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PubMed2003

Evolutionary-based association analysis using haplotype data.

Association studies, both family-based and population-based, can be powerful means of detecting disease-liability alleles. To increase the information of the test, various researchers have proposed targeting haplotypes. The larger number of haplotypes, however, relative to alleles at individual loci, could decrease power because of the additional degrees of freedom required for the test. An optimal strategy would focus the test on particular haplotypes or groups of haplotypes, much as is done with cladistic-based association analysis. First suggested by Templeton et al. ([1987] Genetics 117:343-351), such analyses use the evolutionary relationships among haplotypes to produce a limited set of hypothesis tests and to increase the interpretability of these tests. To more fully utilize the information contained in the evolutionary relationships among haplotypes and in the sample, we propose generalized linear models (GLM) for the analysis of data from family-based and population-based studies. These models fully account for haplotype phase ambiguity and allow for covariates. The models are encoded into a software package (the Evolutionary-Based Haplotype Analysis Package, EHAP), which also provides for various kinds of exploratory data analysis. The exploratory analyses, such as error checking, estimation of haplotype frequencies, and tools for building cladograms, should facilitate the implementation of cladistic-based association analysis with haplotypes.

Genetic Predisposition to Disease↗
PubMed1979

Testing twin means and estimating genetic variance: basic methodology for the analysis of quantitative twin data.

Twin methodology for the analysis of continuously distributed traits is presented as a guideline for initial steps in the analysis of twin data. Tests for heterogeneity of twin means and variances are reviewed along with estimates of genetic variance. Analysis of twin data appears on the surface to be a rather simple task, but investigators may well be confused by the wealth of choices available for hypothesis testing. This paper is designed to help the less experienced investigator, with perhaps a modest amount of data, begin analysis with maximum attention to testing all testable assumptions of the twin model, and using recent examples of applications of the methods.

Female↗
PubMed1990

When cognitive exertion does not yield cognitive gain: toward an informational explanation of learned helplessness.

This study tested a new information-processing explanation of learned helplessness that proposes that an uncontrollable situation produces helplessness symptoms because it is a source of inconsistent, self-contradictory task information during problem-solving attempts. The flow of such information makes hypothesis-testing activity futile. Prolonged and inefficient activity of this kind leads in turn to the emergence of a state of cognitive exhaustion, with accompanying performance deficits. In 3 experiments, Ss underwent informational helplessness training (IHT): They were sequentially exposed to inconsistent task information during discrimination problems. As predicted, IHT was associated with subjective symptoms of irreducible uncertainty and resulted in (a) performance deterioration on subsequent avoidance learning, (b) heightened negative mood, and (c) subjective symptoms of cognitive exhaustion.

Achievement↗
PubMed1993

Planning survival studies to compare a treatment to an active control.

Rubinstein et al. presented a procedure for determining the required duration of accrual for a clinical trial comparing the survival distributions of two treatments using a classical hypothesis testing formulation. Here their testing procedure is modified in two ways. First, the asymptotic variances used in computation of the probabilities of type I and type II errors are based on the values of the parameters specified by the null and alternative hypotheses, respectively. Second, the null hypothesis is modified for situations where it is desired to show that the experimental treatment is better or not much worse than the control.

Clinical Trials as Topic↗
PubMed1996

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group.

BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.

Adult↗
PubMed1995

The standing heel-rise test for ankle plantar flexion: criterion for normal.

BACKGROUND AND PURPOSE: Manual muscle testing with the examiner providing the resistance has long been a standard test of muscle strength. Through the use of extremities acting as levers, clinicians have been able to effectively apply resistance to all muscle groups except the ankle plantar flexors. As a result, a standing heel-rise test that uses body weight as the resistance has been substituted. The number of heel-rises that represent normal plantar-flexor "strength" and the ability of subjects to repeatedly use that "strength" remain unresolved. Because walking is an endurance task, the hypothesis tested by this study was that individuals without known weakness would be able to perform more than the standard recommended one to five standing heel-rises. The purpose of this study was to measure the number of standing heel-rises that individuals without known weakness could accomplish. SUBJECTS: Two hundred three subjects were studied for their ability to do standing heel-rises, as is done when testing plantar-flexion strength using the upright test. There were 122 male subjects and 81 female subjects, ranging in age from 20 to 59 years. METHODS: Each subject was asked to do as many standing heel-rises as he or she could, with careful monitoring of body and limb alignment and of ankle motion, with specific criteria for stopping. RESULTS: The average number of heel-rises was 27.9 (SD = 11.1, minimum = 6, maximum = 70) for all groups and both genders, with no differences between male and female subjects. The lower 99% confidence interval was 25. CONCLUSION AND DISCUSSION: A recommendation is made to change the standard of testing plantar-flexion function, when using the standing heel-rise test, to require 25 repetitions for a grade of Normal. [Lunsford BR, Perry J. The standing heel-rise test for ankle plantar flexion: criterion for normal.

Adult↗
PubMed2001

Molecular identification using flow cytometry histograms and information theory.

Flow cytometry is a common technique for quantitatively measuring the expression of individual molecules on cells. The molecular expression is represented by a frequency histogram of fluorescence intensity. For flow cytometry to be used as a knowledge discovery tool to identify unknown molecules, histogram comparison is a major limitation. Many traditional comparison methods do not provide adequate assessment of histogram similarity and molecular relatedness. We have explored a new approach applying information theory to histogram comparison, and tested it with histograms from 14 antibodies over 3 cell types. The information theory approach was able to improve over traditional methods by recognizing various non-random correlations between histograms in addition to similarity and providing a quantitative assessment of similarity beyond hypothesis testing of identity.

Animals↗
PubMed2000

Effects of glibenclamide, a K(ATP) channel blocker, on warm-up phenomenon in type II diabetic patients with chronic stable angina pectoris.

BACKGROUND: Warm-up phenomenon, one of the clinical models of ischemic preconditioning, refers to an increased tolerance to myocardial ischemia during the second of two consecutive exercise tests. HYPOTHESIS: Blockers of K(ATP) channels, such as the sulfonylurea drugs, can induce loss of ischemic preconditioning. This study aimed to investigate the effects of glibenclamide, a sulfonylurea with a high affinity for myocardial K(ATP) channels, on the results of two consecutive exercise tests in diabetic patients with coronary artery disease. METHODS: Eighteen type II diabetic patients with chronic stable angina pectoris participated in this study. All patients underwent two consecutive treadmill exercise tests with a recovery period of 15 min in fasting state. On the day after these exercise tests, 10 mg oral glibenclamide was given to the same patients and 30 min later 200 ml of 30% glucose solution was given orally. Half an hour later, which is the time of peak plasma levels of glibenclamide, two exercise tests were repeated consecutively with a 15 min recovery period. RESULTS: There was no difference in blood glucose levels before and after exercise tests on each day (p > 0.05). Without glibenclamide, heart rate, rate-pressure product at 1.5 mm ST depression, and peak exercise increased significantly (p < 0.05). Time to 1.5 mm ST-segment depression and onset of pain, as well as duration of exercise also increased, but ST-segment depression and ST-recovery time significantly decreased (p < 0.05). In contrast, these values did not significantly change after glibenclamide (p>0.05), with a significant drug-test interaction (p < 0.05, at two-way ANOVA). CONCLUSIONS: Glibenclamide, an oral hypoglycemic agent with a K(ATP) channel-blocker activity, with a 10 mg oral dose, abolished the warm-up phenomenon which is a clinical finding of ischemic preconditioning on two consecutive exercise tests. Therefore, glibenclamide should be used carefully in patients with coronary heart disease and diabetes mellitus since this agent leads to a decrease in ischemic threshold and exercise capacity.

Adenosine Triphosphatases↗
PubMed1998

Signs of osteoarthrosis of the temporomandibular joints in young patients: a clinical and radiographic study.

OBJECTIVE: The aims of this study were to investigate the occurrence of osteoarthrosis of the temporomandibular joints among young patients referred for consultation and treatment because of pain and dysfunction of the jaws and to study the relationship between signs and symptoms of temporomandibular disorders and osteoarthrosis in these patients. STUDY DESIGN: This was a retrospective study based on case histories, clinical examinations, and temporomandibular joint tomography. A total of 131 patients ranging in age from 12 to 30 years were included in the study. The null-hypothesis tested was that no significant differences in signs and symptoms of temporomandibular disorders would be found between joints with and joints without signs of osteoarthrosis. RESULTS: Osteoarthrosis of the temporomandibular joints was found in 87 patients (66%) and 151 joints (58%). The null-hypothesis was not rejected. CONCLUSION: A high prevalence of temporomandibular joint osteoarthrosis among the studied sample was found. The study did not allow us to draw any conclusions about the cause of temporomandibular joint osteoarthrosis in these patients. The result provided a basis for a subsequent follow-up study.

Adolescent↗
PubMed2006

Evaluation of ozone-nitrogen oxides-volatile organic compound sensitivity of Cincinnati, Ohio.

Ambient concentrations of ozone (O3), nitrogen oxides (NOx), total reactive nitrogen (NOy), nitric acid (HNO3), and hydrogen peroxide (H2O2) were measured during September 2003 at an urban site of Cincinnati, OH. The aim of this study was two-fold: to investigate whether O3 formation in this population exposure-type site is NOx, sensitive or volatile organic compound (VOC) sensitive and to test the practicality of using two combined observational-based methods to identify the sensitivity of O3 formation in midlevel polluted locations. The evaluation of the indicator species: NOy, O3/NOy, O3/HNO3, H2O2/ HNO3, and O3/(estimated NOx reaction products), as well as the combined hypothesis testing analysis of the weekend/weekday (WE/WD) differences of 1-hr and 8-hr average maximum O3 and of the 6:00 a.m.-9:00 a.m. average nitric oxide and NOx concentrations, show evidence that Cincinnati is likely VOC sensitive. Average WE 1-hr and 8-hr maximum O3, as well as duration of WE O3 accumulation, were not lower than the corresponding WD levels in spite of the observed significant reduction in NO, emissions on WE, a typical situation in VOC-sensitive locations. The possibility that the seasonal transition from summer to autumn could have influenced the results was also investigated through an exploratory analysis of the afternoon O3 maximum/NOx measured and of the WE/WD differences of peak O3 and morning average NO and NO, concentrations observed at this site from June through September 2003. The results suggest that a VOC-sensitive chemistry regime dominated along the summer season. The findings of this study suggest that additional reductions in regional NO, emissions in Cincinnati, a potential nonattainment area under the 8-hr O3 standard, may cause an increase in local O3. Future strategies to reduce O3 in Southwest Ohio should be further evaluated carefully. The combination of observational-based methods might provide a consistent complementary approach in the identification of the NO,-VOC sensitive characteristics of mid-to-moderate polluted urban areas.

Air Pollutants↗
PubMedDate not supplied

Antibody prevalence and isolation of Chlamydia psittaci from pigeons (Columba livia).

The isolation of Chlamydia psittaci and serological detection of Chlamydia-specific antibodies in racing pigeons and pigeons from public parks is described. Several serological methods (complement fixation test, indirect microimmunofluorescence test, and enzyme-linked immunosorbent assay) were compared with bacteriological techniques (isolation both in embryonated eggs and McCoy cell monolayers). Tests confirmed that 28.6%, 33.5%, and 35.9% of the pigeons, respectively, were seropositive by the tests mentioned above. Chlamydiae were isolated from 13% of the fecal specimens in ovocultures and from 18% of the fecal specimens in cell cultures. No significant differences between the two groups of pigeons were found (at a 95% confidence level, alpha = 0.05) using the hypothesis test of the difference between proportions of two populations. The serological and bacteriological techniques used are compared and discussed.

Animals↗
PubMed2003

Neurodynamic models of brain in psychiatry.

The history of brain theory is described in terms of three kinds of theory of perception. The most widely used kind sees perception as dependent on passive inflow from the environment of information that is used to make and process representations of objects and events. A second kind views perception as an active search for information that is inherent in the environment and is extracted by tuned resonances in brain circuits. A third kind holds that perception works by the creation of information through chaotic dynamics by forming hypotheses about the environment, through which learning takes place. Experimental evidence for creative dynamics in brains is briefly sketched. The explanation is offered that brains, being finite systems, work this way in order to cope with the infinite complexity of the world. All that brains can know is the hypotheses they construct and the results of testing them by acting into the environment, and learning by assimilation from the sensory consequences of their actions. The process is described as intentionality. It works through the action-perception-assimilation cycle. The cost of this solution to the problem of infinite complexity by hypothesis testing is the progressive isolation of individuals, as they accumulate their unique experiences through which their personalities form. Socialization and the acquisition of shared knowledge requires the emergence of new personality structure by self-organization through chaotic dissolution of existing the structure, as a prelude to the creation of new traits, habits, and values. Dissolution works in a crisis situation by regression to earlier stages of development, from which a fresh start can be made. A state of malleability emerges in the depth of crisis, in which compassionate companions through loving care can invite cooperative actions. Joint actions support the growth of a new lifestyle based on trust. Socialization requires neurochemical mechanisms of affiliation and bonding that evolved through the requirements of parental care of altricial offspring in mammalian reproduction. These mechanisms are invoked by means of behavioral techniques from cultural evolution. The dynamics, neural mechanisms, behavioral signs, methods of induction, and therapeutic utility of dissolution should be known by therapists. Lack of recognition and understanding may cause failure to use brief windows of opportunity to instill long-term relief of psychic pain by restructuring intentionality in distressed patients.

Brain↗
PubMed2004

Establishing mathematical laws of genomic variation.

As the biological arm of the Rasch community, genomic measurement is concerned with asserting and testing hypotheses regarding the quantitative status of genomic variables, including alleles, genotypes, gene expression levels, and phenotypes, as well as DNA, RNA, and protein sequence information. The defining goal of this scientific paradigm, in contrast to the sample-dependent model-fitting and deterministic hypothesis testing of classical statistical genetics, is the identification, validation, and maintenance of a common unit of genomic measurement that maintains its magnitude and meaning, within an allowable range of error, regardless of the laboratory technology used to generate outcomes or the particular group of individuals or organisms under investigation. Such an invariant metric, the basis of a standard genometric scale and associated system of genomic metrology, can be identified, validated, and maintained through 1) routine implementation of the Rasch family of measurement models to construct sample- and scale-free measures from different types of genomic data and 2) cross-calibration of genomic measurement instruments between and among researchers, laboratories, universities, corporations, and databases. This manuscript provides an introductory overview of the guiding principles of fundamental measurement theory and the work of Rasch, connects these concepts to well-known tenets of population genetics, and highlights the potential benefits, both theoretical and applied, associated with achieving objectivity in genomic measurement.

Animals↗
PubMed2005

The 'no-touch' method of intermittent urinary catheter insertion: can it reduce the risk of bacteria entering the bladder?

OBJECTIVE: This in vitro model was designed to determine whether using a no-touch method for catheter preparation and insertion would affect the degree of contamination transmitted to intermittent urinary catheters. SETTING: Northview Laboratories, Northbrook, IL 60062, USA. METHODS: This was a parallel experimental study conducted in vitro at an independent testing laboratory under Good Manufacturing Practices. Six different models of intermittent urinary catheter were tested in triplicate, in accordance with the manufacturer's Instructions For Use (IFU). Gloved hands were contaminated with a known amount of Staphylococcus aureus or Escherichia coli, preparation for insertion was mimicked according to the manufacturer's IFU. The number of bacteria transferred to the catheter was then quantified using a validated technique. The null hypothesis tested was that the bacterial contamination resulting from handling would be the same for all of the catheters. The primary outcome measure was the amount of bacteria, expressed as colony forming units (CFU), recovered from the catheters. The catheter wrappers were sampled to confirm that active transfer of microorganisms had taken place and nonhandled samples served as the negative controls. RESULTS: For both test organisms, the number of bacteria recovered from the catheters was significantly lower (P < 0.05) for the catheters featuring the no-touch design (approximately 5 CFU/plate versus 2.1 x 10(2) to 4.4 x 10(2) for the traditional hydrophilic catheters). The bacterial recovery from those catheters with the no-touch design often fell below the nominal detection limit. CONCLUSION: The results of this study allow the null hypothesis to be rejected; it can be concluded that the no-touch method provides a significant benefit in reducing the potential for external contamination of an intermittent urinary catheter. This result supports the recent recommendations for aseptic intermittent catheterization promoted within the guidelines issued by the European Association of Urologists (EAU).

Bacterial Physiological Phenomena↗
PubMed2026

Estimating protein isoform abundances with [Formula: see text].

A single gene can encode multiple versions of a protein, dubbed isoforms, with varying functionality. Cellular control of isoform abundances is critical for multiple aspects of biology and is only partially regulated by transcript levels. While long-read sequencing facilitates transcript quantification, quantifying the resulting protein isoforms on a large scale is a major challenge, complicating biological interpretation of transcript alterations. Standard "bottom up" mass spectrometry can assess only short portions of isoforms called peptides, and these peptides often map onto more than one isoform. We introduce [Formula: see text] (Protein isoform Abundance Quantification), a Bayesian method that leverages multiomic information from the peptidome and transcriptome to provide accurate estimates of isoform abundance even when peptide mapping is ambiguous. [Formula: see text] offers several advantages over existing methods in a unified framework. It provides uncertainty quantification, integrates multiomic information for improved accuracy, and provides a rigorous framework for hypothesis testing. Extensive simulations show that [Formula: see text] consistently outperforms competing methods in detecting differentially abundant protein isoforms and estimating their abundances. We use [Formula: see text] to investigate differences in isoform abundance levels between people with schizophrenia and control subjects, confirming a long-held hypothesis that levels of the C4A isoform of Complement Component 4 are increased in schizophrenia while C4B is not. These results demonstrate that [Formula: see text] can identify significant variations in isoform abundance levels not previously possible.

Protein Isoforms↗
PubMed1995

Development and intralaboratory evaluation of an in vitro human cell-based test to aid ocular irritancy assessments.

A human cell-based in vitro method was developed to screen for ocular irritancy potential of aqueous compatible and incompatible test agents, such as liquids, insoluble solids, powders, granulars, emulsions, and acids/alkalis. Methods were developed for topical application (an exposure that mimics in vivo testing) and wash-off of test substances on the epithelial surface of human skin derived epithelial-fibroblast cocultures (Skin2 Model ZK1200 from Advanced Tissue Sciences). These cultures contain noncornified stratified squamous epithelium, providing a three-dimensional in vitro model that resembles noncornified mucosal epithelium, such as cornea and conjunctiva. The hypothesis tested and confirmed in this work was that the rate of cytotoxicity induced by topical application of test substances to the stratified epithelial cell cultures would correlate with ocular irritancy. Test substances were applied to the cell system for up to 30 min, and cytotoxicity was measured as decreased 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide (MTT) vital dye metabolism. The time (in minutes) of exposure to test agent that reduced MTT metabolism to 50% of control levels (the t50 value) was calculated for each test substance, and these values showed a good correlation (r = 0.87) with historic rabbit low-volume eye test maximum average scores (MAS) for a range of liquid, solid, granular, powder, and other test materials, including consumer product formulations and ingredient chemicals. Additionally, t50 values confirmed the mild nature of selected cosmetic formulations. Taken together, these data indicate that this in vitro test, termed the tissue equivalent assay, is a valuable tool to screen for irritancy of test substances to mucosal tissues, such as cornea and conjunctiva.

Animal Testing Alternatives↗
PubMedDate not supplied

Resampling techniques in the analysis of non-binormal ROC data.

The methods most commonly used for analyzing receiver operating characteristic (ROC) data incorporate "binormal" assumptions about the latent frequency distributions of test results. Although these assumptions have proved robust to a wide variety of actual frequency distributions, some data sets do not "fit" the binormal model. In such cases, resampling techniques such as the jackknife and the bootstrap provide versatile, distribution-independent, and more appropriate methods for hypothesis testing. This article describes the application of resampling techniques to ROC data for which the binormal assumptions are not appropriate, and suggests that the bootstrap may be especially helpful in determining confidence intervals from small data samples. The widespread availability of ever-faster computers has made resampling methods increasingly accessible and convenient tools for data analysis.

Bias↗
PubMed1988

Experimental approaches to colon cancer prevention in humans.

Colorectal cancer is a major illness in the Western world. International and migrant studies suggest that environmental causes, notably a fat- and calorie-dense diet (even if adopted in adulthood), are associated with the disease. Case-control studies have not conclusively identified specific etiologic dietary factors, however. In addition, the emphasis placed on migrant studies has led many to overlook potentially important genetic factors that might help to explain some of the discrepancies in the epidemiologic data. Thus, the cause(s) of colorectal cancer remain unclear and hence effective preventive strategies are not presently available. Numerous tenable hypotheses have been generated as a consequence of observational and analytical epidemiologic studies, as well as rodent experiments. Controlled trials to test these hypotheses using colorectal cancer as an endpoint are not justifiable at present. It is possible, however, that "intermediate markers" (such as epithelial cell proliferation rates and others) that are associated with colorectal cancer in both humans and experimental animal systems might provide the means for hypothesis testing in short-term clinical trials. Despite the fact that this approach has several caveats, consistent results obtained in short-term studies would more readily justify the undertaking of a large-scale, long-term controlled study using colon cancer or adenomatous polyp recurrence as an endpoint.

Colorectal Neoplasms↗