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How vascular surgeons use noninvasive testing.

A questionnaire was used to determine the patterns of use of noninvasive testing by vascular surgeons. The 494 respondents had been in practice an average of 18 years. Many of the examinations were done outside the office; 85% of laboratories used were hospital facilities. In the area of cerebrovascular testing the ocular pneumoplethysmographic techniques and the periorbital Doppler test continued to be used extensively; however, the acceptance of new technology was confirmed by the finding that 71% used some form of imaging. Arterial insufficiency of the legs was most commonly evaluated with segmental Doppler pressures and stress testing was used only in selected cases. Noninvasive tests were widely used postoperatively for the follow-up of patients. Most venous testing was aimed at the detection of acute deep venous thrombosis, and venous Doppler examination and impedance phlebography were the most widely used techniques. The data from this study document the patterns of use of the vascular laboratory. Unexpected findings included the widespread use of imaging (especially duplex scanning) and the frequent use of multiple tests for cerebrovascular evaluation.

Arteries↗

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Adult↗

Spatiotemporal localization of significant activation in MEG using permutation tests.

We describe the use of non-parametric permutation tests to detect activation in cortically-constrained maps of current density computed from MEG data. The methods are applicable to any inverse imaging method that maps event-related MEG to a coregistered cortical surface. To determine an appropriate threshold to apply to statistics computed from these maps, it is important to control for the multiple testing problem associated with testing 10's of thousands of hypotheses (one per surface element). By randomly permuting pre- and post-stimuius data from the collection of individual epochs in an event related study, we develop thresholds that control the familywise (type 1) error rate. These thresholds are based on the distribution of the maximum intensity, which implicitly accounts for spatial and temporal correlation in the cortical maps. We demonstrate the method in application to simulated data and experimental data from a somatosensory evoked response study.

Algorithms↗

A single-step immunochromatographic test for the detection of Entamoeba histolytica antigen in stool samples.

A rapid, single step, sensitive and specific immunochromatographic test for the detection of E. histolytica antigens in the stool samples is described. Monoclonal antibody AC55 specific for E. histolytica was used as capture antibody on nitrocellulose sheet. The same antibody was conjugated to colloidal gold to detect the presence of antigen. In this test, multiple steps of washing, incubation, etc. are not required and there is no need for secondary colour development as gold particles produce a typical reddish, purple colour, when they bind to the solid phase at the site of immune reaction. 151 stool samples from patients with suspected amoebiasis were screened by this assay. Sensitivity of the test was found to be 97.6% and specificity 92.6%. 25 polyxenic E. histolytica cultures and other cultures were also tested. The test did not show positive reaction with other intestinal parasites.

Animals↗

Association of human leucocyte-DR and DQ antigens in coeliac disease: a family study.

BACKGROUND AND AIMS: No family studies regarding the association of coeliac disease with the human leucocyte antigen (HLA)-DQ locus are available. Moreover, no HLA studies have been carried out in coeliac disease patients from India. The aim of this study was to study the HLA class II (DR and DQ) antigens in children with coeliac disease and in their first-degree relatives. METHODS: Fifteen children with coeliac disease and their first-degree relatives (birth parents of all the coeliac disease patients and fifteen siblings) were studied. A group of 123 healthy unrelated and ethnically matched subjects were used as controls. The HLA-DR and -DQ typing was carried out by a complement-dependent microlymphocytotoxicity assay. The transmission disequilibrium test was used for analysis of results. RESULTS: There was no association of coeliac disease with DR phenotypes. Ninety-three per cent of patients (14/15) carried the DQ2 allele. DQ2 was transmitted in 15 of 19 informative cases (transmission probability of 79%, chi2 6.368 with 1 df, nominal P=0.012 and P value corrected for multiple test=0.035). The haplotype relative risk associated with DQ2 was 5.71 (95% confidence interval 1.71-16.28). CONCLUSION: Coeliac disease in Indian children is predominantly associated with HLA-DQ2.

Adolescent↗

Association analysis of the vitamin D receptor gene, the type I collagen gene COL1A1, and the estrogen receptor gene in idiopathic osteoarthritis.

OBJECTIVE: Evidence has accumulated supporting a role for genes in the etiology of osteoarthritis (OA). Several candidates have been targeted as potential susceptibility loci including genes that are involved in the regulation of bone density. Genetic association analysis has suggested a role for the vitamin D receptor gene (VDR) and the estrogen receptor gene (ER) in susceptibility. Such findings must be tested in additional independent cohorts. We tested for association of these 2 genes, plus a third gene implicated in bone density, COL1A1, with idiopathic OA. METHODS: A case-control cohort of 371 affected probands and 369 unaffected spouses was used. Association was tested using 4 intragenic single nucleotide polymorphisms (SNP), one each for the VDR and COL1A1 genes, and 2 for the ER gene. The VDR and ER SNP are the same SNP that have been associated with OA. All 4 SNP affect restriction enzyme sites and were genotyped using polymerase chain reaction and enzyme digestion. Allele and genotype distributions for each SNP were compared between cases and controls and analyzed using Fisher's exact test. RESULTS: There was no evidence of association of the VDR or the ER gene SNP to OA. There was weak evidence of association of the COL1A1 SNP in female cases (p = 0.017), reflected by a difference in the distribution of genotypes at this SNP between female cases and controls (p = 0.027). However, when corrected for multiple testing, these results were not significant. CONCLUSION: If the VDR, ER, or COL1A1 genes do encode predisposition to OA then the 4 SNP tested are not associated with major susceptibility alleles at these 3 loci.

Aged↗

Detecting change: A comparison of three neuropsychological methods, using normal and clinical samples.

Detecting change in individual patients is an important goal of neuropsychological testing. However, limited information is available about test-retest changes, and well-validated prediction methods are lacking. Using a large nonclinical subject group (N = 384), we recently investigated test-retest reliabilities and practice effects on the Wechsler Adult Intelligence Scale and Halstead-Reitan Battery. Data from this group also were used to develop models for predicting follow-up test scores and establish confidence intervals around them. In this article we review those findings, examine their generalizability to new nonclinical and clinical groups, and explore the sensitivity of the prediction models to real change. Despite similarities across samples in reliability coefficients and practice effects, limits to the generalizability of prediction methods were found. Also, when multiple test measures were considered together, one or more "significant" changes were common in all (including stable) subject groups. By employing normative cut-offs that correct for this, sensitivity of the models to neurological recovery and deterioration was modest to good. More complex regression models were not more accurate than the simpler Reliable Change Index with correction for practice effects when confidence intervals for all methods were adjusted for variations in level of baseline test performance.

Journal Article↗

[Clinicomorphological characteristics of Sezary's disease and mycosis fungoides].

AIM: To try a combined approach to the study of clinicomorphological and immunophenotypical characteristics of primary cutaneous T-cell lymphomas. MATERIAL AND METHODS: Clinical, histological, genotypic and immunophenotypical parameters were studied in 7 patients (4 male and 3 female, mean age 53.1 +/- 7.8%) with Sezary's disease (SD) and 10 patients (6 male, 4 female, mean age 54.0 +/- 4.0 years) with mycosis fungoides (MF) treated in Hematological Research Center in 1998-2004. RESULTS: Six of seven SD patients had SD stage IV with leukemization, Sezary's cells were found in peripheral blood. Bone marrow and lymph nodes involvement was observed in 5 patients. Morphological signs of transformation into lymphosarcoma were detected in three patients. Skin samples of all the patients showed epidermotropism with lymphoid infiltration of the derma and skin appendages. All the patients had clonal rearrangement of T-cell receptor by gamma-chain. Immunophenotyping (IPT) detected T-cell markers CD45RO, CD43, CD3, CD4 on lymphoid cells. IPT of peripheral blood lymphoid cells was typical for SD in 3 patients. Low density of CD4 and CD2, CD4 and CD5, the presence of CD7 were registered in 1 patient each. The disease history was 3.4 +/- 0.7 years. A lethal outcome was related with septic complications after polychemotherapy. MF history in 10 patients was 10.9 +/- 2.1 years. Stages III and IV were diagnosed in 2 of 10 patients. All the patients had typical pathohistological changes. Polymerase chain reaction test detected clone by rearrangement of gamma-chain of T-cell receptor. In 2 patients IPT detected CD4 absence in the presence of CD8 and CD7. The aberrant clone typical for NK-cells was detected in one case. Two patients died of the disease progression after 7 and 20 years of MF. CONCLUSION: Multiple tests help early diagnosis and conduction of optimal therapy for cutaneous T-cell lymphomas.

Adult↗

Community integration following multidisciplinary rehabilitation for traumatic brain injury.

PRIMARY OBJECTIVE: To determine the extent to which participation in a multidisciplinary rehabilitation programme and patient characteristics predict improvement in community integration following mild-to-moderate traumatic brain injury (TBI). RESEARCH DESIGN: A non-randomized case-control study was conducted employing a pre-test-post-test multiple regression design. METHODS AND PROCEDURES: Archival data for 42 patients with mild-to-moderate TBI who completed the Community Integration Questionnaire (CIQ) at intake and again 6-18 months later were analysed. Half the sample participated in an intensive outpatient rehabilitation programme that provided multi-modal interventions, while the other half received no rehabilitation. The two groups were matched on age, education and time since injury. RESULTS: On the CIQ Home Integration scale, participation in rehabilitation and female gender predicted better outcome. On the Productivity scale, patients with a lower age at injury had better outcome. Outcome on both of these scales, as well as on the Social Integration scale, was predicted by the baseline pre-test score (initial severity). CONCLUSIONS: Overall, multidisciplinary rehabilitation appeared to increase personal independence. It is also concluded that: (1) multivariate analysis can reveal the relative importance of multiple predictors of outcome; (2) different predictors may predict different aspects of outcome; and (3) more sensitive and specific outcome measures are needed.

Adult↗

Group testing for pathway analysis improves comparability of different microarray datasets.

MOTIVATION: The wide use of DNA microarrays for the investigation of the cell transcriptome triggered the invention of numerous methods for the processing of microarray data and lead to a growing number of microarray studies that examine the same biological conditions. However, comparisons made on the level of gene lists obtained by different statistical methods or from different datasets hardly converge. We aimed at examining such discrepancies on the level of apparently affected biologically related groups of genes, e.g. metabolic or signalling pathways. This can be achieved by group testing procedures, e.g. over-representation analysis, functional class scoring (FCS), or global tests. RESULTS: Three public prostate cancer datasets obtained with the same microarray platform (HGU95A/HGU95Av2) were analyzed. Each dataset was subjected to normalization by either variance stabilizing normalization (vsn) or mixed model normalization (MMN). Then, statistical analysis of microarrays was applied to the vsn-normalized data and mixed model analysis to the data normalized by MMN. For multiple testing adjustment the false discovery rate was calculated and the threshold was set to 0.05. Gene lists from the same method applied to different datasets showed overlaps between 42 and 52%, while lists from different methods applied to the same dataset had between 63 and 85% of genes in common. A number of six gene lists obtained by the two statistical methods applied to the three datasets was then subjected to group testing by Fisher's exact test. Group testing by GSEA and global test was applied to the three datasets, as well. Fisher's exact test followed by global test showed more consistent results with respect to the concordance between analyses on gene lists obtained by different methods and different datasets than the GSEA. However, all group testing methods identified pathways that had already been described to be involved in the pathogenesis of prostate cancer. Moreover, pathways recurrently identified in these analyses are more likely to be reliable than those from a single analysis on a single dataset.

Biomarkers, Tumor↗

Generalizability of grip strength measurements in patients with tennis elbow.

The purpose of this study was to determine the interrepetition and interoccasion generalizability of grip strength measurements in patients with the diagnosis of proximal extensor carpi radialis brevis tendinitis. Thirty-five consecutive patients (mean age = 44.5 +/- 8.6 years; mean duration of symptoms = 3.9 +/- 3.5 months) fulfilling the eligibility criteria participated in the study. Measurements of pain-free grip strength and maximum grip strength for the involved limb and maximum grip strength for the uninvolved limb were taken on two test dates within seven days of each other. We calculated the variation between measurements within a test session and the variation from one session to the next using generalizability coefficients based on the mean of the six measurements. The coefficients for interrepetition, interoccasion, and overall generalizability were .99, .97, and .96, respectively. The clinical implication of these findings is that the overall generalizability can best be enhanced by averaging grip strength measurements recorded from multiple test sessions rather than by increasing the number of repetitions during a single test session.

Adult↗

Multiple puncture skin test and mantoux test in Southeast Asian refugees.

Skin test reactions to PPD applied by Mantoux techniques were compared with reactions to tuberculin tine test (PPD-tine); tuberculin, old tine test (OT tine); Aplitest; and Mono-Vacc, tuberculin, old (Mono-Vacc) in newly arrived refugees from Cambodia and Laos. The reaction to Mantoux test was accepted as the "true reading" and compared to the reaction size to one of the multiple puncture tests (MPT). A 2 X 2 table was constructed and sensitivity, specificity, false negative, and false positive rates computed over a broad range of cut-off points for MPT. The MPTs were very sensitive (100 percent to 78 percent) but lacked specificity (78 percent to 18 percent) when a cut-off of 1 mm was used. Predictably, as the cut-off is moved to larger reactions, sensitivity decreases and specificity increases. The relationship between the two is emphasized in a receiver-operator characteristics analysis. The MPTs are not intended for diagnostic use. Reaction to the MPT should be interpreted with the same careful consideration that clinicians use to interpret reactions to the Mantoux test.

Asia, Southeastern↗

Basic statistical testing, including interim analysis.

Clinical trials, due to the randomization process, require statistical methods for testing key hypotheses that are straightforward and involve simple comparisons of group proportions or group means. Differences between group proportions are tested using a chi 2 statistic or a Fisher's exact test. Differences between group means are tested using a two-sample t statistic. When there are more than two groups, the F statistic is calculated. When ordinal data or data not normally distributed are analyzed, nonparametric testing is performed. A critical decision prior to analysis is the choice of the endpoint, which must be clearly defined and consistently applied. Monitoring a clinical trial is important, and may lead to interim analysis. This should be done by independent study monitors. Interim results play an important role in analyzing clinical trials; however, they create problems due to multiple testing. An early stoppage rule is frequently applied when independent interim results are obtained. The statistical methods for interim analysis are discussed.

Data Interpretation, Statistical↗

Inference in linkage analysis of multifactorial traits using recombinant inbred strains of mice.

Recombinant inbred strains have been shown to be important tools for segregation and linkage analysis of multifactorial traits. Tests of association have been used as robust methods of linkage detection, however, guidelines for forming inferences from significance levels have not been generally available. In this paper, lessons learned from a Bayesian statistical approach to linkage analysis of Mendelian traits have been applied to studies of multifactorial traits. Criteria for detection of linkage based on Bonferroni's correction for multiple testing are also discussed.

Animals↗

The genetic toxicology of Gene-Tox non-carcinogens.

The Gene-Tox Program has identified 61 chemicals that have been tested in chronic rodent carcinogenesis bioassays and found to be inactive. The genetic toxicology data of these 61 non-carcinogens is reviewed and summarized. A large proportion of these chemicals have been tested to a limited extent in genetic toxicity bioassays: 32 in 2 tests or less. Of the remaining 29 chemicals, 28% have been tested in 9 or more tests which encompass a range of genetic endpoints: gene mutation, chromosomal effects, other genetic endpoints, and cell transformation. The genetic toxicity of 12 chemicals with sufficient data is discussed in detail: benzoin, caffeine caprolactam, ethanol, halothane, hycanthone methanesulfonate, malathion, maleic hydrazide, methotrexate, 1-naphthylamine, 4-nitro-o-phenylenediamine, and p-phenylenediamine. A new technique for the evaluation of multiple test data, the "genetic activity profile", has been applied to 6 of these chemicals, allowing the qualitative and quantitative information to be compared collectively. In the evaluation of the genotoxicity effects of these non-carcinogens, a number of discrepancies between the results from genetic toxicity bioassays and chronic rodent bioassays have been uncovered. These discrepancies are discussed in light of current knowledge on the strengths and weaknesses of both genetic toxicity bioassays and chronic rodent bioassays.

Animals↗

Multiple sleep latency test and maintenance of wakefulness test.

In addition to overnight polysomnography, there are two special tests with which every sleep technologist should be familiar: the multiple sleep latency test and the maintenance of wakefulness test. These two tests classify excessive daytime sleepiness using objective data. The role of the sleep technologist is to understand and perform an accurate test so that sleep clinicians can use that data in diagnosing and treating their patients. This article provides step-by-step directions for performing these tests.

Disorders of Excessive Somnolence↗

The hairless gene in androgenetic alopecia: results of a systematic mutation screening and a family-based association approach.

BACKGROUND: Genetic disposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as androgenetic alopecia (AGA). The genetic factors contributing to AGA are currently unknown. The human hairless gene (HR) has recently been cloned and mutations have been reported in families with autosomal recessive universal congenital alopecia and papular atrichia. The main feature of these disorders is persistent complete absence of hair at or shortly after birth. This suggests that HR is essential and specific for the development of hair. OBJECTIVES: To test the hypothesis that HR may be involved in AGA. METHODS: We systematically screened HR for genetic variability by means of single-strand conformation analysis (SSCA) in 46 unrelated men with AGA. To test for an involvement of HR in the development of AGA, seven common variants were genotyped in 61 families with 93 affected offspring. The results were analysed with the transmission/disequilibrium test (TDT). RESULTS: SSCA showed 15 single nucleotide substitutions: eight missense mutations, four silent mutations and three mutations in exon-flanking intronic sequences. TDT results showed a marginally significant association between AGA and variants 3379-29G/T (P = 0.024) and 2611-68C/T (P = 0.047). These results, however, did not remain significant after applying the conservative Bonferroni correction for multiple testing. CONCLUSIONS: Our results do not provide evidence for a strong involvement of HR in the development of AGA, although a minor role cannot be fully excluded.

Adult↗

Cushing's syndrome in childhood and adolescence.

OBJECTIVE: To review the diagnosis, management and outcome of Cushing's syndrome in children and adolescents. METHODS: We conducted a retrospective review of nine cases treated between 1976 and 1996 at the Royal Children's Hospital, Melbourne, Australia. RESULTS: Six children with Cushing's disease and three with primary adrenal disease were identified. Mean age at diagnosis in the Cushing's disease patients was 11.3 years and in the children with primary adrenal disease 9.5 years. The most common presenting symptoms were weight gain and delayed growth. Two children had the unusual presenting symptoms of an eating disorder and hemihypertrophy, respectively. Laboratory diagnosis of Cushing's syndrome was established by demonstration of elevated urine free cortisol, loss of normal diurnal variation of serum cortisol, and loss of suppressibility of cortisol secretion by low dose dexamethasone. Investigations used to determine the aetiology of hypercortisolism included serum adrenocorticotropic hormone (ACTH) levels, high dose dexamethasone suppression tests, imaging studies, and inferior petrosal sinus sampling. Four patients with Cushing's disease had successful transphenoidal adenomectomies. Two patients with bilateral primary pigmented nodular adrenocortical dysplasia underwent bilateral adrenalectomies. One child with an adrenal adenoma was treated by left adrenalectomy. CONCLUSIONS: Cushing's syndrome in children and adolescents remains a diagnostic challenge. Successful treatment often requires the use of multiple tests to achieve the correct diagnosis, appropriate surgery and a good long-term outcome.

Adenoma↗