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PubMed2005

Molecular testing of multiple HIV-1 transmissions in a criminal case.

OBJECTIVE: To test the a priori hypothesis of HIV-1 transmission from one suspect to six recipients in a criminal case. METHODS: Partial pol and/or env sequences were obtained for at least two samples of the suspect and the victims. Appropriate local controls were sampled based on epidemiological and subtype criteria. Phylogenetic testing was performed using different reconstruction methods. RESULTS: Phylogenetic analyses consistently inferred a monophyletic cluster for the suspect and victim samples in both genome regions. This was highly supported by parametric and non-parametric bootstrapping techniques. Moreover, the controls most closely related to the suspect-victim cluster had a similar geographical origin to the suspect. CONCLUSIONS: Taking into account the limitations on the conclusions that can be drawn from molecular investigations we could infer that our molecular data is consistent with a scenario of multiple HIV transmission between suspect and victims.

Bayes Theorem↗

PubMed1995

The use of multiple-choice tests in anatomy: common pitfalls and how to avoid them.

Multiple-choice questions (MCQ) are widely used to evaluate students in the health sciences, including anatomy. Unusual responses in 90 simple MCQ examinations have been identified and classified as to cause, including a number of illustrated examples. About one-quarter of these errors were attributable to the teacher and could have been avoided by a critical analysis of the questions before use. The increasing use of sophisticated formats of the MCQ in medical education indicates that teachers need to analyze their questions more carefully before and after actual tests to minimize errors.

Anatomy↗

PubMed2005

Using human microarrays to identify differentially expressed genes associated with increased steroidogenesis in boars.

Human microarrays are readily available, and it would be advantageous if they could be used to study gene expression in other species, such as pigs. The objectives of this research were to validate the use of human microarrays in the analysis of porcine gene expression, to assess the variability of the data generated, and to compare gene expression in boars with different levels of steroidogenesis. Cytochrome b5 (CYB5) expression was used to assess array detection sensitivity. Samples having high or low CYB5 RNA levels were hybridized to microarrays to determine if the known expression difference could be detected. Six hybridizations were conducted using human microarrays containing 3840 total spots representing 1718 characterized human ESTs. To analyze gene expression in boars with different levels of steroidogenesis, testis RNA from four boars with high levels of plasma estrone sulphate was hybridized to testis RNA from four boars with lower levels. Eight microarray hybridizations were conducted including fluor-flips. Self-self hybridizations were also conducted to assess the variability of array experiments. The Cy5 and Cy3 intensity values for each array were normalized using a locally weighted linear regression (LOESS). Statistical significance was assessed using a Student's t-test followed by the Benjamini and Hochberg multiple testing correction procedure. Quantitative real-time PCR (Q-RT-PCR) was used to verify select gene expression differences. The results show that CYB5 was significantly overexpressed in the high CYB5 sample by 1.8 fold (P < 0.05), verifying the known expression difference. The average log2 ratio of the majority of genes (1643) falls within one standard deviation of the mean, indicating the data were reproducible. In the high versus low steroidogenesis experiment, seven genes were significantly overexpressed in the high group (P < 0.05). Quantitative real-time PCR was used to validate five genes with the highest fold change, and the results corroborated those found by the microarray experiments. The results of the self-self hybridizations showed that no genes were significantly differentially expressed following the application of the Benjamini and Hochberg multiple testing correction procedure. The results presented in this report show that human arrays can be used for gene expression analysis in pigs.

Animals↗

PubMed1995

Diagnostic value of paraclinical tests in multiple sclerosis: relative sensitivities and specificities for reclassification according to the Poser committee criteria.

The yield of paraclinical tests was evaluated in a prospective study of 189 consecutive patients referred for suspected multiple sclerosis (142 patients with multiple sclerosis, 47 non-multiple sclerosis patients on discharge). Patients were first classified according to the Poser criteria by the clinical findings. Subsequently, the results of paraclinical tests (cranial MRI, visually evoked potentials (VEPs), somatosensory evoked potentials by tibial nerve stimulation (SSEPs), motor evoked potentials (MEPs), and analysis of CSF for oligoclonal banding and IgG-index (CSF)) were taken into account. The percentage of reclassified patients (reclassification sensitivity, RS) was always lower than the percentage of abnormal results (diagnostic sensitivity, DS), and the divergence of RS v DS differed between the tests (60% v 84% in MRI, 31% v 77% in CSF, 29% v 37% in VEPs, 20% v 68% in MEPs, and 12% v 46% in SSEPs respectively). False reclassifications of non-multiple sclerosis patients to multiple sclerosis would have occurred with all tests (MRI: six of 47 patients, (reclassification specificity 88%); CSF: one (98%); VEPs: two (96%); MEPs: two (96%); SSEPs: four (91%); P < 0.05). Although MRI had superior diagnostic capacity, 57 of the 142 patients with multiple sclerosis were not reclassified by the MRI result, 12 of whom were reclassified by CSF and 18 by one of the evoked potential (EP) studies. Of the 98 patients not reclassified by CSF, 53 were reclassified by MRI and 39 by EPs. The results suggest that for the evaluation of paraclinical tests in suspected multiple sclerosis, comparison of diagnostic sensitivities is inappropriate. In general, a cranial MRI contributes most to the diagnosis; however, due to its comparatively low specificity and its considerable number of negative results, EP or CSF studies are often useful to establish the diagnosis of multiple sclerosis.

Adolescent↗

PubMed2002

The emergence of item-specific encoding effects in between-subjects designs: perceptual interference and multiple recall tests.

The perceptual-interference effect occurs when interference with word perception (by backward masking) enhances later memory for the word. In terms of the item-specific-relational framework (Hunt & McDaniel, 1993), this effect is similar to other manipulations that enhance item-specific encoding (such as the generation effect). One similarity is that item-specific effects typically do not arise in between-subjects designs. However, the present experiment demonstrates that a between-subjects perceptual-interference effect emerges over multiple recall tests. Furthermore, perceptual interference produces both more intertest gains (indexing enhanced item-specific processing) and more intertest losses (indexing disrupted relational encoding) compared with the intact (control) condition. Finally, delaying the mask to a point at which it no longer interferes with perception (266 msec) eliminates both the perceptual-interference recall advantage and the increase in intertest gains. This condition still produces more intertest losses, however. Together, these results imply that a delayed mask disrupts relational encoding but produces no item-specific enhancement, dissociating the two effects of the perceptual-interference manipulation.

Attention↗

PubMed2005

Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.

BACKGROUND: Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited. METHODS AND RESULTS: In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n=1446) or hyperemic flow velocity (n=1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured >80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P=0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes. CONCLUSIONS: A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs.

Aged↗

PubMed2004

A Bayesian approach to estimate and validate the false negative fraction in a two-stage multiple screening test.

OBJECTIVES: In estimating sensitivity and specificity of a diagnostic kit it is imperative that all study subjects are verified via a gold standard procedure. However the application of such a procedure to all the study subjects may not be feasible due to associated cost, risk and invasiveness. As a result only a part of the study subjects receive the definitive assessment. The accuracy of a diagnostic kit can also be expressed in terms of its error rates. Our first objective is to estimate the false negative fraction (FNF) under partial verification in a particular case of a two-stage multiple screening test using a beta-binomial model and a Bayesian logistic model. The second objective is to validate the two models in order to determine which fits the data better. METHODS: We estimate the FNF from the above mentioned models using Bayesian approach. The validation of the models is based on their out-of-sample predictive capabilities. RESULTS: For the bowel cancer data that was used in this study we found the median posterior estimate of the FNF, based on the beta-binomial model, to be 26.4% (95% credible interval: 0.123-0.650). The corresponding estimate based on the Bayesian logistic model was 23.3% (95% credible interval: 0.124-0.375). Validation results showed that the betabinomial model gave slightly better predictions compared to the Bayesian logistic model. CONCLUSIONS: Estimation of the FNF can be done by adopting the Bayesian approach. Models fitted can be validated by comparing their performance in terms of their out-of-sample predicitve potential.

Bayes Theorem↗

PubMed2003

Decision making under internal uncertainty: the case of multiple-choice tests with different scoring rules.

This paper assesses framing effects on decision making with internal uncertainty, i.e., partial knowledge, by focusing on examinees' behavior in multiple-choice (MC) tests with different scoring rules. In two experiments participants answered a general-knowledge MC test that consisted of 34 solvable and 6 unsolvable items. Experiment 1 studied two scoring rules involving Positive (only gains) and Negative (only losses) scores. Although answering all items was the dominating strategy for both rules, the results revealed a greater tendency to answer under the Negative scoring rule. These results are in line with the predictions derived from Prospect Theory (PT) [Econometrica 47 (1979) 263]. The second experiment studied two scoring rules, which allowed respondents to exhibit partial knowledge. Under the Inclusion-scoring rule the respondents mark all answers that could be correct, and under the Exclusion-scoring rule they exclude all answers that might be incorrect. As predicted by PT, respondents took more risks under the Inclusion rule than under the Exclusion rule. The results illustrate that the basic process that underlies choice behavior under internal uncertainty and especially the effect of framing is similar to the process of choice under external uncertainty and can be described quite accurately by PT.

Choice Behavior↗

PubMed1981

Exact significance levels for multiple binomial testing with application to carcinogenicity screens.

A simple experimental design consisting of one control group and one or more treatment groups is considered. Relevant research often focuses on the presence or absence of any of several characteristics in the treatment group(s). The statistical analysis frequently includes the comparison of the control group with each treatment group by the use of Fisher-Irwin exact tests for each of many 2 x 2 tables. The multiplicity of comparisons has given rise to concern that individual Fisher-Irwin tests could seriously overstate the experimental evidence in some situations. This paper provides a method for calculating the exact permutational probability of at least one significant Fisher-Irwin test when only one treatment group and one control group is used. For multiple-treatment-group designs, upper and lower bounds on the probability are provided. Emphasis is given throughout to carcinogenesis screening experiments and an example of such an experiment is provided.

Animals↗

PubMed2006

Expanding an existing multiple choice test with a mixed format test: simulation study on sample size and item recovery in concurrent calibration.

When a new set of mixed format items is augmented with a previous old multiple-choice (MC) test, those mixed format items should be linked to the existing old MC test. This study used simulation to investigate sample size effect on recovery of known item parameter from the concurrent calibration in the context of horizontal equating, where the new mixed format tests are equated to the existing MC test which acts as the common linking items. In the partial credit model following the Andrich style parameterization, item location and item step parameters were differentially affected by the sample size. Item location parameters were recovered better than item step parameters at the individual item, the sub-test, and the total test level. This study also shows the outward bias for the item location parameter estimated by the maximum likelihood estimator.

Educational Measurement↗

PubMed1995

Two-dimensional protein electrophoresis and multiple hypothesis testing to detect potential serum protein biomarkers in children with fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) surveillance and intervention efforts are hampered by the lack of a specific biochemical test for diagnosis of the syndrome. Based on the hypothesis that abnormalities in growth and development (key features of FAS) involve altered protein metabolism, we analyzed serum proteins by two-dimensional gel electrophoresis and image analysis to search for potential protein biomarkers of FAS. Serum samples from 12 participants in whom FAS had been diagnosed and 8 sex- and age-matched participants whose mothers did not consume alcohol were analyzed in duplicate to determine whether the integrated intensities of matched proteins are significantly altered in children with FAS. Multiple hypothesis testing on 34 of the gels consisting of more than 1700 spots per gel revealed 21 proteins that we classified as potential protein biomarkers of FAS on the basis of significant t-test differences at p < 0.02. We classified 8 of the proteins as candidate biomarkers on the basis of significant concentration differences between case and control subjects at p < 0.01. One of the proteins is clearly an isoform of retinol binding protein; two appear in the area of the gel where alcohol dehydrogenase is expected to appear; one appears to be an isoform of alpha-1-antitrypsin; three appear to be isoforms of the beta-chain of haptoglobin; three may be forms of immunoglobulin light chains; and several others have not been associated with known proteins. No single protein differentiated all case subjects from control subjects, but stepwise canonical discriminant analyses revealed four groups of spots that distinguished between FAS case and control subjects with no misclassifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗

PubMed2006

Detecting local high-scoring segments: a first-stage approach for genome-wide association studies.

Genetic epidemiology aims at identifying biological mechanisms responsible for human diseases. Genome-wide association studies, made possible by recent improvements in genotyping technologies, are now promisingly investigated. In these studies, common first-stage strategies focus on marginal effects but lead to multiple-testing and are unable to capture the possibly complex interplay between genetic factors. We have adapted the use of the local score statistic, already successfully applied to analyse long molecular sequences. Via sum statistics, this method captures local and possible distant dependences between markers. Dedicated to genome-wide association studies, it is fast to compute, able to handle large datasets, circumvents the the multiple-testing problem and outlines a set of genomic regions (segments) for further analyses. Applied to simulated and real data, our approach outperforms classical Bonferroni and FDR corrections for multiple-testing. It is implemented in a software termed LHiSA for Local High-scoring Segments for Association and available at: http://stat.genopole.cnrs.fr/software/lhisa.

Algorithms↗

PubMed2004

Multivariate search for differentially expressed gene combinations.

BACKGROUND: To identify differentially expressed genes, it is standard practice to test a two-sample hypothesis for each gene with a proper adjustment for multiple testing. Such tests are essentially univariate and disregard the multidimensional structure of microarray data. A more general two-sample hypothesis is formulated in terms of the joint distribution of any sub-vector of expression signals. RESULTS: By building on an earlier proposed multivariate test statistic, we propose a new algorithm for identifying differentially expressed gene combinations. The algorithm includes an improved random search procedure designed to generate candidate gene combinations of a given size. Cross-validation is used to provide replication stability of the search procedure. A permutation two-sample test is used for significance testing. We design a multiple testing procedure to control the family-wise error rate (FWER) when selecting significant combinations of genes that result from a successive selection procedure. A target set of genes is composed of all significant combinations selected via random search. CONCLUSIONS: A new algorithm has been developed to identify differentially expressed gene combinations. The performance of the proposed search-and-testing procedure has been evaluated by computer simulations and analysis of replicated Affymetrix gene array data on age-related changes in gene expression in the inner ear of CBA mice.

Aging↗

PubMed2003

Ensemble averaging and multiple statistical testing of EMG activities of cyclically repeated body motions. A tool for muscle function analysis in experimental and clinical orthopaedics.

Coupled with suitable computerized signal recording and processing methods surface electromyography can be a powerful tool for the analysis of muscle activity in specific body movements. It can be used for this purpose in experimental and in clinical diagnostic orthopaedics as well as in physiotherapy. We describe in this paper a motion analysis system comprising this feature. It has been employed for the diagnosis of the basic angular kinematics and muscle function in human gait and other cyclically repeatable movements of the human locomotive system. Changes in the temporal characteristics of the movements and the muscle activity due to changed physical or experimental conditions can be systematically investigated this way. Such changes can be the result of surgical and/or conservative orthopaedic therapy, a long term physiotherapeutic program, or modified walking conditions as in experimental orthopaedics. They are displayed and validated by signal ensemble averaging and subsequent multiple statistical testing (e.g. by a suitably adapted Bonferroni criterion). The efficiency of the system is demonstrated by an exemplary gait analysis of selected kinematic and muscular effects caused by an experimental simulation of a leg length inequality.

Algorithms↗

PubMed1977

Multiple skin testing of tuberculosis patients with a range of new tuberculins, and a comparison with leprosy and Mycobacterium ulcerans infection.

Four hundred and seventy tuberculosis patients were each skin tested with four of a range of 17 mycobacterial reagents in four countries in all of which tuberculosis and leprosy were endemic. Sixteen of the reagents were new tuberculins prepared from extracts of living mycobacteria disrupted by ultrasonic disintegration and the last was PPD, RT23.The effect that tuberculosis exerted on the delayed-type skin test response to these antigens was assessed by comparing results for tuberculosis patients with those for Tuberculin positive and Tuberculin negative control populations. Tuberculosis patients on Rifampicin therapy showed no difference in their skin test responses to any of the antigens from those patients on other forms of antituberculosis treatment.Amongst the normal population it was found that possession of Tuberculin positivity was associated with an enhanced response to all the other mycobacterial antigens with the exception of A(*)-in which demonstrated a reciprocal relationship with Tuberculin in Burma. It was also noted, in Burma particularly, that sensitization to mycobacterial species other than Mycobacterium tuberculosis, especially to the slow growers, plays a role in determining responses to different mycobacterial species.In tuberculosis patients enhanced skin test responses were also seen but only in those countries, e.g. Libya, where the prevalence of mycobacterial species was low. Where mycobacteria were common, as in Burma, the converse was true and tuberculosis was associated with a diminished skin test response to each antigen. The high prevalence of A(*)-in positivity in Burma, its reciprocal relationship with Tuberculin there and the results for all the antigens in the tuberculosis patients indicate that the cell mediated skin test response may have a threshold. If this is exceeded the skin test becomes negative so that non-reactors then include those who have been excessively sensitized as well as those who have not been sensitized. Despite this, a greater percentage of tuberculosis patients in each country responded to the specific reagent Tuberculin than did the control populations and their mean positive induration sizes were consistently larger. Nevertheless, amongst the tuberculosis patients in Burma 13% were complete non-reactors to Tuberculin and this apparent anergy also applied to the other reagents with which these individuals were tested.This differs from lepromatous leprosy where the anergic state pertains exclusively to M. leprae and a few seemingly closely related species. The breadth of anergy in M. ulcerans infection has not been measured but it is known to effect both Burulin and the PPD, RT23.Just as in leprosy and M. ulcerans infection, tuberculosis can be shown to have a disease spectrum here detected by multiple skin testing. The significance of this spectrum and its similarities with and differences from that of the other mycobacterioses is discussed.

Adolescent↗

PubMed1984

The 'flight of colours' test in multiple sclerosis, retrobulbar neuritis and healthy controls.

The results of the test for afterimages ('flight of colours'; FOC) in healthy controls, MS patients and persons with a history of retrobulbar neuritis are presented. The FOC proved to be a reliable test of involvement of the visual system in these diseases. This concerns the duration of the afterimages as well as the palette of colours. The results were in accordance with those of the VEP, provided patients with a retrobulbar neuritis more than three years ago were omitted. In these persons the FOC proved to be more sensitive than the flash-VEP in detecting old lesions. It was concluded that these methods measure different aspects of the visual system.

Adult↗

PubMed1997

Employing computer technology to assess visual attention in young children and adolescents with severe mental retardation.

The intent of this investigation was to establish a valid and sensitive computer measurement technique for educational assessment applications. An integral part of the investigation was to establish the similarities and differences in how prior reinforcement histories of individual stimuli affect attention to compound visual cues for young children of normal development versus adolescents with severe mental retardation, both groups having comparable mental age. A series of identical conflict compound discrimination tasks was presented to the two groups. In addition, generalization effects were investigated for both groups by presenting compounds containing some or all novel cues. The similarities and differences in performance for young children of normal development and adolescents with severe mental retardation were analyzed using multiple testing procedures. In addition to assessing stimulus control by presenting stimulus components separately following acquisition of compound discriminations, response topographies of the compound stimuli were recorded with a touch screen attached to a computer monitor screen. This study demonstrated that overselective attention did not occur only for students with severe mental retardation but also for young children of normal development if multiple tests were employed. A difference was found, however, between the two populations in the efficiency with which they shifted attention among elements of complex stimuli depending on prior conditioning histories. Presentation of compounds whose components had conflicting reinforcement histories was found to be a more sensitive assessment technique than presentation of compounds containing some or all novel components for distinguishing between the two groups. The use of multiple testing procedures was critical in preventing false conclusions from altered test performances arising from reinforcement contingencies in effect during the test.

Adolescent↗

PubMed1986

Auditory brain stem response test battery for multiple sclerosis patients: evaluation of test findings and assessment of diagnostic criteria.

A battery of auditory brain stem response (ABR) tests has been used to evaluate 39 multiple sclerosis (MS) subjects (9 with probable, 8 with possible, 6 with suspected and 16 with definite MS, according to conventional classification of the disease). Test battery included evaluation of ABR waveform, latencies and interpeak intervals, test-retest variability, rate-induced ABR changes, binaural increase of wave-V amplitude and effect of ipsilateral masking with broad-band noise. Test results allowed a measure of the sensitivity, specificity and efficiency of each test in the battery. The high efficiency values thus obtained validated each test in the battery when normals were compared with definite MS patients. No single test, however, proved to be sufficient--by itself--to reliably distinguish subjects with earlier stages of the disease, suggesting that a combined evaluation of tests is necessary to fit better the clinical classification. When compared with 'conventional' ABR analysis, 'sensitized' ABR tests--i.e. the measures of test-retest variability, binaural increase of wave-V amplitude and the effect of ipsilateral broad-band noise masking--showed higher percentages of positive results in subjects with no clinical signs of brainstem and midbrain involvement. Sensitized tests therefore appeared more suitable to reveal a brainstem subclinical involvement.

Adolescent↗