Evaluation of Finnish Diabetes Risk Score in Screening Undiagnosed Diabetes and Prediabetes among U.S. Adults by Gender and Race: NHANES 1999-2010

Objective

To evaluate the performance of Finnish Diabetes Risk Score (FINDRISC) in detecting undiagnosed diabetes and prediabetes among U.S. adults by gender and race.

Methods

This cross-sectional analysis included participants (aged ≥20 years) from the National Health and Nutrition Examination Survey (NHANES) 1999–2010. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve and the optimal cutoff points for identifying undiagnosed diabetes and prediabetes were calculated for FINDRISC by gender and race/ethnicity.

Results

Among the 20,633 adults (≥20 years), 49.8% were women and 53.0% were non-Hispanic White. The prevalence of undiagnosed diabetes and prediabetes was 4.1% and 35.6%, respectively. FINDRISC was positively associated with the prevalence of diabetes (OR = 1.48 for 1 unit increase, p<0.001) and prediabetes (OR = 1.15 for 1 unit increase, p<0.001). The area under ROC for detecting undiagnosed diabetes was 0.75 for total population, 0.74 for men and 0.78 for women (p = 0.04); 0.76 for White, 0.76 for Black and 0.72 for Hispanics (p = 0.03 for White vs. Hispanics). The area under ROC for detecting prediabetes was 0.67 for total population, 0.66 for men and 0.70 for women (p<0.001); 0.68 for White, 0.67 for Black and 0.65 for Hispanics (p<0.001 for White vs. Hispanics). The optimal cutoff point was 10 (sensitivity = 0.75) for men and 12 (sensitivity = 0.72) for women for detecting undiagnosed diabetes; 9 (sensitivity = 0.61) for men and 10 (sensitivity = 0.69) for women for detecting prediabetes.

Conclusions

FINDRISC is a simple and non-invasive screening tool to identify individuals at high risk for diabetes in the U.S. adults.     

Mass Ligand Binding Screening for Receptor Antagonists: Prototype New Drugs and Blind Alleys

Abstract

The ligand binding assay is a powerful tool in the search for antagonists for novel receptors, and for identification of novel classes of antagonists for well-known receptors. Ligand binding mass screening can be adapted for very high throughput. In order for mass screening to be useful, it is necessary to strictly define the binding characteristics for a compound to be considered a putative receptor antagonist. In practice, we have found that synthetic pursuit of a compound with a K_i of ± 1 uM is likely to lead down a blind alley unless very good evidence for specificity is available. Even potent competitors for binding should be thoroughly evaluated in assays of biological activity before a synthetic program is initiated in earnest.     

The role of phadiatop in the screening of respiratory allergy

Phadiatop is a new in vitro screening test for respiratory allergy. This test, based on the RAST procedure, detects in serum, the presence of specific IgE to a mixture of common inhalent allergens. Among 70 patients (26 children and 44 adults) consulting for respiratory syndrome, Phadiatop was positive in 31 cases. There were a good correlation between this new test and skin tests (59% for adults and 92% for children), total IgE (70% for adults and 65% for children) and RAST (93% for adults and 96% for children). Phadiatop, with a specificity of 100%, a sensitivity of 82% (76% for adults and 92% for children) and an efficiency of 90% (86% for adults and 96% for children), is a more accurate test than total IgE and could be an excellent in vitro screening test for respiratory allergy.     

Tools for comparative protein structure modeling and analysis

The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.     

Estimation and confidence regions for multi-dimensional effective dose

The problem of finding confidence regions for multiple predictor variables corresponding to given expected values of a response variable has not been adequately resolved. Motivated by an example from a study on hyperbaric exposure using a logistic regression model, we develop a conceptual framework for the estimation of the multi-dimensional effective dose for binary outcomes. The k -dimensional effective dose can be determined by conditioning on k - 1 components and solving for the last component as a conditional univariate effective dose. We consider various approaches for calculating confidence regions for the multi-dimensional effective dose and compare them via a simulation study for a range of possible designs. We analyze data related to decompression sickness to illustrate our procedure. Our results provide a practical approach to finding confidence regions for predictor variables for a given response value.     

POPULATION GENETICS OF INTRAGAMETOPHYTIC SELFING

Intragametophytic selfing is a mode of reproduction occurring in homosporous ferns where two gametes from the same haploid gametophyte form a completely homozygous sporophyte. The inbreeding equilibrium is derived for a population with partial intragametophytic selfing, selfing, and outcrossing. Procedures for directly estimating the extent of intragametophytic selfing and selfing using parent-offspring data are given. The conditions for a stable polymorphism from a heterozygous-advantage fitness model are more restrictive for partial intragametophytic selfing than for selfing. The rate of decay of gametic disequilibrium is slower for partial intragametophytic selfing than for selfing. Based on these findings, one would predict that plants with intragametophytic selfing would have less polymorphism for loci with a heterozygous advantage and more gametic disequilibrium between neutral loci than is expected for populations with an equivalent amount of selfing. Data from several studies are consistent with these predictions.     

Screening for functional expression and overexpression of a family of diiron-containing interfacial membrane proteins using the univector recombination system

The large number of uncharacterized genes emerging from genome sequencing projects has resulted in a need for quick and reliable screening methods for protein expression parameters. We have utilized the univector plasmid recombination system (as previously reported) to develop a series of vectors for rapid screening for expression in Escherichia coli. A high level of recombinant protein expression is a requirement for purification of protein for structural determination and other purposes. In other applications, successful complementation of a missing enzyme activity in E. coli, as well as directed evolution studies and metabolic engineering, often require a much lower level of protein expression. In this report we describe the construction of a number of new pHOST vectors that can be screened for both low- and high-level expression. We isolated a mutant vector for MBP fusions that exhibited a more optimal level of expression for complementation of aerobic respiration in hemA(-) E. coli, our functional assay for the alternative oxidase. We then demonstrated the use of our system to rapidly screen for both optimal functional expression and optimal overexpression of the alternative oxidase as well as two other members of a family of membrane-bound diiron carboxylate proteins, the plastid terminal oxidase and 5-demethoxyquinone hydroxylase.     

Integrated allele-specific polymerase chain reaction-capillary electrophoresis microdevice for single nucleotide polymorphism genotyping

An integrated allele-specific (AS) polymerase chain reaction (PCR) and capillary electrophoresis (CE) microdevice has been developed for multiplex single nucleotide polymorphism (SNP) genotyping on a portable instrumentation, which was applied for on-site identification of HANWOO (Korean indigenous beef cattle). Twelve sets of primers were designed for targeting beef cattle's eleven SNP loci for HANWOO verification and one primer set for a positive PCR control, and the success rate for identification of HANWOO was demonstrated statistically. The AS PCR and CE separation for multiplex SNP typing was carried out on a glass-based microchip consisting of four layers: a microchannel plate for microfluidic control, a Pt-electrode plate for a resistance temperature detector (RTD), a poly(dimethylsiloxane) (PDMS) membrane and a manifold glass for microvalve function. The operation of the sample loading, AS PCR, microvalve, and CE on a chip was automated with a portable genetic analyzer, and the laser-induced fluorescence detection was performed on a miniaturized fluorescence detector. The blind samples were correctly identified as a HANWOO by showing one or two amplicon peaks in the electropherogram, while the imported beef cattle revealed more than five peaks. Our genetic analysis platform provides rapid, accurate, and on-site multiplex SNP typing.     

How large a managed area is needed to protect a threatened animal species? Combining simple dispersal and population models

The size and shape of the managed area for a threatened species to have a stable or growing population is a central issue for conservation management, for example for kiwi, Apteryx sp. Combining geometric probability results for retention of juveniles to breed in the protected area with a standard matrix population model allows the creation of an explicit relationship between the minimum area needed and how far juveniles of the species disperse to establish breeding territories. For a given set of demographic parameters for the population, and a rectangular protected area, there is a quadratic relationship between area and dispersal distance. Extensions for a circular protected area, and for a probability distribution on dispersal distance, are considered. The results are applied to kiwi, using established population parameters, giving results that match closely those from a previously published simulation. This approach can provide simple tools, readily implemented in a spreadsheet, for assessment of the size and shape of protected areas needed in conservation management of animals that disperse before breeding.     

The use of a genetic algorithm for simultaneous mapping of multiple interacting quantitative trait loci

Here we describe a general method for improving computational efficiency in simultaneous mapping of multiple interacting quantitative trait loci (QTL). The method uses a genetic algorithm to search for QTL in the genome instead of an exhaustive enumerative ("step-by-step") search. It can be used together with any method of QTL mapping based on a genomic search, since it only provides a more efficient way to search the genome for QTL. The computational demand decreases by a factor of approximately 130 when using genetic algorithm-based mapping instead of an exhaustive enumerative search for two QTL in a genome size of 2000 cM using a resolution of 1 cM. The advantage of using a genetic algorithm increases further for larger genomes, higher resolutions, and searches for more QTL. We show that a genetic algorithm-based search has efficiency higher than or equal to a search method conditioned on previously identified QTL for all epistatic models tested and that this efficiency is comparable to that of an exhaustive search for multiple QTL. The genetic algorithm is thus a powerful and computationally tractable alternative to the exhaustive enumerative search for simultaneous mapping of multiple interacting QTL. The use of genetic algorithms for simultaneous mapping of more than two QTL and for determining empirical significance thresholds using permutation tests is also discussed.     

Hexanoylation of a VPAC2 receptor-preferring ligand markedly increased its selectivity and potency

We synthesized a VIP analog that combines mutations that decrease the affinity for the VPAC1 receptor but maintain a high affinity for the VPAC2 receptor with an amino-terminal hexanoylation that increases the affinity for the VPAC2 receptor with a limited decrease in the affinity of the VPAC1 receptor. The resulting Hexanoyl[A19,K(27,28)]VIP had the expected properties of a high affinity for the VPAC2 receptor and a low affinity for the VPAC1 receptor and also a low affinity for the PAC1 and secretin receptors. With a 1000-fold preference for the VPAC2 receptor and a IC50 value of binding of 1 nM, this compound is the most potent and the most selective agonist presently described.     

A proposed metric set for evaluation of genome assembly quality

Quality control is essential for genome assemblies; however, a consensus has yet to be reached on what metrics should be adopted for the evaluation of assembly quality. N50 is widely used for contiguity measurement, but its effectiveness is constantly in question. Prevailing metrics for the completeness evaluation focus on gene space, yet challenging areas such as tandem repeats are commonly overlooked. Achieving correctness has become an indispensable dimension for quality control, while prevailing assembly releases lack scores reflecting this aspect. We propose a metric set with a set of statistic indexes for effective, comprehensive evaluation of assemblies and provide a score of a finished assembly for each metric, which can be utilized as a benchmark for achieving high-quality genome assemblies.     

Selecting pedigrees for linkage analysis of a quantitative trait: the expected number of informative meioses.

With evidence of segregation at a major locus for a quantitative trait having been found, a logical next step is to select a subset of the pedigrees to include in a linkage study to map the major locus. Ideally this subset should include much of the linkage information in the sample but include only a fraction of the pedigrees. We previously described a strategy for selecting pedigrees for linkage analysis of a quantitative trait on the basis of a pedigree likelihood-ratio statistic. For quantitative traits controlled by a major locus with a rare dominant allele, the likelihood-ratio strategy extracted nearly all the information for linkage while typically requiring marker data on only about one-third of the pedigrees. Here, we describe a new strategy to select pedigrees for linkage analysis on the basis of the expected number of potentially informative meioses in each pedigree. We demonstrate that this informative-meioses strategy provides an efficient and more general means to select pedigrees for a linkage study of a quantitative trait.     

A population model based on a life table that includes marriage and parity.

This paper presents a method for constructing a one-sex life table that incorporates age, marriage and parity. The life table is the basis for a generalized population model, with immediate extension to a stable population differentiated by age, marriage and parity status. The method is quite general and could be extended, without major modification, to more complex life tables.Computation of intrinsic rates of increase for a number of populations adjusted for age, for age and parity, for age and marriage, and for age, marriage and parity shows that adjustment for marriage accounts for most of the difference between the age-adjusted rate and the age-, marriage-, and parity-adjusted rate. Adjustment for parity without adjustment for marriage may be misleading.     

Male × female interaction for a pre-copulatory trait, but not a post-copulatory trait, among cosmopolitan populations of Drosophila melanogaster

Sexual coevolution occurs when changes in the phenotype of one sex select for changes in the other sex. We can identify the "footprint" of this coevolution by mating males and females from different populations and testing for a male-female genotype interaction for a trait associated with male (or female) performance. Here we mated male Drosophila melanogaster from five different continents with females from their own and different continents to test for a male-female interaction for mating speed, a pre-copulatory trait, and female reproductive investment, a post-copulatory trait. We found a strong male-female interaction for mating speed, consistent with previous studies using different populations, suggesting that the potential for sexual coevolution for this trait is present in this species. In contrast, we did not detect a male-female interaction for female reproductive investment. Although a male-female interaction for mating speed is compatible with the hypothesis of ongoing sexual coevolution, the nature of our experimental design is unable to exclude alternate explanations. Thus, the evolutionary mechanisms promoting male-female genotype interactions for pre-copulatory mating traits in D. melanogaster warrant further investigation.     

The search for hematologic-immunological parameters with prognostic value in children with various tumors]

In a total of 35 children affected with malignant sufferings (except leucaemias) the haematological-immunological parameters of children surviving for a short time are compared with those surviving for a long time. Compared with children surviving for a short time those surviving for long time had a more "normal" finding initially and during the control examination made after more than 5 years of a survival time which was free of complaints and recidives. The immunologically intact condition of the organism is assumed to be decisive for this course of disease.     

Microcomputer system for the analysis of muscle function

Though skeletal muscle function has recently been increasingly studied, a system for routine clinical examination in patients is not widely available. A microcomputer based system has been developed for the measurement and analysis of force-frequency characteristics, relaxation rate, fatiguability and endurance in the adductor pollicis muscle. The mobile system consists of a modified displacement transducer fitted with a linear-output Hall-effect sensor, a specially designed signal processing unit and a microcomputer for control of both the electrical stimulus and a suite of menu-driven, user-interactive programs. One hundred normal volunteers have been studied to produce a normal database for comparison with malnourished surgical patients. The system compares favourably with other systems in use for objective measurement of skeletal muscle function and introduces a refined technique for evaluating endurance.     

Modeling Optimal Intervention Strategies for Cholera

While cholera has been a recognized disease for two centuries, there is no strategy for its effective control. We formulate a mathematical model to include essential components such as a hyperinfectious, short-lived bacterial state, a separate class for mild human infections, and waning disease immunity. A new result quantifies contributions to the basic reproductive number from multiple infectious classes. Using optimal control theory, parameter sensitivity analysis, and numerical simulations, a cost-effective balance of multiple intervention methods is compared for two endemic populations. Results provide a framework for designing cost-effective strategies for diseases with multiple intervention methods.     

The effect of exposure to black background and to α-MSH on black-white background preference in the amphibian Xenopus laevis (Daudin)

Young frogs, Xenopus laevis, raised on a white background showed a slight preference for the black background of a black-white preference testing apparatus. Keeping frogs for either 24 hr or 20 days on a black background resulted in a further increase in their preference for black. Injecting 1 μg of synthetic α-MSH into white-adapted frogs had no effect on their black-white preference. On the other hand, Xenopus laevis tadpoles, at an early stage of metamorphosis, raised on a white background showed a significant preference for white. Keeping these tadpoles for 24 hr on a black background resulted in a shift from white to black preference. Injecting synthetic α-MSH into white-adapted tadpoles resulted in an increase in their preference for black. A behavioral feedback mechanism appears to exist between the release of endogenous MSH when a tadpole is exposed to a black background and its subsequent preference for background color.