New era: Prophylactic surgery for patients with multiple endocrine neoplasia-2A

Background: The surgical management of patients with multiple endocrine neoplasia-2A (MEN-2A) continues to evolve with specific genotype-phenotype correlations allowing for a more tailored approach. In this study, we report the surgical management of one of the largest MEN-2A families with a rearranged during transfection (RET) codon 804 mutation. Method: This is a cohort study comprising all at-risk kindred within a single known MEN-2A family. Prophylactic total thyroidectomy with lymph node dissection was recommended to all mutation carriers aged 5 years and older. Results: There were a total of 48 at-risk individuals in the MEN-2A kindred, with 22 patients undergoing thyroidectomy after appropriate preoperative evaluation. A total of 9 patients had medullary thyroid cancer including 5 with a normal preoperative calcitonin level. A total of 11 patients had C-cell hyperplasia and 7 showed histological evidence of parathyroid disease. Only the index case had a phaeochromocytoma. Conclusion: Genetic testing for germline mutations in the RET proto-oncogene has allowed precise identification of affected RET carriers and provided the opportunity for prophylactic or 'preclinical' surgery to treat and in fact to prevent medullary thyroid cancer. This concept of prophylactic surgery based on a genetic test is likely to be applied more widely as the tools of molecular biology advance.

Viewpoint-based testing of concurrent components

The use of multiple partial viewpoints is recommended for specification. We believe they also can be useful for devising strategies for testing. In this paper, we use Object-Z to formally specify concurrent Java components from viewpoints based on the separation of application and synchronisation concerns inherent in Java monitors. We then use the Test-Template Framework on the Object-Z viewpoints to devise a strategy for testing the components. When combining the test templates for the different viewpoints we focus on the observable behaviour of the application to systematically derive a practical testing strategy. The Producer-Consumer and Readers-Writers problems are considered as case studies.

Dealing with non-determinism in testing concurrent java components

The testing of concurrent software components can be difficult due to the inherent non-determinism present in these components. For example, if the same test case is run multiple times, it may produce different results. This non-determinism may lead to problems with determining expected outputs. In this paper, we present and discuss several possible solutions to this problem in the context of testing concurrent Java components using the ConAn testing tool. We then present a recent extension to the tool that provides a general solution to this problem that is sufficient to deal with the level of non-determinism that we have encountered in testing over 20 components with ConAn. © 2005 IEEE

Probing three-way interactions in moderated multiple regression:Development and application of a slope difference test

Researchers often use 3-way interactions in moderated multiple regression analysis to test the joint effect of 3 independent variables on a dependent variable. However, further probing of significant interaction terms varies considerably and is sometimes error prone. The authors developed a significance test for slope differences in 3-way interactions and illustrate its importance for testing psychological hypotheses. Monte Carlo simulations revealed that sample size, magnitude of the slope difference, and data reliability affected test power. Application of the test to published data yielded detection of some slope differences that were undetected by alternative probing techniques and led to changes of results and conclusions. The authors conclude by discussing the test's applicability for psychological research. Copyright 2006 by the American Psychological Association.

Statnote 29:discriminant analysis

Discriminant analysis (also known as discriminant function analysis or multiple discriminant analysis) is a multivariate statistical method of testing the degree to which two or more populations may overlap with each other. It was devised independently by several statisticians including Fisher, Mahalanobis, and Hotelling ). The technique has several possible applications in Microbiology. First, in a clinical microbiological setting, if two different infectious diseases were defined by a number of clinical and pathological variables, it may be useful to decide which measurements were the most effective at distinguishing between the two diseases. Second, in an environmental microbiological setting, the technique could be used to study the relationships between different populations, e.g., to what extent do the properties of soils in which the bacterium Azotobacter is found differ from those in which it is absent? Third, the method can be used as a multivariate ‘t’ test , i.e., given a number of related measurements on two groups, the analysis can provide a single test of the hypothesis that the two populations have the same means for all the variables studied. This statnote describes one of the most popular applications of discriminant analysis in identifying the descriptive variables that can distinguish between two populations.

Self-testing for cancer:a community survey

Background: Cancer-related self-tests are currently available to buy in pharmacies or over the internet, including tests for faecal occult blood, PSA and haematuria. Self-tests have potential benefits (e.g. convenience) but there are also potential harms (e.g. delays in seeking treatment). The extent of cancer-related self-test use in the UK is not known. This study aimed to determine the prevalence of cancer-related self-test use. Methods: Adults (n = 5,545) in the West Midlands were sent a questionnaire that collected socio-demographic information and data regarding previous and potential future use of 18 different self-tests. Prevalence rates were directly standardised to the England population. The postcode based Index of Multiple Deprivation 2004 was used as aproxy measure of deprivation. Results: 2,925 (54%) usable questionnaires were returned. 1.2% (95% CI 0.83% to 1.66%) of responders reported having used a cancer related self test kit and a further 36% reported that they would consider using one in the future. Logistic regression analyses suggest that increasing age, deprivation category and employment status were associated with cancer-related self-test kit use. Conclusion: We conclude that one in 100 of the adult population have used a cancer-related self-test kit and over a third would consider using one in the future. Self-test kit use could alter perceptions of risk, cause psychological morbidity and impact on the demand for healthcare.

Disordered connectivity in the autistic brain:challenges for the 'new psychophysiology'

In 2002, we published a paper [Brock, J., Brown, C., Boucher, J., Rippon, G., 2002. The temporal binding deficit hypothesis of autism. Development and Psychopathology 142, 209-224] highlighting the parallels between the psychological model of 'central coherence' in information processing [Frith, U., 1989. Autism: Explaining the Enigma. Blackwell, Oxford] and the neuroscience model of neural integration or 'temporal binding'. We proposed that autism is associated with abnormalities of information integration that is caused by a reduction in the connectivity between specialised local neural networks in the brain and possible overconnectivity within the isolated individual neural assemblies. The current paper updates this model, providing a summary of theoretical and empirical advances in research implicating disordered connectivity in autism. This is in the context of changes in the approach to the core psychological deficits in autism, of greater emphasis on 'interactive specialisation' and the resultant stress on early and/or low-level deficits and their cascading effects on the developing brain [Johnson, M.H., Halit, H., Grice, S.J., Karmiloff-Smith, A., 2002. Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis. Development and Psychopathology 14, 521-536].We also highlight recent developments in the measurement and modelling of connectivity, particularly in the emerging ability to track the temporal dynamics of the brain using electroencephalography (EEG) and magnetoencephalography (MEG) and to investigate the signal characteristics of this activity. This advance could be particularly pertinent in testing an emerging model of effective connectivity based on the balance between excitatory and inhibitory cortical activity [Rubenstein, J.L., Merzenich M.M., 2003. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior 2, 255-267; Brown, C., Gruber, T., Rippon, G., Brock, J., Boucher, J., 2005. Gamma abnormalities during perception of illusory figures in autism. Cortex 41, 364-376]. Finally, we note that the consequence of this convergence of research developments not only enables a greater understanding of autism but also has implications for prevention and remediation. © 2006.

Spatial coherence does not affect contrast discrimination for multiple Gabor stimuli

Gestalt grouping rules imply a process or mechanism for grouping together local features of an object into a perceptual whole. Several psychophysical experiments have been interpreted as evidence for constrained interactions between nearby spatial filter elements and this has led to the hypothesis that element linking might be mediated by these interactions. A common tacit assumption is that these interactions result in response modulation which disturbs a local contrast code. We addressed this possibility by performing contrast discrimination experiments using two-dimensional arrays of multiple Gabor patches arranged either (i) vertically, (ii) in circles (coherent conditions), or (iii) randomly (incoherent condition), as well as for a single Gabor patch. In each condition, contrast increments were applied to either the entire test stimulus (experiment 1) or a single patch whose position was cued (experiment 2). In experiment 3, the texture stimuli were reduced to a single contour by displaying only the central vertical strip. Performance was better for the multiple-patch conditions than for the single-patch condition, but whether the multiple-patch stimulus was coherent or not had no systematic effect on the results in any of the experiments. We conclude that constrained local interactions do not interfere with a local contrast code for our suprathreshold stimuli, suggesting that, in general, this is not the way in which element linking is achieved. The possibility that interactions are involved in enhancing the detectability of contour elements at threshold remains unchallenged by our experiments.

Data analysis methods in optometry Part 7: multiple linear regression

Multiple regression analysis is a complex statistical method with many potential uses. It has also become one of the most abused of all statistical procedures since anyone with a data base and suitable software can carry it out. An investigator should always have a clear hypothesis in mind before carrying out such a procedure and knowledge of the limitations of each aspect of the analysis. In addition, multiple regression is probably best used in an exploratory context, identifying variables that might profitably be examined by more detailed studies. Where there are many variables potentially influencing Y, they are likely to be intercorrelated and to account for relatively small amounts of the variance. Any analysis in which R squared is less than 50% should be suspect as probably not indicating the presence of significant variables. A further problem relates to sample size. It is often stated that the number of subjects or patients must be at least 5-10 times the number of variables included in the study.5 This advice should be taken only as a rough guide but it does indicate that the variables included should be selected with great care as inclusion of an obviously unimportant variable may have a significant impact on the sample size required.

The effects of negative affectivity on self-reported activity limitations in stroke patients:testing the symptom perception, disability and psychosomatic hypotheses

This study investigated whether Negative Affectivity (NA) causes bias in self-report measures of activity limitations or whether NA has a real, non-artifactual association with activity limitations. The Symptom Perception Hypothesis (NA negatively biases self-reporting), Disability Hypothesis (activity limitations cause NA) and Psychosomatic Hypothesis (NA causes activity limitations) were examined longitudinally using both self-report and objective activity limitations measures. Participants were 101 stroke patients and their caregivers interviewed within two weeks of discharge, six weeks later and six months post-discharge. NA and self-report, proxy-report and observed performance activity (walking) limitations were assessed at each interview. NA was associated with activity limitations across measures. Both the Disability and Psychosomatic Hypotheses were supported: initial NA predicted objective activity limitations at six weeks but, additionally, activity limitations at six weeks predicted NA at six months. These results suggest that NA both affects and is affected by activity limitations and does not simply influence reporting.

When to use the Bonferroni correction

PURPOSE: The Bonferroni correction adjusts probability (p) values because of the increased risk of a type I error when making multiple statistical tests. The routine use of this test has been criticised as deleterious to sound statistical judgment, testing the wrong hypothesis, and reducing the chance of a type I error but at the expense of a type II error; yet it remains popular in ophthalmic research. The purpose of this article was to survey the use of the Bonferroni correction in research articles published in three optometric journals, viz. Ophthalmic & Physiological Optics, Optometry & Vision Science, and Clinical & Experimental Optometry, and to provide advice to authors contemplating multiple testing. RECENT FINDINGS: Some authors ignored the problem of multiple testing while others used the method uncritically with no rationale or discussion. A variety of methods of correcting p values were employed, the Bonferroni method being the single most popular. Bonferroni was used in a variety of circumstances, most commonly to correct the experiment-wise error rate when using multiple 't' tests or as a post-hoc procedure to correct the family-wise error rate following analysis of variance (anova). Some studies quoted adjusted p values incorrectly or gave an erroneous rationale. SUMMARY: Whether or not to use the Bonferroni correction depends on the circumstances of the study. It should not be used routinely and should be considered if: (1) a single test of the 'universal null hypothesis' (Ho ) that all tests are not significant is required, (2) it is imperative to avoid a type I error, and (3) a large number of tests are carried out without preplanned hypotheses.

An online study combining the constructs from the theory of planned behaviour and protection motivation theory in predicting intention to test for chlamydia in two testing contexts

Chlamydia is a common sexually transmitted infection that has potentially serious consequences unless detected and treated early. The health service in the UK offers clinic-based testing for chlamydia but uptake is low. Identifying the predictors of testing behaviours may inform interventions to increase uptake. Self-tests for chlamydia may facilitate testing and treatment in people who avoid clinic-based testing. Self-testing and being tested by a health care professional (HCP) involve two contrasting contexts that may influence testing behaviour. However, little is known about how predictors of behaviour differ as a function of context. In this study, theoretical models of behaviour were used to assess factors that may predict intention to test in two different contexts: self-testing and being tested by a HCP. Individuals searching for or reading about chlamydia testing online were recruited using Google Adwords. Participants completed an online questionnaire that addressed previous testing behaviour and measured constructs of the Theory of Planned Behaviour and Protection Motivation Theory, which propose a total of eight possible predictors of intention. The questionnaire was completed by 310 participants. Sufficient data for multiple regression were provided by 102 and 118 respondents for self-testing and testing by a HCP respectively. Intention to self-test was predicted by vulnerability and self-efficacy, with a trend-level effect for response efficacy. Intention to be tested by a HCP was predicted by vulnerability, attitude and subjective norm. Thus, intentions to carry out two testing behaviours with very similar goals can have different predictors depending on test context. We conclude that interventions to increase self-testing should be based on evidence specifically related to test context.

Probabilistic multiple model neural network based leak detection system:experimental study

This paper presents an effective decision making system for leak detection based on multiple generalized linear models and clustering techniques. The training data for the proposed decision system is obtained by setting up an experimental pipeline fully operational distribution system. The system is also equipped with data logging for three variables; namely, inlet pressure, outlet pressure, and outlet flow. The experimental setup is designed such that multi-operational conditions of the distribution system, including multi pressure and multi flow can be obtained. We then statistically tested and showed that pressure and flow variables can be used as signature of leak under the designed multi-operational conditions. It is then shown that the detection of leakages based on the training and testing of the proposed multi model decision system with pre data clustering, under multi operational conditions produces better recognition rates in comparison to the training based on the single model approach. This decision system is then equipped with the estimation of confidence limits and a method is proposed for using these confidence limits for obtaining more robust leakage recognition results.

Early design verification of complex assembly variability using a hybrid - model based and physical testing - methodology

Design verification in the digital domain, using model-based principles, is a key research objective to address the industrial requirement for reduced physical testing and prototyping. For complex assemblies, the verification of design and the associated production methods is currently fragmented, prolonged and sub-optimal, as it uses digital and physical verification stages that are deployed in a sequential manner using multiple systems. This paper describes a novel, hybrid design verification methodology that integrates model-based variability analysis with measurement data of assemblies, in order to reduce simulation uncertainty and allow early design verification from the perspective of satisfying key assembly criteria.

Successful development and testing of a Method for Aggregating The Reporting of Interventions in Complex Studies (MATRICS)

Objectives: To develop a tool for the accurate reporting and aggregation of findings from each of the multiple methods used in a complex evaluation in an unbiased way. Study Design and Setting: We developed a Method for Aggregating The Reporting of Interventions in Complex Studies (MATRICS) within a gastroenterology study [Evaluating New Innovations in (the delivery and organisation of) Gastrointestinal (GI) endoscopy services by the NHS Modernisation Agency (ENIGMA)]. We subsequently tested it on a different gastroenterology trial [Multi-Institutional Nurse Endoscopy Trial (MINuET)]. We created three layers to define the effects, methods, and findings from ENIGMA. We assigned numbers to each effect in layer 1 and letters to each method in layer 2. We used an alphanumeric code based on layers 1 and 2 to every finding in layer 3 to link the aims, methods, and findings. We illustrated analogous findings by assigning more than one alphanumeric code to a finding. We also showed that more than one effect or method could report the same finding. We presented contradictory findings by listing them in adjacent rows of the MATRICS. Results: MATRICS was useful for the effective synthesis and presentation of findings of the multiple methods from ENIGMA. We subsequently successfully tested it by applying it to the MINuET trial. Conclusion: MATRICS is effective for synthesizing the findings of complex, multiple-method studies.