The diffusion of new genetic tests for predicting disease.

This paper examines the pathways by which new genetic tests will become available to the public. In view of the scarcity of genetic specialists, the pathway is likely to involve primary care physicians. Other pathways entail state-mandated testing, community-based programs, or testing by laboratories without much involvement of primary care physicians. When testing does become available the destination will be either family-centered testing or population-oriented screening. The deterrent to screening will not be the inability to detect disease-causing mutations but the costs and attitudes of providers and the public. When tests are provided primarily to provide information about risks to future children, some people will oppose screening on religious or moral grounds. When there are no inexpensive treatments, some will fear that insurance companies and employers will use tests to deny them health care coverage. Some may not want to know their risks for disorders about which little can be done. For common, multifactorial disorders, genetic tests will have low predictive value. Because of these problems, the decision to be tested, regardless of the destination, requires that testees be fully informed and consent to testing. When acceptance rates are low, screening is less likely to be cost-effective; family-centered testing becomes the default destination.     

Technical reproducibility of genotyping SNP arrays used in genome-wide association studies

During the last several years, high-density genotyping SNP arrays have facilitated genome-wide association studies (GWAS) that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. Moreover, discordance observed in results between independent GWAS indicates the potential for Type I and II errors. High reliability of genotyping technology is needed to have confidence in using SNP data and interpreting GWAS results. Therefore, reproducibility of two widely genotyping technology platforms from Affymetrix and Illumina was assessed by analyzing four technical replicates from each of the six individuals in five laboratories. Genotype concordance of 99.40% to 99.87% within a laboratory for the sample platform, 98.59% to 99.86% across laboratories for the same platform, and 98.80% across genotyping platforms was observed. Moreover, arrays with low quality data were detected when comparing genotyping data from technical replicates, but they could not be detected according to venders' quality control (QC) suggestions. Our results demonstrated the technical reliability of currently available genotyping platforms but also indicated the importance of incorporating some technical replicates for genotyping QC in order to improve the reliability of GWAS results. The impact of discordant genotypes on association analysis results was simulated and could explain, at least in part, the irreproducibility of some GWAS findings when the effect size (i.e. the odds ratio) and the minor allele frequencies are low.     

Genetic dissection methods: designs used for tests of gene-environment interaction

Given recent advances in the field of molecular genetics, many have recognized the need to exploit either study designs or analytical methods to test hypotheses with gene-by-environment (G x E) interactions. The partial-collection designs, including case-only, partial case-control, and case-parent trio designs, have been suggested as attractive alternatives to the complete case-control design both for increased statistical efficiency and reduced data needs. However, common problems in genetic epidemiology studies, such as, presence of G x E correlation in the population, population mixture, and genotyping error may reduce the validity of these designs. On the basis of previous simulation studies and empirical data and given the potential limitations and uncertainty of assumptions of partial-collection designs, the case-control design is the optimal choice versus partial-collection designs.     

Analysis of the diluents used for rubella virus hemagglutination and hemagglutination-inhibition tests

[This corrects the article on p. 222 in vol. 18.].     

The role of aquatic toxicity tests in predicting and monitoring pollution effects

The complementary role of aquatic toxicity tests in relation to other forms of pollution assessment is discussed. These tests may be predictive and designed to estimate hazard, or used for monitoring waters to assess compliance with standards. The effects of pollutants are significantly modified by certain water quality characteristics and by a variety of biological factors. The latter, particularly those causing physiological stress, are discussed.     

Allelism tests of 15 dominant cataract mutations in mice.

Fifteen autosomal dominant mutations that cause cataract of lenses in mice were tested for allelism. The outcrosses of double mutants revealed three allelism groups, consisting of 5, 4 and 2 mutations as well as 4 mutations which segregated independently. The results indicated 7 different cataract loci in the sample of 15 mutations. The biomicroscopic examination of the eyes showed that phenotypically similar as well as very distinct cataract mutations can be alleles of the same gene. Conversely, phenotypically similar mutations were shown to be non-allelic.     

Applying geographic profiling used in the field of criminology for predicting the nest locations of bumble bees

We tested whether geographic profiling (GP) can predict multiple nest locations of bumble bees. GP was originally developed in the field of criminology for predicting the area where an offender most likely resides on the basis of the actual crime sites and the predefined probability of crime interaction. The predefined probability of crime interaction in the GP model depends on the distance of a site from an offender's residence. We applied GP for predicting nest locations, assuming that foraging and nest sites were the crime sites and the offenders’ residences, respectively. We identified the foraging and nest sites of the invasive species Bombus terrestris in 2004, 2005, and 2006. We fitted GP model coefficients to the field data of the foraging and nest sites, and used GP with the fitting coefficients. GP succeeded in predicting about 10-30% of actual nests. Sensitivity analysis showed that the predictability of the GP model mainly depended on the coefficient value of buffer zone, the distance at the mode of the foraging probability. GP will be able to predict the nest locations of bumble bees in other area by using the fitting coefficient values measured in this study. It will be possible to further improve the predictability of the GP model by considering food site preference and nest density.     

Potentially difficult smears of women with squamous cell carcinoma pose fewer problems when PAPNET is used for primary screening

The diagnosis of squamous cell carcinoma (SCC) on a cervical smear is often far from easy. This study reports the analysis of 40 true-positive SCC smears detected in primary PAPNET screening and eight false-negative (FN) conventionally screened smears. All FN cases contained sparse abnormal material (< 10% of the slide). In these potentially difficult cases the diagnosis on the PAPNET images was not hard. Statistical analysis of the quantitative data indicated that the PAPNET images of the FN cases and the true-positive cases differed in some aspects. PAPNET highlighted the importance of background information (old blood, fibrin and necrosis). In addition, all FN smears contained cancer cells in the PAPNET images, allowing a correct diagnosis.     

Concurrent validity of four clinical tests used to measure hamstring flexibility

The purpose of this study was to examine the concurrent validity of 4 clinical tests used to measure hamstring muscle length. A pilot study (N = 10) was conducted to determine the intratester reliability of 4 hamstring length measures: knee extension angle (KEA), sacral angle (SA), straight leg raise (SLR), and sit and reach (SR). The pilot investigation revealed good to excellent intratester reliability (intraclass correlation coefficient = 0.92-0.95) for each of the 4 tests. Eighty-one subjects (42 men and 39 women) participated in the main investigation. Subjects were randomly tested for each of 4 assessments of hamstring length. Concurrent validity was determined using linear regression, correlation, and kappa statistics. Correlation coefficients corresponding to the concurrent validity of the six combinations of the 4 clinical tests revealed poor to fair correlation (r = 0.45-0.65). The correlation coefficients for each pair from greatest to least were SR-SA= 0.65, SLR-SR = 0.65, KEA-SLR = 0.63, KEA-SR = 0.57, SLR-SA = 0.50, and KEA-SA = 0.45. Despite the common clinical use of these measures to assess hamstring length, these tests do not have sufficient concurrent validity to be used interchangeably or to assume that they each measure the same construct (hamstring length). Based on the results of this investigation and a review of the literature, the authors recommend that researchers, clinicians, and strength and conditioning specialists adopt the KEA test as the gold standard measure for hamstring muscle length.     

Evaluation of data transformations used with the square root and schoolfield models for predicting bacterial growth rate.

A comparison was made between mathematical variations of the square root and Schoolfield models for predicting growth rate as a function of temperature. The statistical consequences of square root and natural logarithm transformations of growth rate use in several variations of the Schoolfield and square root models were examined. Growth rate variances of Yersinia enterocolitica in brain heart infusion broth increased as a function of temperature. The ability of the two data transformations to correct for the heterogeneity of variance was evaluated. A natural logarithm transformation of growth rate was more effective than a square root transformation at correcting for the heterogeneity of variance. The square root model was more accurate than the Schoolfield model when both models used natural logarithm transformation.     

Evaluation of data transformations used with the square root and schoolfield models for predicting bacterial growth rate.

A comparison was made between mathematical variations of the square root and Schoolfield models for predicting growth rate as a function of temperature. The statistical consequences of square root and natural logarithm transformations of growth rate use in several variations of the Schoolfield and square root models were examined. Growth rate variances of Yersinia enterocolitica in brain heart infusion broth increased as a function of temperature. The ability of the two data transformations to correct for the heterogeneity of variance was evaluated. A natural logarithm transformation of growth rate was more effective than a square root transformation at correcting for the heterogeneity of variance. The square root model was more accurate than the Schoolfield model when both models used natural logarithm transformation.