions regarding the "closeness" of the treatments cannot be drawn. When the purpose of the investigation is to exhibit "closeness," misinterpretations may result in inappropriate, or even incorrect, conclusions. Here methodology for use when the goal is to exhibit the equivalence (noninferiority) of the treatments is discussed. The techniques allow direct conclusions to be drawn regarding the equivalence of the treatments. A review is presented.

Binomial Distribution↗

Simultaneous testing strategy for comparing two treatments in a stratified binomial trial.

The Mantel-Haenszel (M-H) procedure is commonly used to compare two treatments in a stratified binomial trial. However, this procedure is asymptotically optimal only if the odds ratio is constant across strata. We propose an alternative analytic strategy based on the simultaneous use of two statistics, ZS and ZI, each involving a weighted averaging of within-stratum differences between proportions. The two treatments are declared significantly different at overall level alpha if either min(ZS, ZI) > Zalpha/2 or max(ZS, ZI) > Zalpha*/2, where alpha* is data dependent. Our strategy is shown to be more powerful than the M-H and other related procedures. Numerical examples are provided for illustration.

Adrenergic beta-Antagonists↗

Optimal two-stage designs for single arm phase II cancer trials.

In this article, we provide a minimax design for the two-stage single binomial trial with given exact upper bounds for type I and type II errors (operating characteristics). Amongst all two-stage designs exceeding the specified operating characteristics, the proposed design is minimax in the sense that it has the smallest globally maximized expected sample size. Tables are provided for interested users, covering planning differences in response rates of 15 and 20%.

Algorithms↗

Intermediate conductances during deactivation of heteromultimeric Shaker potassium channels.

A previous study of the T442S mutant Shaker channel revealed activation-coupled subconductance levels that apparently represent kinetic intermediates in channel activation (Zheng, J., and F.J. Sigworth. 1997. J. Gen. Physiol. 110:101-117). We have now extended the study to heteromultimeric channels consisting of various numbers of mutant subunits as well as channels without mutant subunits, all in the background of a chimeric Shaker channel having increased conductance. It has been found that activation-coupled sublevels exist in all these channel types, and are traversed in at least 80% of all deactivation time courses. In symmetric K+ solutions, the currents in the two sublevels have a linear voltage dependence, being 23-44% and 54-70% of the fully open conductance. Sublevels in different channel types share similar voltage dependence of the mean lifetime and similar ion selectivity properties. However, the mean lifetime of each current level depends approximately geometrically on the number of mutant subunits in the channel, becoming shorter in channels having fewer mutant subunits. Each mutant subunit appears to stabilize all of the conducting states by approximately 0.5 kcal/mol. Consistent with previous results in the mutant channel, sublevels in channels with two or no mutant subunits also showed ion selectivities that differ from that of the fully open level, having relatively higher K+ than Rb+ conductances. A model is presented in which Shaker channels have two coupled activation gates, one associated with the selectivity filter and a second associated with the S6 helix bundle.

Animals↗

Monotony of surprise and large-scale quest for unusual words.

The problem of characterizing and detecting recurrent sequence patterns such as substrings or motifs and related associations or rules is variously pursued in order to compress data, unveil structure, infer succinct descriptions, extract and classify features, etc. In molecular biology, exceptionally frequent or rare words in bio-sequences have been implicated in various facets of biological function and structure. The discovery, particularly on a massive scale, of such patterns poses interesting methodological and algorithmic problems and often exposes scenarios in which tables and synopses grow faster and bigger than the raw sequences they are meant to encapsulate. In previous study, the ability to succinctly compute, store, and display unusual substrings has been linked to a subtle interplay between the combinatorics of the subword of a word and local monotonicities of some scores used to measure the departure from expectation. In this paper, we carry out an extensive analysis of such monotonicities for a broader variety of scores. This supports the construction of data structures and algorithms capable of performing global detection of unusual substrings in time and space linear in the subject sequences, under various probabilistic models.

Algorithms↗

Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci.

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.

Age Factors↗

Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer.

To study genetic changes associated with the development of breast cancer and the extent of its hereditary predisposition, paraffin-embedded tissue samples were obtained from monozygotic twin pairs concordant for breast cancer through the linked Swedish Twin and Cancer Registries. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a series of microsatellite markers on chromosomes 13 and 17, containing loci with known tumour suppressor genes. Multiple losses of constitutional heterozygosity (LOH), consistent with a loss of large genomic region, the whole chromosome or chromosome arm, was found in at least three pairs of twins. One double mitotic crossover was identified in one tumour sample in a pair concordant for LOH at multiple loci on both chromosomes. Recombination breakpoints were mapped to regions delineated by D13S218 and D13S263, and D13S155 and D13S279, respectively. In general, no genetic effect of losing the same allele within a twin pair was found. However, for one marker at chromosome 13 (D13S328, between the BRCA2 and the RB-1 loci) and two markers on chromosome 17 (D17S786, distal to the p53 locus, and D17S855, an intragenic BRCA1 marker) the proportion of twin pairs with the same LOH was significantly higher than expected. These regions may reflect hereditary genomic changes in our sample set. In addition, tumour DNA samples from a subset of 12 twin pairs were analysed for BRCA1 and BRCA2 mutations using exon-by-exon single-strand conformation polymorphism analysis. Two unclassified BRCA2 variants, with a putative pathogenic effect, were identified, but no pathogenic alterations were found in the BRCA1 gene.

Adult↗

Concurrent correlates and predictors of reading and spelling achievement in deaf and hearing school children.

Seven- and eight-year-old deaf children and hearing children of equivalent reading age were presented with a number of tasks designed to assess reading, spelling, productive vocabulary, speechreading, phonological awareness, short-term memory, and nonverbal intelligence. The two groups were compared for similarities and differences in the levels of performance and in the predictors of literacy. Multiple regressions showed that both productive vocabulary and speechreading were significant predictors of reading for the deaf children after hearing loss and nonverbal intelligence had been accounted for. However, spelling ability was not associated with any of the other measures apart from reading. For hearing children, age was the main determinant of reading and spelling ability (due to selection criterion). Possible explanations for the role of speechreading and productive vocabulary in deaf children's reading and the differences between the correlates of literacy for deaf and hearing children are discussed.

Analysis of Variance↗

Association rate between deep peritoneal endometriosis and other forms of the disease: pathogenetic implications.

BACKGROUND: It has been suggested recently that deep endometriosis and the other forms of the disease do not share a common pathogenetic mechanism. In this study, we hypothesize that, if this is true, deep peritoneal endometriosis and the other forms should not be significantly associated. METHODS: Clinical and surgical records of all women who were referred to the Department of Obstetrics and Gynecology, Clinica 'L.Mangiagalli' between January 1995 and June 2002 and who were diagnosed with deep peritoneal pelvic endometriosis at the time of surgery were retrieved. The concomitant presence of superficial endometriotic implants, endometriomas and pelvic adhesions was evaluated. A binomial probability distribution model was used to calculate the 95% confidence interval (95% CI) of the association rates. RESULTS: Ninety-three women with deep peritoneal endometriosis were identified. The presence of superficial endometriotic implants, endometriomas and pelvic adhesions was documented in 61.3% (95% CI 51.4-71.2%), 50.5% (95% CI 40.3-60.7%) and 74.2% (95% CI 65.3-83.1%) of patients with deep endometriotic nodules, respectively. Overall, deep peritoneal endometriosis was the only form of the disease in only 6.5% (95% CI 2.8-12.3%) of cases. No relevant differences regarding these associations were observed according to the location and the size of the deep endometriotic nodules. CONCLUSIONS: Results from this study do not support the hypothesis that deep endometriosis should be considered as a distinct entity of the disease.

Adnexal Diseases↗

A likelihood-based method of identifying contaminated lots of blood product.

BACKGROUND: In 1994 a small cluster of hepatitis-C cases in Rhesus-negative women in Ireland prompted a nationwide screening programme for hepatitis-C antibodies in all anti-D recipients. A total of 55 386 women presented for screening and a history of exposure to anti-D was sought from all those testing positive and a sample of those testing negative. The resulting data comprised 620 antibody-positive and 1708 antibody-negative women with known exposure history, and interest was focused on using these data to estimate the infectivity of anti-D in the period 1970-1993. METHODS: Any exposure to anti-D provides an opportunity for infection, but the infection status at each exposure time is not observed. Instead, the available data from antibody testing only indicate whether at least one of the exposures resulted in infection. Using a simple Bernoulli model to describe the risk of infection in each year, the absence of information regarding which exposure(s) led to infection fits neatly into the framework of 'incomplete data'. Hence the expectation-maximization (EM) algorithm provides estimates of the infectiousness of anti-D in each of the 24 years studied. RESULTS: The analysis highlighted the 1977 anti-D as a source of infection, a fact which was confirmed by laboratory investigation. Other suspect batches were also identified, helping to direct the efforts of laboratory investigators. CONCLUSIONS: We have presented a method to estimate the risk of infection at each exposure time from multiple exposure data. The method can also be used to estimate transmission rates and the risk associated with different sources of infection in a range of infectious disease applications.

Algorithms↗

Hepatitis C virus (HCV) infection and liver-related mortality: a population-based cohort study in southern Italy. The Association for the Study of Liver Disease in Puglia.

BACKGROUND: Hepatitis C virus (HCV) is a common cause of chronic liver diseases but the degree to which these diseases contribute to liver-related mortality is not well established. The aim of this study was to estimate the absolute and relative effects of HCV infection on liver-related mortality. METHODS: A population random sample of 2472 subjects aged > or = 30 years was enrolled and followed up from 1985 to 1996. At enrollment, a structured interview and a clinical evaluation were performed. Serum samples were tested using HCV ELISA and RIBA HCV. Outcomes were overall and liver-related mortality and tracing procedures included review of office and hospital records, death certificates, and interviews with general practitioners, attending hospital and next of kin. Statistical analysis was performed using Poisson and binomial prospective data regression. RESULTS: Crude overall and liver-related mortality rates were 7.66 (95% CI : 6.68-8.79) and 0.9 (95% CI : 0.3-2.2) per 10(3) person-years, respectively. For HCV infection effect, incidence rate ratio and difference (per 10(3) person-year), risk ratio and difference were 27.5 (95% CI : 6.5-115.6), 4 (95% CI : 3-7), 33.1 (95% CI : 7.8- 139.3) and 0.06 (95% CI : 0.04-0.08), respectively; all measures were adjusted for age at death, sex and daily alcohol intake. CONCLUSIONS: The results show a strong relative but weak absolute effect of HCV infection on liver-related mortality in the 10-year period considered. Poisson and binomial models are virtually equivalent, but the choice of the summarizing measure of effect may have a different impact on health policy.

Adult↗

Proper interpretation of non-differential misclassification effects: expectations vs observations.

BACKGROUND: Many investigators write as if non-differential exposure misclassification inevitably leads to a reduction in the strength of an estimated exposure-disease association. Unfortunately, non-differentiality alone is insufficient to guarantee bias towards the null. Furthermore, because bias refers to the average estimate across study repetitions rather than the result of a single study, bias towards the null is insufficient to guarantee that an observed estimate will be an underestimate. Thus, as noted before, exposure misclassification can spuriously increase the observed strength of an association even when the misclassification process is non-differential and the bias it produced is towards the null. METHODS: We present additional results on this topic, including a simulation study of how often an observed relative risk is an overestimate of the true relative risk when the bias is towards the null. RESULTS: The frequency of overestimation depends on many factors: the value of the true relative risk, exposure prevalence, baseline (unexposed) risk, misclassification rates, and other factors that influence bias and random error. CONCLUSIONS: Non-differentiality of exposure misclassification does not justify claims that the observed estimate must be an underestimate; further conditions must hold to get bias towards the null, and even when they do hold the observed estimate may by chance be an overestimate.

Bias↗

Using hierarchical models to analyse clinical indicators: a comparison of the gamma-Poisson and beta-binomial models.

BACKGROUND: Clinical indicators (CIs) are used to assess, compare and determine the potential to improve the care provided by hospitals and physicians. The results for Australian hospitals in 1998-2000 have been reported using a new methodology. The gamma-Poisson hierarchical model was used to correct for the effects of sampling variation by obtaining the empirical Bayesian shrunken estimates for the CI proportions for each hospital. Then, an estimate of the potential system gains that could be achieved if the mean proportion was shifted to the 20th centile is obtained for each of the 185 CIs. The results are sed to prioritize quality improvement activity. OBJECTIVES: To describe the 20th centile method of calculating potential system gains in the health care system; to determine the impact of using the beta-binomial model rather than the gamma-Poisson model to obtain shrunken estimates for the CI proportions; and to compare the computationally simpler Method of Moments (MoM) with the maximum likelihood (ML) method for parameter estimation. METHODS: The formulae for the gamma-Poisson and beta-binomial shrinkage estimators were compared analytically. Each of the shrinkage estimators and the two methods of parameter estimation were applied to the Obstetric and Gynecological CIs, and the results compared. RESULTS The comparison of the formulae for the two shrinkage estimators showed that the gamma-Poisson model results in: greater shrinkage towards the overall mean. This was verified empirically using the clinical indicators. Additionally, the MoM was not a viable alternative to the ML method. CONCLUSIONS: The gamma-Poisson model provided smaller estimates of the potential system gains by up to 6.7% of the numerator for the clinical indicators. The difference in estimation increased with increasing mean proportions and between-hospital variation. We recommend that the beta-binomial model should be used on the basis of both theoretical and empirical grounds.

Australia↗