Similarity Measures for Clustering SNP and Epidemiological Data

The issue of suitable similarity measures for a joint consideration of so called SNP data and epidemiological variables arises from the GENICA (Interdisciplinary Study Group on Gene Environment Interaction and Breast Cancer in Germany) casecontrol study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. A single nucleotide polymorphism is a point mutation that is present in at least 1 % of a population. SNPs are the most common form of human genetic variations. In particular, we consider 43 SNP loci in genes involved in the metabolism of hormones, xenobiotics and drugs as well as in the repair of DNA. Assuming that these single nucleotide changes may lead, for instance, to altered enzymes or to a reduced or enhanced amount of the original enzymes – with each alteration alone having minor effects – the aim is to detect combinations of SNPs that under certain environmental conditions increase the risk of sporadic breast cancer. The search for patterns in the present data set may be performed by a variety of clustering and classification approaches. I consider here the problem of suitable measures of proximity of two variables or subjects as an indispensable basis for a further cluster analysis. In the present data situation these measures have to be able to handle different numbers and meaning of categories of nominal scaled data as well as data of different scales. Generally, clustering approaches are a useful tool to detect structures and to generate hypothesis about potential relationships in complex data situations. Searching for patterns in the data there are two possible objectives: the identification of groups of similar objects or subjects or the identification of groups of similar variables within the whole or within subpopulations. The different objectives imply different requirements on the measures of similarity. Comparing the individual genetic profiles as well as comparing the genetic information across subpopulations I discuss possible choices of similarity measures suitable for genetic and epidemiological data, in particular, measures based on the ÷2-statistic, Flexible Matching Coefficients and combinations of similarity measures. --GENICA,single nucleotide polymorphism (SNP),sporadic breast cancer,similarity,cluster analysis,Flexible Matching Coefficient

Similarity Measures for Clustering SNP Data

The issue of suitable similarity measures for a particular kind of genetic data – so called SNP data – arises from the GENICA (Interdisciplinary Study Group on Gene Environment Interaction and Breast Cancer in Germany) case-control study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. A single nucleotide polymorphism is a point mutation that is present in at least 1 % of a population. SNPs are the most common form of human genetic variations. In particular, we consider 65 SNP loci and 2 insertions of longer sequences in genes involved in the metabolism of hormones, xenobiotics and drugs as well as in the repair of DNA and signal transduction. Assuming that these single nucleotide changes may lead, for instance, to altered enzymes or to a reduced or enhanced amount of the original enzymes – with each alteration alone having minor effects – we aim to detect combinations of SNPs that under certain environmental conditions increase the risk of sporadic breast cancer. The search for patterns in the present data set may be performed by a variety of clustering and classification approaches. We consider here the problem of suitable measures of proximity of two variables or subjects as an indispensable basis for a further cluster analysis. Generally, clustering approaches are a useful tool to detect structures and to generate hypothesis about potential relationships in complex data situations. Searching for patterns in the data there are two possible objectives: the identification of groups of similar objects or subjects or the identification of groups of similar variables within the whole or within subpopulations. Comparing the individual genetic profiles as well as comparing the genetic information across subpopulations we discuss possible choices of similarity measures, in particular similarity measures based on the counts of matches and mismatches. New matching coefficients are introduced with a more flexible weighting scheme to account for the general problem of the comparison of SNP data: The large proportion of homozygous reference sequences relative to the homo- and heterozygous SNPs is masking the accordances and differences of interest. --GENICA,single nucleotide polymorphism (SNP),sporadic breast cancer,similarity,Matching Coefficient,Flexible Matching Coefficient

Comparison of the toxicokinetics of daidzein and bisphenol A in pregnant and non-pregnant DA/Han rats

Potentially adverse human and environmental effects due to hormone mimicry of environmental estrogens are a matter of current concern. Environmental estrogens belong to the socalled endocrine active compounds (EAC) and may alter signalling processes of the endocrine system leading to a broad range of effects during fetal and postnatal development, puberty, adulthood, and aging. A number of synthetic chemicals as well as several plant-derived compounds, socalled phytoestrogens, are known to have weak estrogenic activity. The present study is part of the risk assessment of the weak environmental estrogens daidzein and bisphenol A. The isoflavone daidzein is an important phytoestrogen with respect to dietary exposure (soy beans and soy products) whereas bisphenol A is an industrial chemical that occurs at much lower concentrations as a contaminant in food. The toxicokinetics of these compounds in female pregnant and non-pregnant DA/Han rats after single intravenous application were compared by the use of the Mann-Whitney- U-statistic. --Bisphenol A,daidzein,xenoestrogens,phytoestrogens,endocrine active compounds,Mann-Whitney-U-test

Cluster Analysis : A Comparison of Different Similarity Measures for SNP Data

The issue of suitable similarity measures for a particular kind of genetic data - so called SNP data - arises, e.g., from the GENICA (The Interdisciplinary Study Group on Gene Environmental Interactions and Breast Cancer in Germany) case-control study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. It is very unlikely that there exists one main effect, say only one polymorphism, being responsible for such a complex disease as sporadic breast cancer as the role of a single gene within the carcinogenic process is limited (Garte, 2001). Nevertheless, it is assumed that a number of interacting SNPs in combination with certain environmental risk factors increase the individual susceptibility. The search for SNP patterns in the present data set may be performed by a variety of clustering and classification approaches. Here we consider the problem of adequate similarity measures for variables or subjects as an indispensable basis for a further cluster analysis. The term ?similarity? is still vague for SNP data. A main problem arises by the general structure of such data sets: the proportion of hetero- or homozygous SNPs is rather small compared with the homozygous reference sequence. Thus, the relevant information of combinations of genetic alterations is often masked by a huge amount of common occurrences of homozygous reference types. Therefore, we examine different similarity measures, conventional ones as well as new coefficients which we created especially for SNP data. Furthermore, we compare the resulting partitions with each other adapting the clustering of clustering methods of Rand (1971) for different similarity measures. --cluster analysis,clustering clustering methods,GENICA,similarity,single nucleotide polymorphism,sporadic breast cancer

The influence of glutathione S-transferases M1 and M3 on the development of bladder cancer

Problem: Cigarette smoking is the most important risk factor of transitional cell carcinoma of the urinary bladder. The effect of the glutathione S- transferases M1 (GSTM1) and M3 (GSTM3) on the influence of this risk factor was investigated. Methods: A total of 293 bladder cancer patients from Dortmund and Wittenberg as well as 176 surgical patients without any malignancy from Dortmund were genotyped for GSTM1 und GSTM3 according to standard PCR/RFLP methods. Smoking habits were also qualified by a standardized interview. Results: The percentage of GSTM1 negative cases was 63 % in the entire bladder cancer patient group compared to 50 % in the control group. GSTM3*A/*A genotype was 76 % in the entire group of bladder cancer cases and 74 % in controls. Smokers and ex-smokers were overrepresented in the bladder cancer patient group. A significant association between smoking status and GSTM1 or GSTM3 genotype could not be revealed. Conclusion: The elevated percentage of GSTM1 negative bladder cancer cases shows the important effect of this polymorphic enzyme on the development of bladder cancer. In contrast to some other studies, an influence of GSTM1 on the risk due to cigarette smoking could not be observed. --Bladder cancer,glutathione S-transferase M1,glutathione S-transferase M3,smoking

Estimation of the Mean AUC of the Xenoestrogens Daidzein, Bisphenol A, and p-tert-Octylphenol

Potentially adverse human and environmental effects due to hormone mimicry of environmental estrogens are a matter of current concern. Environmental estrogens belong to the so-called endocrine active compounds (EAC), which alter signalling processes of the endocrine system leading to a broad range of effects during foetal and postnatal development, puberty, adulthood, and aging. A number of synthetic chemicals as well as several plant-derived compounds, so-called phytoestrogens, are known to have weak estrogenic activity. The present study is part of the risk assessment of the weak environmental estrogens daidzein, p-tert-octylphenol, and bisphenol A. The isoflavone daidzein is an important phytoestrogen with respect to dietary exposure (soy beans and soy products). p-tert-Octylphenol and bisphenol A are industrial chemicals. The toxicokinetics and the bioavailability of these three substances in female DA/Han rats after oral and single intravenous application were investigated by the use of population models accounting for the differences in the individual metabolism. Furthermore, populations of pregnant and non-pregnant rats are compared

Similarity Measures for Clustering SNP Data

Abstract The issue of suitable similarity measures for a particular kind of genetic data -so called SNP data -arises from the GENICA (Interdisciplinary Study Group on Gene Environment Interaction and Breast Cancer in Germany) case-control study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. A single nucleotide polymorphism is a point mutation that is present in at least 1 % of a population. SNPs are the most common form of human genetic variations. In particular, we consider 65 SNP loci and 2 insertions of longer sequences in genes involved in the metabolism of hormones, xenobiotics and drugs as well as in the repair of DNA and signal transduction. Assuming that these single nucleotide changes may lead, for instance, to altered enzymes or to a reduced or enhanced amount of the original enzymes -with each alteration alone having minor effects -we aim to detect combinations of SNPs that under certain environmental conditions increase the risk of sporadic breast cancer. 2 The search for patterns in the present data set may be performed by a variety of clustering and classification approaches. We consider here the problem of suitable measures of proximity of two variables or subjects as an indispensable basis for a further cluster analysis. Generally, clustering approaches are a useful tool to detect structures and to generate hypothesis about potential relationships in complex data situations. Searching for patterns in the data there are two possible objectives: the identification of groups of similar objects or subjects or the identification of groups of similar variables within the whole or within subpopulations. Comparing the individual genetic profiles as well as comparing the genetic information across subpopulations we discuss possible choices of similarity measures, in particular similarity measures based on the counts of matches and mismatches. New matching coefficients are introduced with a more flexible weighting scheme to account for the general problem of the comparison of SNP data: The large proportion of homozygous reference sequences relative to the homo-and heterozygous SNPs is masking the accordances and differences of interest

Estimation of N-acetyltransferase 2 haplotypes

N-Acetyltransferase 2 (NAT2) genotyping may result in a considerable percentage in several ambiguous allele combinations. PHASE 2.1 is a statistical program which is designed to estimate the probability of different allele combinations. We have investigated haplotypes of 2088 subjects genotyped for NAT2 according to standard PCR/RFLP methods. In 856 out of 2088 cases the genotype was clearly defined by PCR/RFLP only. In many of the remaining cases the program clearly defined the most probable allele combination: In the case of *5A/*6C, *5B/*6A the probability for *5B/*6A is 99% whereas the alternative allele combination *5A/*6C can be neglected. Other combinations cannot be allocated with a comparable high probability. For example the allele combination *5A/*5C, *5B/*5D provides for *5A/*5C a probability of 69% whereas the estimation for *5B/*5D allele is only 31%. In the two most often observed constellations in our data [(*12A/*5B, *12C/*5C); (*12A/*6A, *12B/*6B, *4/*6C)] the probability of allele combination was ascertained as follows: *12A/*5B, 98%; *12C/*5C, 1.4% and *12A/*6A, 82%; *4/*6C, 17%; *12B/*6B, 0%. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B or *13 as a rapid or slow genotype has been discussed controversially. Otherwise the classification of alleles in subjects which are not showing a clearly allocation can result in a rapid or slow acetylation state. This assignment has an important role in survey of bladder cancer cases in the scope of occupational exposure with aromatic amines. --PHASE 2.1,NAT2 genotyping,single nucleotide polymorphism

Protocol for a Randomized Phase II Trial for Mesh Optimization by Autologous Plasma Coating in Prolapse Repair: IDEAL Stage 3

Introduction: Mesh-related complications especially after vaginal implantation have raised awareness lately because of severe adverse reactions and legal aspects. About 20% of patients suffer from complications after mesh insertion in the anterior vaginal wall. Autologous plasma coating of meshes prior to implantation has shown potential to improve the biocompatibility of meshes in vivo and in vitro. This innovative approach has been developed according to the IDEAL recommendations for surgical innovations. The method has still to be assessed at stage 3 accordingly. Methods: A protocol is developed for a prospective single-blinded randomized controlled phase II trial for biocompatibility optimization of anterior vaginal meshes for prolapse repair by autologous plasma coating versus non-coated meshes. Results: The protocol aims at fulfilling the requirements for stage 3 (assessment) according to IDEAL. Eligible for inclusion are women with primary cystocele, requiring a surgical procedure, suitable for randomization, and willing to be randomized. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomization) and will also be reviewed in clinic 12 and 24 months post surgery. Primary endpoint is the assessment of mesh-related complications following the Clavien–Dindo classifications. QoL, sexual function assessment, efficacy, and validation of an already developed long-term register are considered secondary endpoints. To afford a calculated 10% reduction of postoperative complications through plasma-coated meshes vs. non-coated meshes at 1-year follow-up, a total 214 women in each arm will be necessary to achieve 80% power at a significance level of 5%. Conclusion: The protocol for this randomized clinical trial represents the conditions to assess the surgical innovation of plasma coating of meshes in order to improve the meshes’ biocompatibility at stage 3 according to the IDEAL recommendations. © 2017 Springer Healthcar

Prostate specific antigen (PSA) as predicting marker for clinical outcome and evaluation of early toxicity rate after high-dose rate brachytherapy (HDR-BT) in combination with additional external beam radiation therapy (EBRT) for high risk prostate cancer

High-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT) is a common treatment option for locally advanced prostate cancer (PCa). Seventy-nine male patients (median age 71 years, range 50 to 79) with high-risk PCa underwent HDR-BT following EBRT between December 2009 and January 2016 with a median follow-up of 21 months. HDR-BT was administered in two treatment sessions (one week interval) with 9 Gy per fraction using a planning system and the Ir192 treatment unit GammaMed Plus iX. EBRT was performed with CT-based 3D-conformal treatment planning with a total dose administration of 50.4 Gy with 1.8 Gy per fraction and five fractions per week. Follow-up for all patients was organized one, three, and five years after radiation therapy to evaluate early and late toxicity side effects, metastases, local recurrence, and prostate-specific antigen (PSA) value measured in ng/mL. The evaluated data included age, PSA at time of diagnosis, PSA density, BMI (body mass index), Gleason score, D’Amico risk classification for PCa, digital rectal examination (DRE), PSA value after one/three/five year(s) follow-up (FU), time of follow-up, TNM classification, prostate volume, and early toxicity rates. Early toxicity rates were 8.86% for gastrointestinal, and 6.33% for genitourinary side effects. Of all treated patients, 84.81% had no side effects. All reported complications in early toxicity were grade 1. PSA density at time of diagnosis (p = 0.009), PSA on date of first HDR-BT (p = 0.033), and PSA on date of first follow-up after one year (p = 0.025) have statistical significance on a higher risk to get a local recurrence during follow-up. HDR-BT in combination with additional EBRT in the presented design for high-risk PCa results in high biochemical control rates with minimal side-effects. PSA is a negative predictive biomarker for local recurrence during follow-up. A longer follow-up is needed to assess long-term outcome and toxicities