Identification of interactions of binary variables associated with survival time using survivalFS.

Many medical studies aim to identify factors associated with a time to an event such as survival time or time to relapse. Often, in particular, when binary variables are considered in such studies, interactions of these variables might be the actual relevant factors for predicting, e.g., the time to recurrence of a disease. Testing all possible interactions is often not possible, so that procedures such as logic regression are required that avoid such an exhaustive search. In this article, we present an ensemble method based on logic regression that can cope with the instability of the regression models generated by logic regression. This procedure called survivalFS also provides measures for quantifying the importance of the interactions forming the logic regression models on the time to an event and for the assessment of the individual variables that take the multivariate data structure into account. In this context, we introduce a new performance measure, which is an adaptation of Harrel's concordance index. The performance of survivalFS and the proposed importance measures is evaluated in a simulation study as well as in an application to genotype data from a urinary bladder cancer study. Furthermore, we compare the performance of survivalFS and its importance measures for the individual variables with the variable importance measure used in random survival forests, a popular procedure for the analysis of survival data. These applications show that survivalFS is able to identify interactions associated with time to an event and to outperform random survival forests.

Assessment of usefulness of synchrotron radiation techniques to determine arsenic species in hair and rice grain samples.

The arseniasis in Southwest Guizhou, China has been identified as a unique case of endemic arseniasis caused by exposure to indoor combustion of high As-content coal. Present investigation targeted the microdistribution and speciation of the element arsenic in human hair and environmental samples collected in one of the hyper-endemic villages of arseniasis in the area. Analyses were performed by micro-beam X-ray fluorescence (µ-XRF) and X-ray absorption fine structure (XAFS). The total As level in hair samples of diagnosed patients was detected at almost the same level as in their asymptomatic neighbors. Concentrations in the lateral cut of hair samples were high-low-high (from surface to center). XAFS revealed the coexistence of both the As+3 and As+5 states in hair samples. However, the samples from patients displayed a tendency of higher As+3 / As+5 ratio than the asymptomatic fellow villagers. The µ-XRF mapping of rice grains shows that arsenic penetrates the endosperm, the major edible part of the grain, when rice grains were stored over the open fire of high As-content coal. Synchrotron radiation techniques are suitable to determine arsenic species concentrations in different parts of hair and rice grain samples. As arsenic penetrates the endosperm, rinsing the rice grains with water will remain largely ineffective.

Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results.

Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandirma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 ± 69.49 ng/g) of the high exposure group workers in Bandirma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child).

Assessment criteria for compensation of occupational bladder cancer.

In Germany, more than 100 bladder tumor cases are annually recognized as occupational disease and compensated, given that medical experts regard exposure to carcinogenic aromatic amines as a likely cause of cancer. The amount of compensation is initially based on the tumor staging and grading at the time of initial diagnosis ("basic MdE") (MdE--reduction of earning capacity) and is adapted after a recurrence-free period of 2 and 5 years, respectively. In the event of treatment or tumor-related secondary conditions, the monthly compensation increases based on the severity of the objectified functional disorder. In the following article, medical experts specializing in this field provide a complete list of all known disorders, including treatment-related loss of a kidney or erectile dysfunction. In addition, the weighting of medical criteria in the assessment and calculation of the compensation is analyzed in greater detail. Since the given criteria are based on comprehensible experiences of urologists with their patients, they also provide medical experts in other countries with valuable points of reference for the calculation of the compensation.

Miners compensated for pneumoconiosis and glutathione s-transferases M1 and T1 genotypes.

Chronic inhalation of quartz-containing dust produces reversible inflammatory changes in lungs resulting in irreversible fibrotic changes termed pneumoconiosis. Due to the inflammatory process in the lungs, highly reactive substances are released that may be detoxified by glutathione S-transferases. Therefore, 90 hard coal miners with pneumoconiosis as a recognized occupational disease (in Germany: Berufskrankheit BK 4101) were genotyped for glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) according to standard methods. Furthermore, occupational exposure and smoking habits were assessed by questionnaire. Changes in a chest x-ray were classified according to ILO classification 2000. Of the investigated hard coal miners 43% were GSTM1 negative whereas 57% were GSTM1 positive. The arithmetic mean of the age at time of investigation was 74.2 yr (range: 42-87 yr). Seventy-four percent of the hard coal miners reported being ever smokers, while 26% denied smoking. All hard coal miners provided pneumoconiosis-related changes in the chest x-ray. The observed frequency of GSTM1 negative hard coal miners was not different from frequencies reported for general Caucasian populations and in agreement with findings reported for Chinese coal miners. In contrast, in a former study, 16 of 19 German hard coal miners (84%) with urinary bladder cancer displayed a GSTM1 negative genotype. The outcome of this study provides evidence that severely occupationally exposed Caucasian hard coal miners do not present an elevated level of GSTM1 negative individuals.

Assessment of DNA integrity (COMET assay) in sperm cells of boron-exposed workers.

An extension of a male reproductive study conducted in a boric acid/borate production zone at Bandirma, Turkey, is presented. The relation between DNA-strand breaks (COMET assay, neutral and alkaline version) in sperm cells and previously described sperm quality parameters was investigated in boron-exposed males. A correlation between blood boron levels and mean DNA-strand breaks in sperm was weak, and DNA-strand breaks in sperm were statistically not different between control and exposed groups. Therefore, increasing boron exposures had no additional contribution in addition to already pre-existing DNA-strand breaks in the sperm cells. Weak but statistically significant correlations between DNA-strand breaks and motility/morphology parameters of sperm samples were observed in the neutral version of the COMET assay, while correlations between the same variables were statistically not significant in the alkaline version. A likely reason for these negative results, even in highly exposed humans, is that experimental exposures that had led to reproductive toxicity in animals were significantly higher than any boron exposures, which may be reached under realistic human conditions.

Re-assessment of the influence of polymorphisms of phase-II metabolic enzymes on renal cell cancer risk of trichloroethylene-exposed workers.

PROBLEM: Individual differences in susceptibility to trichloroethylene-induced nephrocarcinogenicity may be conferred by genetic polymorphisms of glutathione S-transferases (GST), because enzymes of this group are pivotal for the metabolic activation of trichloroethylene. Because of a potential involvement of N-acetylation in the detoxication of reactive trichloroethylene metabolite(s) to N-acetyl-cysteine derivatives, polymorphisms of the NAT2 gene may also be relevant. METHODS: The primary collective used for a re-investigation of these questions was that of a hospital-based case-control study by Brüning et al. (Am J Ind Med 43:274-285, 2003) of 134 renal cell cancer cases (20 cases exposed to trichloroethylene) and 401 matched controls. Genetic polymorphisms of GSTT1, GSTM1, GSTP1 and NAT2 were studied. Additional control collectives of non-diseased persons were used for comparison of allele frequencies. RESULTS: No genetic influences on the development of renal cancer due to trichloroethylene were apparent, related to the deletion polymorphisms of GSTT1 and GSTM1, as well as to the NAT2 rapid/slow acetylator states. However, renal cell cancer cases displayed a somewhat higher proportion of the homozygous GSTP1 313A wild type (GSTP1*A), although this was not statistically significant (chi(2) test: P=0.1071, when using only the original controls of Brüning et al. (2003); P=0.0781 with inclusion of the additional controls). CONCLUSION: The re-investigation does not confirm the working hypothesis of an influence of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 on renal cell cancer development due to high occupational exposures to trichloroethylene.