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PubMed1988

Bayesian interval estimation of genetic relationships: application to paternity testing.

Using genetic marker data, we have developed a general methodology for estimating genetic relationships between a set of individuals. The purpose of this paper is to illustrate the practical utility of these methods as applied to the problem of paternity testing. Bayesian methods are used to compute the posterior probability distribution of the genetic relationship parameters. Use of an interval-estimation approach rather than a hypothesis-testing one avoids the problem of the specification of an appropriate null hypothesis in calculating the probability of paternity. Monte Carlo methods are used to evaluate the utility of two sets of genetic markers in obtaining suitably precise estimates of genetic relationship as well as the effect of the prior distribution chosen. Results indicate that with currently available markers a "true" father may be reliably distinguished from any other genetic relationship to the child and that with a reasonable number of markers one can often discriminate between an unrelated individual and one with a second-degree relationship to the child.

Bayes Theorem↗
PubMed2006

[Principles of an outbreak investigation in public health practice].

An outbreak (or epidemic) is a higher number of cases of a given disease in a given population and time interval. A timely investigation has for aim to identify the source and vehicle of the outbreak and provides unique opportunities to better understand its occurrence and the role of contributing risk factors to implement the most appropriate measures to control it and prevent further recurrences. The investigation of an outbreak is based on a multidisciplinary approach (clinical, epidemiological, environmental, and microbiological) with a descriptive and analytical (hypothesis testing) phase. In this article, we describe the methodological approach of a field outbreak investigation illustrated by examples taken from our experience. The investigation includes the following steps: establishing the existence of the outbreak; defining the disease; finding cases; describing cases by time, place, and person characteristics; establishing a hypothesis related to the mode of occurrence; testing the hypotheses; conducting an environmental investigation; conducting a microbiological investigation; controlling the outbreak, preventing further occurrences, and writing an investigation report to share experience with the public health and scientific community. The investigation of an outbreak is an evolving process: information gathered or conclusions made at a given stage must be fully used for following steps. The social, institutional, and political background associated with outbreaks usually makes their investigation complex and should be taken into account. The earlier the outbreak is detected and investigated in close relation with public health authorities, the greater will be the potential preventive impact of control measures.

Adult↗
PubMed2002

Sib-parentage testing using molecular markers when parents are unknown.

The formulae for computing the so-called Sib Index using codominant alleles for (1) full-sib and (2) half-sib parentage are given. Hypothesis testing is based on the distribution of conditional likelihood ratio or Bayes' factor. Thresholds for rejecting the null hypothesis and P-values were obtained in function of the number of alleles and their frequency distributions. Simulations showed that a relatively low number of marker systems (e.g. 20) are enough to accept the hypothesis of sib parentage with a reasonable power for usual significance levels, but that a higher number would be necessary if full-sib against half-sib parentage is the contrast to be carried out. The effect of sampling variation on the allele frequencies on power calculations is also analysed.

Alleles↗
PubMed2005

A global goodness-of-fit test for receiver operating characteristic curve analysis via the bootstrap method.

OBJECTIVE: Medical classification accuracy studies often yield continuous data based on predictive models for treatment outcomes. A popular method for evaluating the performance of diagnostic tests is the receiver operating characteristic (ROC) curve analysis. The main objective was to develop a global statistical hypothesis test for assessing the goodness-of-fit (GOF) for parametric ROC curves via the bootstrap. DESIGN: A simple log (or logit) and a more flexible Box-Cox normality transformations were applied to untransformed or transformed data from two clinical studies to predict complications following percutaneous coronary interventions (PCIs) and for image-guided neurosurgical resection results predicted by tumor volume, respectively. We compared a non-parametric with a parametric binormal estimate of the underlying ROC curve. To construct such a GOF test, we used the non-parametric and parametric areas under the curve (AUCs) as the metrics, with a resulting p value reported. RESULTS: In the interventional cardiology example, logit and Box-Cox transformations of the predictive probabilities led to satisfactory AUCs (AUC=0.888; p=0.78, and AUC=0.888; p=0.73, respectively), while in the brain tumor resection example, log and Box-Cox transformations of the tumor size also led to satisfactory AUCs (AUC=0.898; p=0.61, and AUC=0.899; p=0.42, respectively). In contrast, significant departures from GOF were observed without applying any transformation prior to assuming a binormal model (AUC=0.766; p=0.004, and AUC=0.831; p=0.03), respectively. CONCLUSIONS: In both studies the p values suggested that transformations were important to consider before applying any binormal model to estimate the AUC. Our analyses also demonstrated and confirmed the predictive values of different classifiers for determining the interventional complications following PCIs and resection outcomes in image-guided neurosurgery.

Adolescent↗
PubMed2002

A statistical method for identification of polymorphisms that explain a linkage result.

Suppose that many polymorphic sites have been identified and genotyped in a region showing strong linkage with a trait. A key question of interest is which site (or combination of sites) in the region influences susceptibility to the trait. We have developed a novel statistical approach to this problem, in the context of qualitative-trait mapping, in which we use linkage data to identify the polymorphic sites whose genotypes could fully explain the observed linkage to the region. The information provided by this analysis is different from that provided by tests of either linkage or association. Our approach is based on the observation that if a particular site is the only site in the region that influences the trait, then-conditional on the genotypes at that site for the affected relatives-there should be no unexplained oversharing in the region among affected individuals. We focus on the affected sib-pair study design and develop test statistics that are variations on the usual allele-sharing methods used in linkage studies. We perform hypothesis tests and derive a confidence set for the true causal polymorphic site, under the assumption that there is only one site in the region influencing the trait. Our method is appropriate under a very general model for how the site influences the trait, including epistasis with unlinked loci, correlated environmental effects within families, and gene-environment interaction. We extend our method to larger sibships and apply it to an NIDDM1 data set.

Alleles↗
PubMed1999

A randomized clinical trial of triazolam in 3- to 5-year-olds.

Triazolam has shown promise as a sedative agent for use in pediatric dentistry. However, the efficacy of triazolam has not been previously examined in a placebo-controlled study. The present clinical trial used a two-group, randomized, double-blind study design to compare the efficacy of oral triazolam with that of a placebo. The primary hypothesis tested was that triazolam would reduce negative behaviors of pediatric dental patients compared with a placebo. A secondary hypothesis was that triazolam would increase the efficiency of dental treatment by reducing the need for time-consuming behavior management by the pediatric dentist. The subjects were 54 3- to 5-year-old children, randomly assigned to the drug and placebo groups. The active drug, 0.03 mg/kg triazolam (Halcion), or lactose placebo was given orally 30 min before dental treatment. Behavior management techniques commonly used in pediatric dentistry were used during dental treatment. A single pediatric dentist provided all of the dental treatment. The procedure included an inferior block anesthesia and careful attention to anesthesia effectiveness. All sessions were video-taped and the tapes coded for child and dentist behaviors by an independent observer. There were no statistically significant differences between the groups with respect to completion of dental treatment. There were no significant differences found in either the total time or the percent of time that the subjects exhibited disruptive movements, verbal or non-verbal distress. The total use of time in the dental chair was slightly higher in the placebo than in the drug group due to more time spent preparing the child. Contrary to preliminary reports in the literature, this investigation found little or no improvement in child behavior when triazolam was used as a sedative compared with a placebo. However, triazolam did shorten the length of dental treatment, primarily by reducing dentist time in preparing the child for the dental procedure (e.g., establishing rapport and shaping behavior).

Administration, Oral↗
PubMed2003

Proving non-inferiority or equivalence of two treatments with dichotomous endpoints using exact methods.

Since the early work of RA Fisher, exact methods have been recognized as important tools in data analysis because they provide valid statistical inference even with small sample sizes, or with sparse or skewed data. With the recent advance of computational power and the availability of commercial software packages, exact methods have gained substantial popularity over the past two decades. However, most of these exact methods have been devoted to testing classical null hypotheses of no differences, and until recently little was known about exact methods dealing with non-inferiority or equivalence hypotheses. The presence of nuisance parameters in testing non-inferiority/equivalence hypotheses presents a special challenge for exact methods because of the intense computational requirement. In this paper, we review exact methods available for proving non-inferiority or equivalence of two treatments with a dichotomous endpoint. First, we present the general methodology for conducting exact tests for non-inferiority or equivalence; we then discuss several unconditional and conditional methods available for constructing hypothesis tests and confidence intervals based on three commonly used measures, namely, the difference, relative risk, and odds ratio of two independent proportions or rates. Finally, we illustrate with several examples the application of these exact methods in analysing and planning non-inferiority or equivalence trials.

Biomedical Research↗
PubMed1992

Is the morphology of ventricular premature beats a marker for left ventricular dysfunction?

The morphology of ventricular premature beats has been described as a marker for the presence or absence of myocardial disease. Furthermore, the premature beat has been reported to be a potential marker for a dilated and hypokinetic left ventricle. To verify this previously tested hypothesis, 37 healthy patients with ventricular premature beats on an electrocardiogram (ECG), Holter monitor ECG, or a stress test ECG were classified according to the ventricular premature beat morphology. Group 1 had ventricular premature beat QRS complexes with a smooth contour or with narrow (less than 40 msec) notching. Group 2 had ventricular premature beats with broad (greater than 40 msec) notching or shelves. All of these patients had normal or borderline normal ECGs and normal multiple-gated acquisition (MUGA) scans. Nine patients had type 1 ventricular premature beats, 20 patients had type II ventricular premature beats, and eight patients had both type I and type II ventricular premature beats. We conclude that the presence of group 2 ventricular premature beats is so frequent in patients with normal left ventricular ejection fractions that the use of this marker in identifying abnormal left ventricular function is suspect.

Adult↗
PubMed1983

Count-rate variations with orientation of camera detector.

Variations of count rate with orientation of the detector were investigated. Scaled difference images (SDI) were generated from pairs of arrays acquired at different detector orientations. The hypothesis tested was that any variations could be totally explained by random disintegration noise. We accepted or rejected this hypothesis according to the statistical significance of the difference between the measured and theoretical means and variances of the SDIs. When two images acquired at the same angle were compared, no significant differences were noted. Differences were significant between most pairs of images obtained at different angular orientations. Cameras with inadequate magnetic shielding were more sensitive to orientation effects than those with proper magnetic shielding. The mode of variation strongly suggests an interaction with a magnetic field.

Magnetics↗
PubMed1986

Studies on the mechanism of systemic suppression of contact hypersensitivity by ultraviolet B radiation.

Exposure of mice to ultraviolet (UV) B radiation (280-320 nm) induces suppressor T lymphocytes (Ts) that prevent the rejection of primary skin cancers. A model for understanding how UVB radiation activates the suppressor cell pathway is based on the finding that UVB irradiation of mice also induces hapten-specific Ts following application of a contact sensitizing agent to unirradiated skin. Studies presented here address the mechanism by which the Ts pathway is activated in UV-irradiated mice. The hypothesis tested is that the induction of Ts results from a direct alteration of circulating antigen-presenting cells (monocytes) by the radiation. This hypothesis predicts that the UV-induced suppression of contact hypersensitivity will be reversed by replacing the antigen-presenting cells (monocytes or macrophages) after irradiation. To test this prediction, UVB-irradiated mice were given normal bone marrow cells, spleen fragments, splenic antigen-presenting cells, or stimulants of endogenous bone marrow cells. None of these procedures reversed the effects of the irradiation. Furthermore, immunization of UVB-irradiated mice with hapten-coupled splenic macrophages also failed to restore the contact hypersensitivity reaction. Therefore, direct inactivation of circulating monocytes does not appear to be the mechanism by which UVB radiation induces Ts. Experiments are also presented indicating that passive accumulation of inflammatory cells in the skin does not explain the UVB-induced systemic suppression of contact hypersensitivity. Collectively, these results support the hypothesis that a soluble mediator, induced by exposure of the skin to UVB radiation, is involved in UVB-induced systemic immunosuppression.

Animals↗
PubMed2002

Cough provocation tests: their clinical value.

Cough provocation testing was originally developed for testing new anti-tussive agents and still remains a mandatory tool in their development. The methodology has been developed into single breath and multiple breath techniques. Neither has been fully validated; however, single breath techniques have been used in a number of patient series of more than 100 patients. These studies show that the cough reflex is more sensitive in patients with cough and becomes normal on recovery. Studies in the common cold and in angiotensin converting enzyme inhibitor-associated cough suggest that this may be cause and effect. These results point to a utility for cough provocation testing in epidemiology but not in routine clinical practice. The one exception in clinical practice is in the assessment of patient post stroke where it is a better method, than voluntary cough testing, for assessing damage to the cough reflex. Other than use in epidemiology it remains an invaluable tool in hypothesis testing.

Cough↗
PubMed1992

Theory-driven research in pediatric psychology: a little bit on why and how.

Introduces a Special Issue, covering two published issues (5 and 6) of this journal, on theory-driven research in pediatric psychology. A rationale for conducting research from a conceptual basis is presented. It is emphasized that science is primarily an intellectual activity, demonstrated in the form of theory building, testing, and reformulation. Furthermore, it is argued theory serves as a planning and communication aide for scientific pursuit. The process and components of theory-driven research are then highlighted. Theoretical constructs, theoretical and empirical definitions of constructs, and the use of variables are discussed. A definition of scientific theory is offered. Theory testing is distinguished from post hoc theorizing. Differences in the scope of theories are noted. Connections between theory and hypothesis testing and research design are addressed, especially for nonexperimental or correlational research.

Child↗
PubMed1998

Arm pain among Swedish fighter pilots during +Gz flight and centrifuge exposures.

BACKGROUND: The purpose was to survey the occurrence of arm pain among Swedish fighter or test pilots in connection with exposures to high +Gz load when flying or performing centrifuge tests. HYPOTHESIS: +Gz induced arm pain occurs in connection with high +Gz loads in flight as well as in centrifuge tests of high performance fighter pilots. METHODS: A questionnaire was used for data collection regarding +Gz induced arm pain. Respondents were 35 Swedish Air Force Viggen and Gripen fighter pilots who had previously participated as subjects in centrifuge tests between 1990 and 1995 at Brooks Air Force Base, TX, either with the standard anti-G suit or with extended coverage anti-G suit with pressure breathing during +Gz. RESULTS: Of the respondents, 55% reported that they had experienced arm pain during flight at least once and 42% experienced it more than three times. However, arm pain was more common in the centrifuge tests (82% once; and 42% more than 3 times). CONCLUSIONS: Presence of arm pain during high performance fighter aircraft flights is a phenomenon that should be taken into consideration when designing high performance aircraft or +Gz protective equipment.

Adult↗
PubMed2002

Significance-testing the validity of idiographic methods: a little derangement goes a long way.

We present an experimental design for validating idiographic data and the mathematical basis for subjecting this to statistical hypothesis testing. The method involves matching descriptions of four or more objects to the people from which they arose. If four or more can be matched, this is unlikely (p < 0.05) to have arisen by chance alone and the null hypothesis that the data communicate no information can be rejected. This criterion score of 4 is sufficient for statistical significance regardless of the total number of objects on which matching was attempted. The mathematics of this somewhat counterintuitive result is given, and we argue that this method is of value in validating idiographic data. Its relationship with the 'method of mismatched cases' is discussed.

Cognition↗
PubMed2002

Social stimuli, testosterone, and aggression in gull chicks: support for the challenge hypothesis.

We tested the challenge hypothesis for the hormonal regulation of aggression in chicks of the black-headed gull, Larus ridibundus. Chicks of this species are highly aggressive toward conspecifics, but never to peers that hatched from the same clutch (modal clutch size is three). Therefore, in the first experiment small families were housed together in large groups (challenged condition) and compared to families kept isolated (nonchallenged condition). As expected, in the challenged condition during the initial stage of territory establishment basal levels of testosterone (T) were clearly higher than those in the nonchallenged condition. In the second experiment we tested the effect of a short social challenge on short-term T-fluctuations. The design was based on an earlier experiment, showing that after temporary T-treatment chicks become very sensitive to social challenges while having low basal T-levels. We now show that these social challenges induce brief elevations in plasma T-levels. These peaks are similar to those in previously untreated chicks but untreated chicks do not respond with aggression to a challenge. Therefore, we conclude that the initial exposure to elevated T-levels increases the sensitivity to brief changes in T induced by social challenges. In this way exposure to T, that may be detrimental for development, is minimized while birds remain able to defend territories. This is the first report showing that the challenge hypothesis as established for adult birds, is also applicable for aggressive behavior in young birds outside the sexual context. Furthermore we suggest that a phase of priming with T is necessary to obtain the high behavioral responsiveness to a challenge.

Aggression↗
PubMed2004

Target selection and the superior colliculus: goals, choices and hypotheses.

The intermediate and deep layers of the superior colliculus (SC) compose a retinotopically organized motor map and are known to be important for the control of saccadic eye movements. However, recent studies have shown that the functions of the SC are not restricted to the motor control of saccades. The pattern of activity observed during multi-saccade movements, combined eye-head movements, and pursuit eye movements argue that activity in the SC indicates the location of the goal, but does not specify the particular movements that will be used to acquire the goal. Prior to the onset of a movement, the SC is involved in representing possible targets, as has been shown by the effects of manipulating target probability and the changes in pre-motor activity found during visual search tasks. A major unresolved issue is how target-related activity in the SC is transformed into the signal that triggers the movement. One possibility is that the levels of activity across the SC motor map correspond to the likelihood of the possible targets, and that the movement decision is based on the neural equivalent of hypothesis testing. In one version of this mechanism, the decision to select a new goal would occur each time the null hypothesis, represented by neurons in the rostral SC, was rejected in favor of an alternative represented elsewhere in the SC.

Attention↗
PubMed2006

Mouse Phenome Database (MPD).

The Mouse Phenome Database (MPD; http://www.jax.org/phenome) is a repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice. Strain characteristics data are contributed by members of the scientific community. Electronic access to centralized strain data enables biomedical researchers to choose appropriate strains for many systems-based research applications, including physiological studies, drug and toxicology testing and modeling disease processes. MPD provides a community data repository and a platform for data analysis and in silico hypothesis testing. The laboratory mouse is a premier genetic model for understanding human biology and pathology; MPD facilitates research that uses the mouse to identify and determine the function of genes participating in normal and disease pathways.

Animals↗
PubMed1992

Statistical tests in medical research.

Various propositions have been made to improve the statistical quality of medical journals: using statistical referees, promoting better collaboration between statisticians and researchers, and teaching of basic statistics to clinicians. The most frequent errors found in medical articles are misinterpretation of p-values or non-significant results and confusion between statistical and clinical significance, inappropriate use of tests requiring precise assumptions, inappropriate or not controlled multiple testing and particularly testing of post hoc hypotheses, and overemphasis on p-values. Many errors arising from the misinterpretation of results of statistical hypothesis tests, the basic principles of this methodology are emphasized, and the usual fallacies found in the medical literature are reviewed.

Research↗