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Key Concepts in Model Selection: Performance and Generalizability.

What is model selection? What are the goals of model selection? What are the methods of model selection and how do they work? Which methods perform better than others and in what circumstances? These questions rest on a number of key concepts in a relatively underdeveloped field. The aim of this paper is to explain some background concepts, to highlight some of the results in this special issue, and to add my own. The standard methods of model selection include classical hypothesis testing, maximum likelihood, Bayes method, minimum description length, cross-validation, and Akaike's information criterion. They all provide an implementation of Occam's razor, in which parsimony or simplicity is balanced against goodness-of-fit. These methods primarily take account of the sampling errors in parameter estimation, although their relative success at this task depends on the circumstances. However, the aim of model selection should also include the ability of a model to generalize to predictions in a different domain. Errors of extrapolation, or generalization, are different from errors of parameter estimation. So, it seems that simplicity and parsimony may be an additional factor in managing these errors, in which case the standard methods of model selection are incomplete implementations of Occam's razor. Copyright 2000 Academic Press.

Journal Article↗

Impairment of type III group B Streptococcus-stimulated superoxide production and opsonophagocytosis by neutrophils in diabetes.

The effect of hyperglycemia upon susceptibility to bacterial infection in diabetes mellitus is incompletely elucidated. The present experiments assessed the effect of hyperglycemia upon neutrophil-mediated phagocytosis of type III group B Streptococcus (GBS). Type III GBS was chosen for study because the incidence of invasive GBS disease is substantially increased in type 2 diabetic compared with nondiabetic subjects. The hypothesis tested was that severe hyperglycemia would alter neutrophil metabolism by diverting NADPH from superoxide production into the aldose reductase-dependent polyol pathway that converts glucose into sorbitol and thus would impair opsonophagocytosis (OP) of type III GBS. Neutrophils from 10 adults with type 2 diabetes had no intrinsic phagocytic defect under baseline glycemic conditions. After equilibration in 60 or 120 mM glucose or in 60 mM choline chloride, OP activity was reduced significantly (P < or = 0.03). Neutrophil superoxide production correlated with glucose concentration and also was significantly reduced during hyperglycemia (P < 0.05). Addition of III GBS capsular polysaccharide-specific IgG in a sufficient concentration supported efficient OP, even during hyperglycemia. Alrestatin, an aldose reductase inhibitor, increased superoxide production and significantly improved OP of type III GBS (P = 0.03). Thus, diversion of NADPH into the polyol pathway is one mechanism by which OP of GBS III is impaired during hyperglycemia, and this effect is mitigated when levels of capsular polysaccharide-specific IgG are sufficient.

Adult↗

Myocardial venous O2 saturation becomes more heterogeneous during hypoxic and carbon monoxide hypoxia.

The hypothesis tested was that myocardial venous O2 saturation (SvO2) heterogeneity, a measure of microregional O2 supply/consumption balance, would increase under hypoxic and CO-hypoxia conditions. Since we are able to determine both O2 supply and the O2 supply/consumption ratio, we could also determine whether regional myocardial O2 consumption was heterogeneous. Twenty open-chest anesthetized dogs were studied under control and four hypoxic conditions, hypoxic hypoxia induced by ventilation with either an 8% O2 (SaO2 = 56%) or a 6% O2 (SaO2 = 40%) gas mixture for 20 min, or CO hypoxia induced by ventilation with a 1% CO gas mixture for either 7 min (SaO2 = 67%) or 20 min (SaO2 = 40%). Regional myocardial blood flow was measured using radioactive microspheres in 40 pieces (approximately 0.5 g) of the left ventricular free wall. Arterial and venous O2 saturations were determined with a four-wavelength microspectrophotometric method. A total of 28 veins (20-100 microns) were examined to determine SvO2 for each condition within each animal. The coefficient of variation (CV = SD/mean x 100), an index of heterogeneity, was calculated for both flow and SvO2 under each condition. Flow increased with increasing severity of hypoxia but its heterogeneity did not change with hypoxic or CO hypoxia. However, SvO2 heterogeneity significantly increased with increasing severity of hypoxia. A linear regression of SvO2 CV and mean SvO2 showed a significant correlation (CV = -0.84 (mean SvO2) + 51.1, R = 0.59). All possible myocardial O2 consumptions were calculated by multiplying all of the flows and O2 extractions. In 53 subepicardial and subendocardial measurements, only 10% of the flow and O2 supply/consumption heterogeneity observations could be explained by uniform O2 consumption if our acceptance criterion was 0.06-0.1 ml O2/min/100 g, and 50% could be explained with an acceptance criterion of 0.3-0.4 ml O2/min/100 g. Therefore, there must be some regional myocardial O2 consumption heterogeneity. The increase in venous O2 saturation heterogeneity during hypoxia may be due to increased variation in regional myocardial O2 consumption or variation in the control of O2 supply/consumption coupling.

Animals↗

Sarcomere length-induced alterations of capillary hemodynamics in rat spinotrapezius muscle: vasoactive vs passive control.

Skeletal muscle blood flow is reduced as fibers are stretched longitudinally. Neither the underlying cause(s) of this decrement in blood flow nor the consequences in terms of capillary red blood cell (rbc) hemodynamics has been established clearly within the physiological range of muscle sarcomere length. Using intravital microscopy, this investigation determined arteriolar diameter and capillary rbc velocity (Vrbc), flux (Frbc), and hematocrit (Hct(t)) in the rat spinotrapezius muscle at shortened/resting (2.6 microm) and physiological extended (3.2 microm) sarcomere lengths under control (c) and local maximally vasodilated (v, phentolamine, 1 micromol/L; prazosin, 0.1 micromol/L; nitroprusside, 10 micromol/L) conditions. The hypothesis tested was that muscle stretch would reduce Vrbc and Frbc proportionally such that Hct(t) would remain unchanged and that these reductions in Vrbc and Frbc would be attenuated following maximal vasodilation. Vrbc and Frbc were increased significantly following maximal vasodilation at 2.6-microm (59 and 84%) and 3.2-microm (64 and 104%) sarcomere lengths, respectively. Irrespective of sarcomere length, Hct(t) was elevated significantly following vasodilation (c, 0.20 +/- 0.01; v, 0.27 +/- 0.01). At 3.2 microm compared with the 2.6-microm sarcomere length, Vrbc and Frbc were both reduced significantly under control and vasodilated conditions as expected. However, the percent reduction in either Vrbc (c, 27%, and v, 29%) or Frbc (c, 26%, and v, 33%) was not significantly different between the 2.6- and 3.2-microm sarcomere lengths. In addition, arteriolar diameter was not altered discernably as sarcomere length was increased from 2.7 microm (c, 29.0 +/- 4.5; v, 37.9 +/- 6.7 microm) to 3.2 microm (c, 29.4 +/- 4.5; v, 37.3 +/- 6.2 microm). These data suggest that increasing sarcomere length from resting to the upper extreme of the physiological range in the rat spinotrapezius muscle reduces Vrbc and Frbc (at constant hematocrit) by a mechanism that is independent of stretch-activated arteriolar vasoconstriction.

Animals↗

Experimental design and the relative sensitivity of BOLD and perfusion fMRI.

This paper compares the statistical power of BOLD and arterial spin labeling perfusion fMRI for a variety of experimental designs within and across subjects. Based on theory and simulations, we predict that perfusion data are composed of independent observations in time under the null hypothesis, in contrast to BOLD data, which possess marked autocorrelation. We also present a method (sinc subtraction) of generating perfusion data from its raw source signal that minimizes the presence of oxygen-sensitive signal changes and can be used with any experimental design. Empirically, we demonstrate the absence of autocorrelation in perfusion noise, examine the shape of the hemodynamic response function for BOLD and perfusion, and obtain a measure of signal to noise for each method. This information is then used to generate a model of relative sensitivity of the BOLD and perfusion methods for within-subject experimental designs of varying temporal frequency. It is determined that perfusion fMRI provides superior sensitivity for within-subject experimental designs that concentrate their power at or below approximately 0.009 Hz (corresponding to a "blocked" experimental design of 60-s epochs). Additionally, evidence is presented that across-subject hypothesis tests may be more sensitive when conducted using perfusion imaging, despite the better within-subject signal to noise obtained in some cases with BOLD.

Adult↗

Collective Induction: Twelve Postulates.

Collective induction is the cooperative search for descriptive, predictive, and explanatory generalizations, rules, and principles. This article presents 12 postulates on collective induction and supportive evidence for the postulates. Postulates 1-6 set collective induction within the general social combination approach to cooperative group decision making. Postulates 7 and 8 formalize the social combination processes of group hypothesis formation in collective induction. Postulates 9-12 summarize research on collective versus individual induction, the relative importance of multiple hypotheses and multiple evidence, influence in simultaneous collective and individual induction, and the relative effectiveness of positive and negative hypothesis tests. We then consider the history and fundamental emphasis of the social combination approach to small group performance. Copyright 1999 Academic Press.

Journal Article↗

An alternative approach to the analysis of animal carcinogenicity studies.

Long-term animal carcinogenicity studies are an important part of the risk analysis process assessing the carcinogenic potential of products to humans. Results from the statistical analysis of the data from such studies are generally presented as a series of hypothesis tests indicating whether there was a significant rise in the number of tumors at given sites. The conclusion from such an analysis depends on the size of the experiment. In particular, the number of false-negative results can be high when tumors are rare. In this paper, a test for equivalence fixing the proportion of false negatives is proposed. The effect on the required sample size is also discussed.

Animal Testing Alternatives↗

Evidence for embryonic peroxidase-catalyzed bioactivation and glutathione-dependent cytoprotection in phenytoin teratogenicity: modulation by eicosatetraynoic acid and buthionine sulfoximine in murine embryo culture.

Phenytoin teratogenicity may result from embryonic, peroxidase-catalyzed bioactivation of phenytoin to a toxic reactive free radical intermediate for which embryonic glutathione (GSH) is cytoprotective. This hypothesis was tested in embryo culture using 5,8,11,14-eicosatetraynoic acid (ETYA), a dual inhibitor of two peroxidase systems, prostaglandin synthetase, and lipoxygenases. Embryos from CD-1 mice were explanted on Gestational Day 9.5 (vaginal plug, Day 1) and incubated for 24 hr at 37 degrees C in culture medium (35% male rat serum, 15% fetal bovine serum, and 50% Waymouth's medium) saturated with 5% CO2 in air. Initially, a nonembryotoxic concentration of ETYA (0,40,80, or 100 microM) was established within its peroxidase inhibitory range (Ki = 4-8 microM). Subsequently, embryos were incubated with vehicle alone, a therapeutic concentration of phenytoin alone (20 micrograms/ml or 80 microM), ETYA alone (40 microM), or phenytoin and ETYA combined. ETYA alone below 100 microM had no effect on yolk sac diameter (YSD), crown-rump length (CRL), somite development (SD), anterior neuropore closure (ANPC), or turning, but at 100 microM reduced CRL, YSD, and SD (p < or = 0.05). Phenytoin alone was embryotoxic, causing reduced CRL, YSD, and SD (p < or = 0.0001). Phenytoin and ETYA (40 microM) together resulted in an increase in YSD, SD, and CRL relative to those with phenytoin alone (p < or = 0.01), indicating that inhibition by ETYA of embryonic, peroxidase-catalyzed bioactivation of phenytoin is cytoprotective. GSH may play a critical role in detoxifying a phenytoin free radical or subsequent activated oxygen species, thereby reducing covalent binding, lipid peroxidation, and oxidative stress that may initiate embryotoxicity or death. To test this hypothesis, embryos were cultured in the presence or absence of 1 mM buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, for 3 hr, at which time BSO was washed out and the embryos were incubated for 24 hr in fresh culture medium containing 80 microM phenytoin or its vehicle. Soluble thiols, including GSH, and disulfides, including oxidized GSH (GSSG), were measured using high-performance liquid chromatography. Immediately after BSO treatment, there were no differences in the concentrations of GSH or GSSG between BSO-exposed embryos and controls. However, at 24 hr, GSH concentrations in untreated embryos increased almost 17-fold over those at 3 hr concentrations, while GSH in BSO-exposed embryos were reduced to 15% of control values (p = 0.0008).(ABSTRACT TRUNCATED AT 400 WORDS)

5,8,11,14-Eicosatetraynoic Acid↗

Hardy-Weinberg equilibrium diagnostics.

We propose two diagnostics for the statistical assessment of Hardy-Weinberg equilibrium. One diagnostic is the posterior probability of the complement of the smallest highest posterior density credible region that includes points in the parameter space consistent with the hypothesis of equilibrium. The null hypothesis of equilibrium is to be rejected if this probability is less than a pre-selected critical level. The second diagnostic is the proportion of the parameter space occupied by the highest posterior density credible region associated with the critical level. These Bayesian diagnostics can be interpreted as analogues of the classical types I and II error probabilities. They are broadly applicable: they can be computed for any hypothesis test, using samples of any size generated according to any distribution.

Alleles↗

Statistical representation and simulation of high-dimensional deformations: application to synthesizing brain deformations.

This paper proposes an approach to effectively representing the statistics of high-dimensional deformations, when relatively few training samples are available, and conventional methods, like PCA, fail due to insufficient training. Based on previous work on scale-space decomposition of deformation fields, herein we represent the space of "valid deformations" as the intersection of three subspaces: one that satisfies constraints on deformations themselves, one that satisfies constraints on Jacobian determinants of deformations, and one that represents smooth deformations via a Markov Random Field (MRF). The first two are extensions of PCA-based statistical shape models. They are based on a wavelet packet basis decomposition that allows for more accurate estimation of the covariance structure of deformation or Jacobian fields, and they are used jointly due to their complementary strengths and limitations. The third is a nested MRF regularization aiming at eliminating potential discontinuities introduced by assumptions in the statistical models. A randomly sampled deformation field is projected onto the space of valid deformations via iterative projections on each of these subspaces until convergence, i.e. all three constraints are met. A deformation field simulator uses this process to generate random samples of deformation fields that are not only realistic but also representative of the full range of anatomical variability. These simulated deformations can be used for validation of deformable registration methods. Other potential uses of this approach include representation of shape priors in statistical shape models as well as various estimation and hypothesis testing paradigms in the general fields of computational anatomy and pattern recognition.

Algorithms↗

BrainIT: a trans-national head injury monitoring research network.

BACKGROUND: Studies of therapeutic interventions and management strategies on head injured patients are difficult to undertake. BrainIT provides validated data for analysis available to centers that contribute data to allow post-hoc analysis and hypothesis testing. METHODS: Both physiological and intensive care management data are collected. Patient identification is eliminated prior to transfer of data to a central database in Glasgow. Requests for missing/ ambiguous data are sent back to the local center. Country coordinating centers provide advice, training, and assistance to centers and manage the data validation process. RESULTS: Currently 30 centers participate in the group. Data collection started in January 2004 and 242 patients have been recruited. Data validation tools were developed to ensure data accuracy and all analysis must be undertaken on validated data. CONCLUSION: BrainIT is an open, collaborative network that has been established with primary objectives of i) creating a core data set of information, ii) standardizing the collection methodology, iii) providing data collection tools, iv) creating and populating a data base for future analysis, and v) establishing data validation methodologies. Improved standards for multi-center data collection should permit the more accurate analysis of monitoring and management studies in head injured patients.

Biomedical Research↗

Regulation of cell apoptosis by insulin-like growth factor I.

Correct temporal and spatial regulation of apoptosis is critical for normal mammary gland development and lactation. Previous work with a strain of transgenic mice that overexpress des(1-3)hIGF-I during pregnancy and lactation suggested that this growth factor inhibits apoptosis. The hypothesis tested within these studies is that overexpression of des(1-3)hIGF-I within the mammary gland inhibits apoptosis and the expression of apoptosis-associated genes that are known to be activated by the transcription factor AP-1. This inhibition of apoptosis was further posited to predispose the tissue to carcinogenesis. TUNEL analysis of mammary tissue from transgenic mice that overexpress des(1-3)hIGF-I under control of the rat whey acidic protein promoter showed only 25% (P < 0.05) of the number of apoptotic cells found in nontransgenic mice at the same stage of lactation. Northern analysis of RNA from these animals showed a 75% (P = 0.08) reduction in c-Jun mRNA abundance. Histological analysis of mammary tissue from nonlactating multiparous WAP-DES mice ranging in age from 13 to 25 months showed a variety of hyperplastic lesions. These lesions aberrantly expressed the transgene. At 23 months of age 50% of the transgenic mice within this study developed adenocarcinomas. These results support the conclusion that inhibition of apoptosis within the mammary gland by IGF-I involves decreased activity of AP-1 and predisposes the tissue to tumors.

Animals↗

The use of multilevel analysis in health economics: an application to examining the effect of competition on general practitioners' behaviour.

Multilevel modelling is a relatively new technique developed in the area of educational research. To illustrate the use of this technique in health economics, this paper estimates a multilevel logit model to examine the effect of competition on the behaviour of Australian general practitioners. The main hypothesis tested is that GPs in areas of high competition are more likely to recommend a follow up consultation compared to GPs in areas of low competition. The results suggest that competition influences the decision to recommend a follow up visit for one out of the five medical conditions analysed. The use of multilevel analysis represents a methodological improvement on previous models of GP behaviour. However, before multilevel analysis is more widely adopted it is argued that it should be more formally assessed against more standard and equivalent methods already used by economists, such as random effects panel data models.

Australia↗

Are there any normal clones?

An exhaustive study of the fidelity of a clone to its parent is prohibitive because of cost and the necessary scope of experimental design. Therefore, these data must be gathered from existing observational evidence. This in itself cannot provide a definitive accounting of the abnormalities and variation found among clones or between clones and parents because there is no standardization in the data points collected between one study and another. This literature survey shows that clone developmental abnormalities, variation among clones, and variation between clone and parent are prevalent at most stages of development (cleavage, placental, fetal, neonatal, maturity), and that occasionally the observed variation greatly exceeds that which might be expected. Some variation can be explained by differences in protocols and procedures between studies. The choice of nuclear donor cell is particularly influential of variation observed between a clone and its parent. In general, however, it appears that there is an inherent stochastic response to nuclear transfer that results in clone infidelity and variation. The survey of characteristics of clone infidelity to parent and documentation of abnormalities provided here should not be viewed as exhaustive or limiting in the recording of such data from future studies. Because controlled hypothesis testing of clone fidelity or clone health may not be possible, meticulous documentation of such observational evidence is a valuable contribution to the field.

Animals↗

The effect of leukotriene C4 on the permeability of brain capillary endothelial cell monolayer.

The role of leukotrienes as mediator of brain edema is still controversial. Recently, the ability of gamma-GTP to act as enzymatic barrier and to inactivate leukotrienes in normal brain capillaries was pointed out. A hypothesis tested in our experiments was that Leukotriene C4 (LTC4) increases permeability of a cerebral capillary endothelial monolayer which lacks gamma-GTP activity. Brain capillary endothelial cells were obtained of 10 rats from cerebral cortex by an enzymatic isolation procedure. The cells have an intact function, however, lack gamma-GTP activity. The endothelial cells were cultured on an optically clear collagen membrane mounted on a plastic frame. Effects of bradykinin (1 x 10(-5) M) and LTC4 (1 x 10(-7) M, 1 x 10(-6) M, 5 x 10(-6) M, 1 x 10(-5) M) were tested on permeability of the endothelial cell monolayer by measuring leakage of 14C-sucrose. The effect of LTC4 and bradykinin on intracellular calcium was studied by laser scanning confocal microscopy. LTC4 did not increase permeability of the brain capillary endothelial cell monolayer which lacked gamma-GTP activity. LTC4 did neither increase the concentration of intracellular calcium. Differences of LTC4 receptor function in normal brain capillaries and tumor capillaries remain to be studied.

Animals↗

Effects of calcium channel agonism by Bay-K-8644 on ventricular fibrillation threshold of isolated heart.

The hypothesis tested was that enhanced entry of calcium into cardiac cells would increase the susceptibility to ventricular fibrillation as measured by the ventricular fibrillation threshold (VFT) of the isolated perfused rat heart. Bay-K-8644 was used as a calcium-channel agonist. There was a biphasic effect with a maximal increase in left ventricular systolic pressure and oxygen uptake at a concentration of 10(-7) M. The same concentration caused a major reduction in the VFT. The bell-shaped pattern of fall of the VFT was inversely related to the effect on LV developed pressure. The changes in VFT could be dissociated from those on myocardial metabolites. Although Bay-K-8644 increased the heart rate, reduction of the VFT could also be obtained in paced hearts. The addition of ryanodine, an agent known to interrupt intracellular recycling of calcium through the sarcoplasmic reticulum, was able to abolish approximately half the effect of Bay-K-8644 on the VFT. Therefore, increased entry of calcium via the calcium channel is able to reduce VFT, acting in part through enhanced recycling of calcium through the sarcoplasmic reticulum.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Ascidian larval tunic: Extraembryonic structures influence morphogenesis.

The larval tunic of Corella inflata is composed of two cuticular layers, extracellular filaments and ground substance. It lies outside the epidermis and most of it is known to be produced by the epidermis. The dorsal, ventral and caudal fins are specialized parts of the tunic that are essential for larval locomotion. The following hypothesis was tested: Morphogenesis of the larval fins is dependent upon the presence of extraembryonic structures (test cells, chorion or follicle cells) before completion of the late tail bud stage of development. We tested this by dechorionating embryos of Corella inflata and Ascidia paratropa. The operation removes all extraembryonic structures. It was performed mainly on neurula, early tail-bud and late tail-bud stages. Fin formation is inhibited when neurulae are dechorionated but not when late tail-bud or older embryonic stages are dechorionated. Dechorionated neurulae produce all of the major components of the tunic (cuticular layers, filaments and ground substance) but they are unable to form functional fins. At the time of dechorionation, in all experiments, the embryos had no fins. Removal of the follicle cells does not inhibit fin formation. The test cells are known to secrete granular "ornaments" that attach to the surface of the tunic. The fibrous, acellular chorion may serve to contain the test cells and their products or products of the embryo that are not firmly attached. The test cells may induce or control the morphogenesis of the larval fins in ascidians before the late tail-bud stage of development. We suggest ways of testing this hypothesis and an alternative hypothesis.

Animals↗

The metabolic brain pattern of young subjects given scopolamine.

The effect of an intravenous dose of 0.5 mg of scopolamine on the functional brain activity of normal subjects performing auditory discrimination (CPT) was determined in two independent positron emission tomography studies with [18F] 2-fluoro-deoxyglucose. In the first preliminary study, the most significant effect found was a reduction in the functional activity of the thalamus. In the second "hypothesis-testing" study, an equally prominent effect on thalamic functional activity was seen. Because the second study was performed on a high-resolution scanner with improved methodology, we re-examined scopolamine's effects on those brain regions established as determinants of CPT. Of the regions affected, the reduction in cingulate and the increase in basal ganglia metabolic rates were the most notable. We concluded that scopolamine's effects on the functions of thalamic, cingulate and basal ganglia are the likely causes of scopolamine's well-described attention-altering properties. Alterations in these same brain structures could be responsible for scopolamine's effects on other cognitive functions, e.g., memory. Alternatively, scopolamine's effects on other brain structures such as the hippocampus and frontal cortex could underlie scopolamine's effects on these other cognitive functions. Studies of scopolamine's regional metabolic effects in subjects performing these other cognitive tasks at more than a single dose and at more than one post-drug time are needed to discriminate between these two possibilities.

Acoustic Stimulation↗