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PubMed2002

Assessment of differential gene expression in human peripheral nerve injury.

BACKGROUND: Microarray technology is a powerful methodology for identifying differentially expressed genes. However, when thousands of genes in a microarray data set are evaluated simultaneously by fold changes and significance tests, the probability of detecting false positives rises sharply. In this first microarray study of brachial plexus injury, we applied and compared the performance of two recently proposed algorithms for tackling this multiple testing problem, Significance Analysis of Microarrays (SAM) and Westfall and Young step down adjusted p values, as well as t-statistics and Welch statistics, in specifying differential gene expression under different biological states. RESULTS: Using SAM based on t statistics, we identified 73 significant genes, which fall into different functional categories, such as cytokines / neurotrophin, myelin function and signal transduction. Interestingly, all but one gene were down-regulated in the patients. Using Welch statistics in conjunction with SAM, we identified an additional set of up-regulated genes, several of which are engaged in transcription and translation regulation. In contrast, the Westfall and Young algorithm identified only one gene using a conventional significance level of 0.05. CONCLUSION: In coping with multiple testing problems, Family-wise type I error rate (FWER) and false discovery rate (FDR) are different expressions of Type I error rates. The Westfall and Young algorithm controls FWER. In the context of this microarray study, it is, seemingly, too conservative. In contrast, SAM, by controlling FDR, provides a promising alternative. In this instance, genes selected by SAM were shown to be biologically meaningful.

Journal Article↗
PubMed2003

[Junior physicians' acquisition of theoretical knowledge at a surgical department. Evaluation in the form of multiple-choice tests].

INTRODUCTION: Denmark has no tradition of formal assessment of junior doctors' theoretical knowledge. We therefore wanted to investigate whether the knowledge of surgical junior doctors has actually increased. MATERIAL AND METHODS: Twenty-three junior doctors were confronted with the same multiple-choice questionnaires twice during a six months period. Subsequently, they were asked whether they would approve the implementation of multiple-choice questionnaires and formal assessment (exam) in the Danish specialist training in surgery. RESULTS: The participants got a significantly higher score the second time they were confronted with the multiple-choice questionnaires (p = 0.0003). When dividing the participants into two groups, viz. young vs. old junior doctors, it was observed that the latter group had a higher score overall but augmented their scores less in relation to their young colleagues (p = 0.038). Forty percent of the participants replied that the multiple-choice questionnaires had motivated them to do further theoretical studies, and half of them approved the introduction of an exam in surgery in the Danish specialist training. DISCUSSION: The theoretical knowledge of junior doctors does actually increase in a relatively short period of time during their employment at a department of surgery. As expected the old junior doctors got a higher score compared to their young colleagues. However, the latter group augments its knowledge relatively more. Multiple-choice questionnaires are easy, accessible, and inexpensive tools for evaluation as well as stimulation for doing further theroretical studies.

Clinical Competence↗
PubMed2004

Pairwise multiple comparison test procedures: an update for clinical child and adolescent psychologists.

Locating pairwise differences among treatment groups is a common practice of applied researchers. Articles published in this journal have addressed the issue of statistical inference within the context of an analysis of variance (ANOVA) framework, describing procedures for comparing means, among other issues. In particular, 1 article (Jaccard & Guilamo-Ramos, 2002b) presented some new methods of performing contrasts of means whereas another presented a framework for obtaining robust tests within this same context (Jaccard & Guilamo-Ramos, 2002a). The purpose of this article is to add to these contributions by presenting some newer methods for conducting pairwise comparisons of means, that is by extending the contributions of the first article and applying the framework of the second article to pairwise multiple comparisons. The newer methods are intended to provide additional sensitivity to detect treatment group differences and provide tests that are robust to the effects of variance heterogeneity, nonnormality, or both.

Adolescent↗
PubMed2006

A hypothesis test for the end of a common source outbreak.

The objective of this article is to develop a hypothesis-testing procedure to determine whether a common source outbreak has ended. We consider the case when neither the calendar date of exposure to the pathogen nor the exact incubation period distribution is known. The hypothesis-testing procedure is based on the spacings between ordered calendar dates of disease onset of the cases. A simulation study was performed to evaluate the robustness of the methods to various models for the incubation period of infectious diseases. We investigated the impact of multiple testing on the overall outbreak-wise type I error probability. We derive expressions for the outbreak-wise type I error probability and show that multiple testing has minimal effect on inflating that error probability. The results are discussed in the context of the 2001 U.S. anthrax outbreak.

Anthrax↗
PubMed2006

Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1.

We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.

Alleles↗
PubMed2005

Growth hormone response to arginine test distinguishes multiple system atrophy from Parkinson's disease and idiopathic late-onset cerebellar ataxia.

OBJECTIVE: Multiple system atrophy (MSA) is difficult to distinguish from idiopathic Parkinson's disease (PD) and idiopathic late-onset cerebellar ataxia (ILOCA). This study aimed to evaluate GH response to three different GH stimulation tests in order to establish a reliable test to differentiate these degenerative disorders. DESIGN: Twelve patients with MSA, 10 with PD, eight with ILOCA and 30 healthy controls entered the study. They were submitted to clonidine, arginine, and GH-releasing-hormone (GHRH) + arginine tests in a random manner on three different nonconsecutive days. The peak serum GH response was used as a primary variable for analysis of stimulation tests. By ROC analysis, the optimum cut-off level was considered as the cut-off with the maximal sum of sensitivity and specificity. RESULTS: After clonidine administration, GH peak was significantly lower in patients with MSA than in those with ILOCA (P < 0.05) and in the controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the clonidine test distinguished patients with MSA from those with PD with a sensitivity and specificity of 78%. Moreover, this test distinguished patients with MSA from those with ILOCA with a sensitivity of 100% and a specificity of 75% at a cut-off level of 5 mU/l, and with a sensitivity of 75% and a specificity of 100% at the cut-off level of 7.6 mU/l. After arginine administration, the GH peak was significantly lower in patients with MSA than in those with ILOCA (P = 0.001) and in controls (P < 0.001). At the optimum cut-off level of 5 mU/l, the arginine test distinguished patients with MSA from those with PD with a sensitivity and a specificity of 100%. At a GH peak cut-off value of 3.6 mU/l the arginine test distinguished patients with MSA from those with ILOCA with a sensitivity and specificity of 100%. After GHRH + arginine administration, a significant GH increase was found in all groups of patients and controls. CONCLUSIONS: The GH response to arginine administration is impaired in MSA. Therefore, the arginine test showed the highest diagnostic accuracy to distinguish MSA from both PD and ILOCA, and could be used in the clinical practice of these neurodegenerative diseases.

Arginine↗
PubMed2005

Nonparametric methods for analysing the accuracy of diagnostic tests with multiple readers.

The evaluation of diagnostic agents or imaging procedures is governed by the same scientific and regulatory rules as that of other medical products. Receiver operating characteristic (ROC) curves, and especially the area under these ROC curves, are indices for the accuracy of a diagnostic test for continuous as well as ordinal data. The methodology of multivariate rank statistics for the nonparametric Behrens-Fisher problem is used to evaluate the accuracy of a diagnostic test in a complex factorial design with repeated measurements. Hypotheses are formulated by means of relative treatment effects and are tested by a multivariate extension of the Mann-Whitney statistic in a heteroscedastic model. The application of this method is demonstrated by the analysis of a data set from a diagnostic clinical trial.

Biometry↗
PubMed1995

Model-free association analysis of a rare disease.

Model-free methods of testing for association of a disease with alleles at a marker locus were used to analyze simulated data for a rare disease locus and 360 marker loci distributed at 2 cM intervals along six chromosomes. After adjustment for multiple tests, there was no evidence of significant heterogeneity of parental allele frequencies between a sample of parents with at least one affected child and a sample of parents with no affected children. Several significant deviations from Hardy-Weinberg equilibrium were detected after Bonferroni correction but these were Type I errors. After adjusting for multiple tests, the model-free test for association detected significant associations of alleles at two loci with the disease. These associations were in fact part of the generating model for the simulated data. However, these methods were unable to detect two other major loci contributing to the disease since these loci were not associated with any of the marker loci.

Alleles↗
PubMed1993

[Paraclinical tests in multiple sclerosis. Clinical correlation and predictive value].

The correlation between clinical signs and symptoms, Evoked Potentials (EP) and Magnetic Resonance Imaging (MRI) in Multiple Sclerosis (MS) is still uncertain. It seems necessary to perform comparative studies with homogeneous groups of patients to avoid the error provoked by the selection of patients and the use in the diagnosis of EP and MRI. The aims of this paper were to calculate the sensitivity of EP and MRI in MS in relation to time of evolution and type of MS, to determine the correlation between clinical data and EP and MRI alterations, and to show the predictive value of the paraclinical tests. We have performed clinical examination, EP and MRI in 47 patients with clinically definite MS, Poser's category 1a, without acute attack. Our results show significant correlation between VEP and visual functional scale (FS) (r = 0.43), brainstem auditory EP (BAEP) and Expanded Disability Status Scale (EDSS) (r = 0.33), BAEP and cerebellar FS (r = 0.36), BAEP and brainstem FS (r = 0.29) and somatosensory EP (SEP) and pyramidal FS (r = 0.4). Also, we found significant correlation among clinical data and MRI abnormalities in cerebellum (p < 0.01), brainstem (p < 0.001), and spinal cord (p < 0.01). The SEP (74%), cerebellar (92%) and spinal (83%) MRI alterations provided the greatest agreement with presumed clinical abnormalities. These data confirm the efficacy of EP and MRI to describe the status of MS and support its utility to evaluate the evolution.

Adolescent↗
PubMed2004

Augmentation procedures for control of the generalized family-wise error rate and tail probabilities for the proportion of false positives.

This article shows that any single-step or stepwise multiple testing procedure (asymptotically) controlling the family-wise error rate (FWER) can be augmented into procedures that (asymptotically) control tail probabilities for the number of false positives and the proportion of false positives among the rejected hypotheses. Specifically, given any procedure that (asymptotically) controls the FWER at level alpha, we propose simple augmentation procedures that provide (asymptotic) level-alpha control of: (i) the generalized family-wise error rate, i.e., the tail probability, gFWER(k), that the number of Type I errors exceeds a user-supplied integer k, and (ii) the tail probability, TPPFP(q), that the proportion of Type I errors among the rejected hypotheses exceeds a user-supplied value 0<q<1. Existing approaches for control of the proportion of false positives typically rely on the assumption that the test statistics are independent, while our proposed augmentation procedures control the gFWER and TPPFP for general data generating distributions, with arbitrary dependence structures among variables. Applying the augmentation methods to step-down multiple testing procedures that control the FWER asymptotically exactly at level alpha (van der Laan et al., 2004), yields procedures that also provide exact asymptotic control of the gFWER and TPPFP at level alpha. The adjusted p-values for the gFWER and TPPFP-controlling augmentation procedures are shown to be simple functions of the adjusted p-values for the original FWER-controlling procedure. Finally, two simple conservative procedures are proposed for controlling the false discovery rate.

Journal Article↗
PubMed1992

Inhalant allergens in asthmatic children in Taiwan: comparison evaluation of skin testing, radioallergosorbent test and multiple allergosorbent chemiluminescent assay for specific IgE.

The multiple allergosorbent chemiluminescent assay (MAST-CLA) is a method for measuring total and allergen-specific IgE in human serum by a chemiluminescent immuno-enzymatic system. To compare the results of MAST tests with those of radioallergosorbent (RAST) and skin tests as an adjunct to the diagnosis of inhalant allergens in Taiwan, 195 asthmatic children, aged 5 to 15 years, were studied. All MAST tests had valid positive and negative control threads. The most important allergens in our patients were the two mite species: Dermatophagoid pteronyssinus and Dermatophagoid farinae (87.5% and 82.1%, respectively). There were also large responses (MAST-CLA class > or = 2) to the cockroach mix (28.45%), Alternaria (24.3%), and Eucalyptus (32.6%). The individual efficiency percentage between MAST-CLA and skin tests was D. pteronyssinus 91%, D. farinae 88%, cockroach mix 85%, feather mix 75%, dog dander 64%, Candida 75%, Aspergillus 79%, Alternaria 88%, ragweed mix 62% and Eucalyptus 76%. Comparison of the results of allergen-specific IgE measured by MAST-CLA and RAST were also significantly correlated for all four allergens (D. farinae, Candida, Alternaria and grass mix, r = 0.79-0.92). MAST-CLA was randomly duplicated and proven reproducible in 89% of the tests. Changes between positive and negative results occurred in only 3.6% of the tests. MAST-CLA is a simple in vitro test for specific IgE to 35 allergens, which compares favorably with RAST. It is concluded that MAST-CLA and RAST are similar in their ability to measure allergen-specific IgE, and correlate equally well with skin tests and clinical history in asthmatic children.

Administration, Inhalation↗
PubMed2026

Sex- and age-specific associations of VEGFA polymorphisms with multiple sclerosis susceptibility.

AIM: To evaluate six VEGFA polymorphisms (rs1570360, rs699947, rs3025033, rs2146323, rs1413711 and rs833061) and serum VEGFA concentrations in 270 Lithuanian patients with multiple sclerosis (MS) and 270 matched healthy controls. METHODS: Genotyping was performed using real-time PCR, and serum VEGFA levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were conducted using IBM SPSS version 31.0. RESULTS: Nominal differences in VEGFA genotype and allele distributions were observed in sex- and age-stratified analyses. Among females, the rs1413711 C allele was more frequent (p&#x2009;=&#x2009;0.005), whereas the rs833061 C allele was less frequent (p&#x2009;=&#x2009;0.006), in MS patients than controls. In participants aged >38 years, the rs1413711 C allele was also more frequent in MS cases (57.5% vs. 46.0%, p&#x2009;=&#x2009;0.008). Logistic regression identified nominal associations, particularly for rs1413711, rs699947 and rs833061, but none remained significant after correction for multiple testing. Serum VEGFA levels were higher in MS patients than controls (p&#x2009;=&#x2009;0.004). Nominal genotype-related differences in serum VEGFA levels and haplotype associations with reduced MS odds were also observed, but did not remain significant after multiple-testing correction. No consistent associations were found between VEGFA variants and clinical parameters. CONCLUSION: VEGFA genetic variation and elevated serum VEGFA may be associated with MS, but the genetic findings require confirmation in larger independent cohorts.

Humans↗