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PubMed1987

A test of the social support hypothesis.

As a test of the social support hypothesis, highly anxious primiparous mothers were assigned in the post-natal stage to either a professional intervention, a lay intervention or to a control group. It was hypothesised that those receiving an active intervention (be it lay or professional assistance) would become less anxious as a consequence of a central therapeutic ingredient--social support. Improvement was assessed by measuring state anxiety levels at baseline and at 12 months, while the degree to which therapists were incorporated into the social network was assessed by the Interview Schedule for Social Interaction (ISSI), given at baseline and at 12 months. While we established that anxiety levels were significantly lowered in those receiving the professional intervention and moderately (but not significantly) lowered in those receiving the lay intervention, ISSI scores for the separate groups appeared stable over the study. Reasons are considered why ISSI scores remained unchanged while intervention groups showed a reduction in anxiety levels.

Anxiety Disorders↗
PubMed2002

A cognitive complexity metric applied to cognitive development.

Two experiments tested predictions from a theory in which processing load depends on relational complexity (RC), the number of variables related in a single decision. Tasks from six domains (transitivity, hierarchical classification, class inclusion, cardinality, relative-clause sentence comprehension, and hypothesis testing) were administered to children aged 3-8 years. Complexity analyses indicated that the domains entailed ternary relations (three variables). Simpler binary-relation (two variables) items were included for each domain. Thus RC was manipulated with other factors tightly controlled. Results indicated that (i) ternary-relation items were more difficult than comparable binary-relation items, (ii) the RC manipulation was sensitive to age-related changes, (iii) ternary relations were processed at a median age of 5 years, (iv) cross-task correlations were positive, with all tasks loading on a single factor (RC), (v) RC factor scores accounted for 80% (88%) of age-related variance in fluid intelligence (compositionality of sets), (vi) binary- and ternary-relation items formed separate complexity classes, and (vii) the RC approach to defining cognitive complexity is applicable to different content domains.

Child↗
PubMed2002

A reactivity pattern for discrimination of ER agonism and antagonism based on 3-D molecular attributes.

Various models have been developed to predict the relative binding affinity (RBA) of chemicals to estrogen receptors (ER). These models can be used to prioritize chemicals for further tiered biological testing to assess the potential for endocrine disruption. One shortcoming of models predicting RBA has been the inability to distinguish potential receptor antagonism from agonism, and hence in vivo response. It has been suggested that steroid receptor antagonists are less compact than agonists; thus, ER binding of antagonists may prohibit proper alignment of receptor protein helices preventing subsequent transactivation. The current study tests the theory of chemical bulk as a defining parameter of antagonism by employing a 3-D structural approach for development of reactivity patterns for ER antagonists and agonists. Using a dataset of 23 potent ER ligands (16 agonists, 7 antagonists), molecular parameters previously found to be associated with ER binding affinity, namely global (E(HOMO)) and local (donor delocalizabilities and charges) electron donating ability of electronegative sites and steric distances between those sites, were found insufficient to discriminate ER antagonists from agonists. However, parameters related to molecular bulk, including solvent accessible surface and negatively charged Van der Waal's surface, provided reactivity patterns that were 100% successful in discriminating antagonists from agonists in the limited data set tested. The model also shows potential to discriminate pure antagonists from partial agonist/antagonist structures. Using this exploratory model it is possible to predict additional chemicals for their ability to bind but inactivate the ER, providing a further tool for hypothesis testing to elucidate chemical structural characteristics associated with estrogenicity and anti-estrogenicity.

Animals↗
PubMed1985

Adenosine as putative regulator of hepatic arterial flow (the buffer response).

In anesthetized cats, reduction of portal flow by occlusion of the superior mesenteric artery results in rapid increase in hepatic arterial (HA) flow that compensates for (buffers) 25.5 +/- 2.7% of the decreased portal flow. The hypothesis tested is that adenosine concentration produced near the HA resistance vessels is regulated by washout into portal vessels in intimate contact with the HA. Reduced portal flow leads to accumulation of adenosine and HA dilation. Several criteria for this hypothesis are met. First, adenosine is a potent dilator of the HA. Second, portal blood has access to HA resistance vessels as shown by a marked dilator effect of adenosine infused into the portal vein; it is therefore possible for adenosine produced locally to diffuse into portal blood. Third, dipyridamole potentiated the dilator response to adenosine as well as potentiating the buffer response from a 23% compensation for reduced portal flow to 34%. Fourth, 1-methyl-3-isobutylxanthine (MIX) antagonized exogenous adenosine and reduced the buffer response from 19% down to 5%. These data strongly support the hypothesis that the hepatic arterial buffer response is mediated by local concentrations of adenosine that are controlled by the rate of washout into portal blood.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Prediction of the financial performance of Ontario hospitals: a test of environmental determinist and adaptationist perspectives.

While other industries for many years have been concerned with the problem of financial distress, it is only recently that this issue has become a matter of interest to hospital managers, policy makers, and the general public. However, the determinants of hospital financial performance are neither well studied nor understood. The objectives of this study were to identify factors that affect the financial performance of Ontario hospitals and to construct a model that could be used to predict financial performance in the future. A number of organization and environmental factors that could influence financial performance were postulated and then tested for their statistical impact and predictive ability. Cross-sectional data over the 3-year-period 1986-1988 for 223 Ontario public hospitals were used. The first 2 years of data served as a derivation sample for hypothesis testing and development of a predictive model. The third year of data was used as a holdout sample for cross validation. Information on the variables investigated came from secondary sources, in particular Statistics Canada's Annual Hospital Returns. Univariate analyses revealed distressed hospitals were more likely to earn more revenues from non-government sources, to be non-teaching institutions and have longer chronic lengths of stay, and to be found in areas with higher per capita incomes, number of females in the population, physician supply, and area wage rates. A five variable prediction model was developed which accounted for 25% of the variance in financial performance in the derivation sample and on cross validation dropped to 21%. The model identified greater hospital size, older plants, higher technological complexity, more intensive care services, and location in areas with more females to be significant predictors of financial distress. Overall, environmental factors (community and structural characteristics) were more important in influencing financial performance. The implication for hospital managers is to underscore that an important dimension of successful leadership requires they remain outwardly focused and involved in managing the external environment. For policy makers the need is to develop funding formulae which encourage efficiency and are also responsive to differences in community and structural characteristics across hospitals.

Cross-Sectional Studies↗
PubMed2002

A viral sampling design for testing the molecular clock and for estimating evolutionary rates and divergence times.

MOTIVATION: The high pace of viral sequence change means that variation in the times at which sequences are sampled can have a profound effect both on the ability to detect trends over time in evolutionary rates and on the power to reject the Molecular Clock Hypothesis (MCH). Trends in viral evolutionary rates are of particular interest because their detection may allow connections to be established between a patient's treatment or condition and the process of evolution. Variation in sequence isolation times also impacts the uncertainty associated with estimates of divergence times and evolutionary rates. Variation in isolation times can be intentionally adjusted to increase the power of hypothesis tests and to reduce the uncertainty of evolutionary parameter estimates, but this fact has received little previous attention. RESULTS: We provide approximations for the power to reject the MCH when the alternative is that rates change in a linear fashion over time and when the alternative is that rates differ randomly among branches. In addition, we approximate the standard deviation of estimated evolutionary rates and divergence times. We illustrate how these approximations can be exploited to determine which viral sample to sequence when samples representing different dates are available.

Computational Biology↗
PubMedDate not supplied

Tests for interaction in epidemiologic studies: a review and a study of power.

Tests for statistical interaction have come into increasing use in epidemiologic analysis, with most based on either an additive or multiplicative model for joint effects. Further procedures have been proposed for testing the goodness-of-fit and comparing the fit of the latter models. This paper reviews the relationships between the various tests and model comparison methods, and, for the special case of two dichotomous risk factors, presents asymptotic power functions for tests of additivity and multiplicativity. For a range of sample sizes and factor effects, the powers of the tests are computed using both the asymptotic power function and simulation studies. The powers of the tests are very low in several commonly encountered situations. In addition, convergence to the asymptotic distribution appears slow for some of the statistics. The results also indicate that likelihood comparison procedures can provide a useful adjunct to the classical hypothesis-testing approach.

Epidemiologic Methods↗
PubMed2000

Eye irritation responses in rabbit and man after single applications of equal volumes of undiluted model liquid detergent products.

A criticism of the use of the rabbit low-volume eye test to determine eye irritation hazard for man is the lack of comparative data in man and rabbit with undiluted products. To address this, such a study has been performed in man and rabbit using undiluted model liquid detergents. The hypothesis tested was that if, under identical test conditions, the effects in the rabbit were the same or greater than the response in man, then it is valid to use the low-volume eye test to assess eye irritation hazard for man. The studies were carried out using 29 human volunteers and 12 rabbits. The effects in the rabbit were unequivocally greater than the effects observed in man, but clearly less than the expected response from these types of product in the Draize test. The results from this study confirm the sensitivity of the rabbit as a test species, and support the use of the low-volume eye test to assess eye irritation hazard for man. Any in vitro/ex vivo alternative to assess eye irritation should be developed against the rabbit low-volume eye test or human data where available.

Animals↗
PubMed2004

Beyond the F test: Effect size confidence intervals and tests of close fit in the analysis of variance and contrast analysis.

This article presents confidence interval methods for improving on the standard F tests in the balanced, completely between-subjects, fixed-effects analysis of variance. Exact confidence intervals for omnibus effect size measures, such as or and the root-mean-square standardized effect, provide all the information in the traditional hypothesis test and more. They allow one to test simultaneously whether overall effects are (a) zero (the traditional test), (b) trivial (do not exceed some small value), or (c) nontrivial (definitely exceed some minimal level). For situations in which single-degree-of-freedom contrasts are of primary interest, exact confidence interval methods for contrast effect size measures such as the contrast correlation are also provided.

Analysis of Variance↗
PubMed2003

miLD and booLD programs for calculation and analysis of corrected linkage disequilibrium.

We describe software which calculates a set of linkage disequilibrium statistics, including multiallelic D' corrected by the bootstrap and permutation. The software also provides a tool for maximum likelihood and least squares estimation and testing of a set of hierarchical hypotheses formulated within the framework of the Malecot model of the decay of linkage disequilibrium with distance. Additionally, the bootstrap approach is used for estimation of the model parameter's confidence intervals and for hypothesis testing. The programs are available from http://www.geneticepi.com/Research/software/software.html

Algorithms↗
PubMed1981

Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart.

The hypothesis tested was that functional blockade of a pathway known to travel from the frontal cortex through the posterior hypothalamus to the brain stem might prevent the occurrence of ventricular fibrillation (VF) in the ischemic heart of conscious stressed pigs. The hypothesis was based on previous findings that 1) psychological stress is a necessary factor for the initiation of VF in the ischemic heart of conscious pigs, 2) the frontal cortex and its related thalamic gating mechanism, uniquely show neuroelectric responses to stressful stimuli, and 3) direct electric stimulation of either the frontal cortex, posterior hypothalamus, or fields of Forel will produce ventricular arrhythmias and myocardial necrosis. In the present study it was found that cryogenic blockade of the forebrain, posterior hypothalamus, or fields of Forel prevents or delays VF after left anterior descending coronary artery occlusion in conscious stressed pigs (P less than 0.01). Blockade of control structures adjacent to these loci in another group of pigs had no effect on VF latency. Neither heart rate nor electroencephalographic changes could explain the differences between the groups. The results show that blockade of the frontocortical-brain stem pathway prevents the lethal consequences of myocardial ischemia in stressed animals.

Animals↗
PubMed2006

Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects.

CONTEXT: The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T(4) to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance. OBJECTIVE: The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a beta-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits. DESIGN AND PATIENTS: The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients. RESULTS: We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area under the serum insulin curve during an oral glucose tolerance test (P = 0.03) and elevated fasting plasma glucose (P = 0.02) in homozygous Ala92 allele carriers, the latter strengthened by epistasis with the ADRB2 Gly16Arg variant in a double recessive model (P = 0.004). However, after permutation procedure, performed to correct for multiple hypothesis testing, the associations did not reach study-wide significance. CONCLUSIONS: The DIO2 Thr92Ala variant does not confer an increased risk of T2D, obesity, or insulin resistance.

Adult↗
PubMed2006

The strengthening mechanism of resin cements on porcelain surfaces.

All-ceramic crowns bonded with resin cements have increased performance, and two theories have been proposed. Marquis (1992) suggested that the resin modified defects by crack healing, while Nathanson (1993) proposed that resin polymerization shrinkage strengthened porcelains. Both theories imply a sensitivity of strengthening to defect size. The hypothesis tested was that resin strength enhancement is independent of defect severity. We ground 200 porcelain discs to remove imperfections and indented 120 to create a large defect. Discs were tested dry, wet, and after being coated with 75-100 microm of resin cement in bi-axial flexure. Disc strength with and without indentations was increased significantly when coated with 2 resin cements. Both cements significantly increased the strength independent of defect population, and the hypothesis was accepted. It is proposed that the combination of surface pre-treatment and cement moved the fracture origin from the porcelain/cement interface to the cement surface, consistent with resin strength enhancement independent of defect severity.

Acid Etching, Dental↗
PubMed2002

Small-sample adjustments in using the sandwich variance estimator in generalized estimating equations.

The generalized estimating equation (GEE) approach is widely used in regression analyses with correlated response data. Under mild conditions, the resulting regression coefficient estimator is consistent and asymptotically normal with its variance being consistently estimated by the so-called sandwich estimator. Statistical inference is thus accomplished by using the asymptotic Wald chi-squared test. However, it has been noted in the literature that for small samples the sandwich estimator may not perform well and may lead to much inflated type I errors for the Wald chi-squared test. Here we propose using an approximate t- or F-test that takes account of the variability of the sandwich estimator. The level of type I error of the proposed t- or F-test is guaranteed to be no larger than that of the Wald chi-squared test. The satisfactory performance of the proposed new tests is confirmed in a simulation study. Our proposal also has some advantages when compared with other new approaches based on direct modifications of the sandwich estimator, including the one that corrects the downward bias of the sandwich estimator. In addition to hypothesis testing, our result has a clear implication on constructing Wald-type confidence intervals or regions.

Adult↗
PubMed2001

Transmission/disequilibrium test meets measured haplotype analysis: family-based association analysis guided by evolution of haplotypes.

Family data teamed with the transmission/disequilibrium test (TDT), which simultaneously evaluates linkage and association, is a powerful means of detecting disease-liability alleles. To increase the information provided by the test, various researchers have proposed TDT-based methods for haplotype transmission. Haplotypes indeed produce more-definitive transmissions than do the alleles comprising them, and this tends to increase power. However, the larger number of haplotypes, relative to alleles at individual loci, tends to 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. In this report we develop such an approach by combining the theory of TDT with that of measured haplotype analysis (MHA). MHA uses the evolutionary relationships among haplotypes to produce a limited set of hypothesis tests and to increase the interpretability of these tests. The theory of our approach, called the "evolutionary tree" (ET)-TDT, is developed for two cases: when haplotype transmission is certain and when it is not. Simulations show the ET-TDT can be more powerful than other proposed methods under reasonable conditions. More importantly, our results show that, when multiple polymorphisms are found within the gene, the ET-TDT can be useful for determining which polymorphisms affect liability.

Alleles↗
PubMed2004

Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies.

The calpain-10 gene (CAPN10) on chromosome 2q37.3 was the first candidate gene for type 2 diabetes (T2D) identified through a genomewide screen and positional cloning. One polymorphism (UCSNP-43: G-->A) and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and -63) were linked to an increased risk of T2D in several populations. To quantitatively assess the collective evidence for the effects of CAPN10 on risk of T2D, we conducted a meta-analysis of both population-based and family-based association studies. We retrieved data from the MEDLINE, PubMed, and Online Mendelian Inheritance in Man databases, as well as from other relevant reports and abstracts published up to July 2003. From a total of 26 studies with primary data (21 population-based studies: 5,013 cases and 5,876 controls; 5 family-based studies: 487 parent-offspring trios), we developed a summary database that contains variables of study design, study population/ethnicity, specific polymorphisms and haplotype combinations in CAPN10, and diabetes-related metabolic phenotypes. For population-based studies, we used both fixed-effects and random-effects models to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) for the associations of CAPN10 genotypes with the risk of T2D. We also calculated weighted mean differences for the associations between CAPN10 and diabetes-related quantitative traits. Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk. However, under a recessive model, individuals homozygous for the common G allele had a statistically significant 19% higher risk of T2D than carriers of the A allele (OR 1.19; 95% CI 1.07-1.33). The association between the 112/121 haplotype combination and T2D risk appeared to be overestimated by several initial small studies with positive findings (OR 1.38; 95% CI 1.04-1.84). After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35). Moreover, we found no evidence for the associations between the UCSNP-43 G/G genotype and the 112/121 haplotype combination and metabolic phenotypes. Our meta-analysis of family-based studies showed only an overtransmission of the rare allele C in UCSNP-44 from heterozygous parents to their affected offspring with T2D. Our analysis indicates that inadequate statistical power, racial/ethnic differences in frequencies of alleles, haplotypes and haplotype combinations, potential gene-gene or gene-environment interactions, publication bias, and multiple hypothesis testing may contribute to the significant heterogeneity in previous studies of CAPN10 and T2D. Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk.

Alleles↗
PubMed1986

Social ties and mortality in Evans County, Georgia.

In an attempt to replicate Berkman and Syme's study of social networks and mortality in Alameda County, California, the authors investigated the relationship between a social network index and survivorship from 1967 to 1980 in the Evans County, Georgia, cohort. They constructed an index modeled after the Berkman Social Network Index and tested it in race- and sex-specific proportional hazards models for 2,059 subjects who were examined in 1967-1969 during the Evans County Cardiovascular Epidemiologic Study. The present study emphasized a priori specification of the social network index and statistical hypothesis test. Descriptive analyses were consistent with a modest social networks effect (e.g., hazard ratio (95 per cent confidence interval) of 1.6 (1.2-2.2) ). Among white males, the age-adjusted hazard ratio comparing the lowest to the highest value of our six-level index was 2.0 (1.2-3.4), but control for potential confounders (principally cardiovascular disease risk factors) reduced this value to 1.5 (0.8-2.6). The social networks effect among white females, black males, and black females was weaker and clearly nonsignificant. Exploratory analyses suggested that marital status, church activities, and an alternate social network index predicted survivorship, but not in a dose-response fashion. Reduced survivorship among older subjects with few social ties was the most important feature of the data.

Adolescent↗
PubMed2006

Selecting promising ALS therapies in clinical trials.

Riluzole is the only approved medication that extends survival for patients with amyotrophic lateral sclerosis (ALS). While other potential neuroprotective agents have been evaluated in randomized clinical trials, none has shown unequivocal success and none has been approved by regulatory agencies. Few symptomatic therapies have been tested in ALS. Effectiveness for drugs with modest benefit can be established only through large phase III randomized clinical trials. With numerous potential agents but limited resources, priority should be given to agents that show promise in phase II trials before proceeding to evaluation in phase III trials. In this article, we review drug development in early phase ALS trials and introduce novel designs. First, to maximize the therapeutic potential of the test medication, we need to identify the highest dose that produces a tolerable level of side effects. Second, candidate treatments should be ranked by conducting randomized selection trials between competing new treatments. The selection paradigm adopts a statistical viewpoint different from the hypothesis testing framework in conventional trials. We exemplify this approach by describing a group-sequential selection design developed for a phase II, randomized, multicenter trial of two combination treatments in patients with ALS, and illustrate the sample size reduction from a conventional trial.

Amyotrophic Lateral Sclerosis↗