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The symmetry of symptom patterns in pre-post treatment designs.

This article proposes a new nonparametric method for statistical evaluation of clinical pre-post treatment designs. In clinical research, models of marginal symmetry typically are estimated from log-linear models of axial and quasi-symmetry. As such, they provide overall goodness-of-fit information concerning change in probabilities of categories of one variable that was observed twice. This paper proposes the following three extensions: (1) using models of marginal symmetry for changes in patterns of two or more variables, and (2) following up global marginal symmetry tests using Lehmacher's sign tests. (3) To protect the experiment-wise alpha, a modified Bonferroni-Holm procedure is proposed. The new approach allows researchers to make statements about treatment effects at the level of single symptoms. Examples illustrate application of all three symmetry models and the follow-up test using data from pharmaco-psychiatry. The discussion relates Lehmacher's tests to two-sample Configural Frequency Analysis of multi-discrimination types. Strategies of statistical significance testing are presented and the importance of the proposed methodological approach for psychiatric research is discussed.

Humans↗

Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases.

Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease models (MMLS) and the "nonparametric" linkage (NPL) statistic. In previous work, we evaluated the increase of type I error when maximizing over two or more genetic models, and we compared the power of MMLS to detect linkage, in a number of complex modes of inheritance, with analysis assuming the true model. In the present study, we compare MMLS and NPL directly. We simulated 100 data sets with 20 families each, using 26 generating models: (1) 4 intermediate models (penetrance of heterozygote between that of the two homozygotes); (2) 6 two-locus additive models; and (3) 16 two-locus heterogeneity models (admixture alpha = 1.0,.7,.5, and.3; alpha = 1.0 replicates simple Mendelian models). For LOD scores, we assumed dominant and recessive inheritance with 50% penetrance. We took the higher of the two maximum LOD scores and subtracted 0.3 to correct for multiple tests (MMLS-C). We compared expected maximum LOD scores and power, using MMLS-C and NPL as well as the true model. Since NPL uses only the affected family members, we also performed an affecteds-only analysis using MMLS-C. The MMLS-C was both uniformly more powerful than NPL for most cases we examined, except when linkage information was low, and close to the results for the true model under locus heterogeneity. We still found better power for the MMLS-C compared with NPL in affecteds-only analysis. The results show that use of two simple modes of inheritance at a fixed penetrance can have more power than NPL when the trait mode of inheritance is complex and when there is heterogeneity in the data set.

Gene Frequency↗

[Digital radiography in urography].

The clinical utility was evaluated of a computed radiographic system in urography. The system (FCR 101, Philips Medical Systems, Inc., Shelton, CT) is based on a photo-stimulatable phosphor screen (imaging plate) for X-ray image detection and storage. The X-ray information recorded on the imaging plate is converted into digital from and processed by means of a computer. After processing is completed, the digitized image is reversed back to analogic signals, which modulate the intensity of a laser beam scanning the image on a single-emulsion film (Fuji CR 633). Two hundred IVP's were obtained in four groups, of 50 patients each, with normal azotemic values by rapid infusion of a low osmolality contrast medium (iopamidol 150 mgI/ml). While conventional radiographs were performed on the first group of patients with the injection of 0.6 gI/kg body weight of contrast medium, digital examinations were carried out, in the remaining three groups, with the injection of 0.6, 0.3 and 0.12 gI/kg, respectively. The digital images were processed with the "Abdomen-routine" program. A specific algorithm was implemented in order to reduce the excessive contrast resolution of the bladder, which is due to the characteristics of the nonionic contrast medium and enhanced by the reading program. The image details were evaluated by two observers and then statistically analyzed with nonparametric tests. Statistical analysis did not show any difference in the quality of digital and screen-film images. Image processing improved some inadequate images, by reducing the contrast resolution of the bladder, and allowed a better detection of some details. Low doses (0.3 gI/kg) of a low osmolality (150 mgI/kg) contrast medium were enough to obtain good images. Another biological advantage was obtained by a consistent radiation dose reduction (about 40%).

Adolescent↗

Statistical significance levels of nonparametric tests biased by heterogeneous variances of treatment groups.

The statistical significance levels of the Wilcoxon-Mann-Whitney test and the Kruskal-Wallis test are substantially biased by heterogeneous variances of treatment groups--even when sample sizes are equal. Under these conditions, the Type I error probabilities of the nonparametric tests, performed at the .01, .05, and .10 significance levels, increase by as much as 40%-50% in many cases and sometimes as much as 300%. The bias increases systematically as the ratio of standard deviations of treatment groups increases and remains fairly constant for various sample sizes. There is no indication that Type I error probabilities approach the significance level asymptotically as sample size increases.

Computer Simulation↗

Statistics review 10: further nonparametric methods.

This review introduces nonparametric methods for testing differences between more than two groups or treatments. Three of the more common tests are described in detail, together with multiple comparison procedures for identifying specific differences between pairs of groups.

Clinical Trials as Topic↗

An empirical evaluation of Tukey's control chart for use in health care and quality management applications.

Recently in this journal, F. Alemi (Qual Manage Health Care. 2004;13(4):216-221) proposed the use of Tukey's Control Chart because of the unique benefits associated with nonparametric inferential statistics including robust performance with (1) low N sizes, (2) nonnormal data, and (3) the presence of outliers, However, an assumption that applies to virtually all inferential statistical procedures (parametric and nonparametric) is that the observations in question are independent from each other. Unfortunately, there is good reason to suspect violation of this assumption when evaluating quality processes over time (as is often the case in health care settings). In this article, the power (ability to detect real changes in a data process) and type I error (probability of false positives) performance of Tukey's Control Chart technique is empirically evaluated. When observations are not independent, Tukey's Control Chart technique demonstrates unacceptable type I error performance. Additionally, regardless of whether observations are independent, the technique demonstrates low power to detect real effects unless the effects are quite large.

Bias↗

On the analysis and interpretation of outcome measures in stroke clinical trials: lessons from the SAINT I study of NXY-059 for acute ischemic stroke.

BACKGROUND AND PURPOSE: A variety of primary end points have been used in acute stroke trials. We focus on the modified Rankin Scale, a reliable and valid ordinal outcome measure that assesses disability on a 7-point scale. METHODS: We provide an abbreviated discussion of analytical methods for ordinal scales, and related effect size measures; we illustrate these methods and their interpretation with outcome data from the SAINT I study of NXY-059 in acute ischemic stroke. RESULTS: The nonparametric Mann-Whitney statistic provides a straightforward method for analysis of the modified Rankin Scale, and incorporates associated measures of effect size. These measures are directly related to the concepts of Number Needed to Treat and Number Needed to Harm. CONCLUSIONS: Our re-examination of the outcome data from the SAINT I study provides little evidence for the purported efficacy of NXY-059. More broadly, analysis and interpretation of ordinal outcome scales based on ascribed numerical values to the steps of the scale should be done cautiously. Statistical treatment of multiple primary outcome measures in acute stroke clinical trials should be established before analysis. Lastly, conflating statistical and clinical significance should be avoided.

Acute Disease↗

Analysis of distortions in children with and without phonological disorders.

PURPOSE: To verify using 4 different tests the incidence of distortions in children with and without phonological disorders. METHOD: Forty children between 4 and 10.2 years of age, divided into 2 groups: 20 with normal development and 20 with phonological disorders. All children underwent the phonology tests of the Child Language Assessment ABFW and 2 spontaneous speaking tests to assess for phonologic alterations. After recording, the data were printed, analyzed, and classified according to the distortions. Nonparametric (Mann-Whitney) statistical analysis was performed with the significance level being set at P <.05. RESULTS: The phonological disorder group had significantly more occurrences of distortions in all tests compared to the control group (naming, P = .04; imitation P <.001; spontaneous speaking 1, P = .01; and spontaneous speaking 2, P = .002. The Pearson correlation coefficients of the distortion occurrences among the 4 tests were high. CONCLUSION: The phonological disorder group presented a greater number of distortions in all tests. The most frequent ones were /s, z, 3/ and the variability found within the phonological disorder group was very high. The children in this group had unstable phonological systems and so presented a high number of different distortions. Regarding the evaluation of the phonologic system, all the tests were good evaluation methods since the correlations between them were high.

Case-Control Studies↗

Nonparametric simulation-based statistical analyses for bipolar affective disorder locus on chromosome 21q22.3.

Straub et al. [1994: Nat Genet 8:291-296] reported a candidate bipolar affective disorder (BAD) locus on chromosome 21q22.3. As a replication study, we analyzed 12 Australian BAD pedigrees for the presence of excess allele sharing and cosegregation with the putative chromosome 21q22.3 BAD locus, using six microsatellite markers. The nonparametric simulation-based statistic SimAPM produced positive results for the marker PFKL (P < 0.001) and D21S198 (P = 0.007). PFKL also demonstrated linkage (P < 0.001) when analyzed using the more conservative statistic, SimIBD. Comparable results were obtained when using the original APM statistic (P = 0.02 for D21S198). However, other nonparametric analyses such as GENEHUNTER and model-free linkage (MFLINK) analysis did not yield significant results. Combined LOD scores for the 12 families were strongly negative for all six markers under six genetic models. Two-point and multipoint analyses of individual families revealed one family, family 17, with maximal LOD scores greater than 1.41 for the 10.5-cM region between PFKL and D21S198. This report provides additional support for the suggestive linkage of a susceptibility locus for BAD on chromosome 21q22.3.

Bipolar Disorder↗

Bayesian approach to inverse quantum statistics

A nonparametric Bayesian approach is developed to determine quantum potentials from empirical data for quantum systems at finite temperature. The approach combines the likelihood model of quantum mechanics with a priori information on potentials implemented in the form of stochastic processes. Its specific advantages are the possibilities to deal with heterogeneous data and to express a priori information explicitly in terms of the potential of interest. A numerical solution in maximum a posteriori approximation is obtained for one-dimensional problems. As nonparametric estimates, the results depend strongly on the implemented a priori information.

Journal Article↗

An ophthalmologist's guide to understanding antibiotic susceptibility and minimum inhibitory concentration data.

PURPOSE: To address the need to establish appropriate evaluation criteria for analyzing in vitro antibiotic susceptibility based on original data. DESIGN: In vitro laboratory investigation. PARTICIPANTS: Bacterial isolates from patients with conjunctivitis. MAIN OUTCOME MEASURES: Minimum inhibitory concentrations (MICs), descriptive statistics, antibiotic susceptibility, potency, and statistical analysis. METHODS: Minimum inhibitory concentrations were determined for 80 bacterial conjunctivitis isolates to moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, and ofloxacin. Using the MIC values, descriptive statistics (median, MIC50, MIC90, mode, range), antibiotic susceptibility, and potency of each antibiotic were calculated for each bacterial group. The data were analyzed statistically using appropriate randomization and nonparametric tests. RESULTS: The descriptive statistics of gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae) followed a consistent trend where the median, MIC50, MIC90, and mode demonstrated the lowest values, in all instances, for moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, and ofloxacin. The descriptive statistics for Haemophilus species (the predominant gram-negative bacteria implicated in conjunctivitis) did not describe any consistent trend. In contrast, antibiotic susceptibility testing did not demonstrate any advantage among the 5 fluorquinolones tested, except for moxifloxacin in the S. aureus fluoroquinolone-resistant group. Potency studies indicated that moxifloxacin and gatifloxacin were the most potent for gram-positive bacteria, whereas gatifloxacin and ciprofloxacin were the most potent for Haemophilus species. CONCLUSION: In the absence of human clinical trial data to guide care, in vitro susceptibility data should be analyzed with a set of descriptive statistics along with a nonparametric statistical analysis. No single parameter or test should be relied upon in all instances to demonstrate the in vitro superiority of one antibiotic over another. In this study, fourth-generation fluoroquinolones did have some potency advantages over second-generation fluoroquinolones against gram-positive conjunctival bacterial isolates, but not for Haemophilus isolates.

Anti-Infective Agents↗

Absence of a significant linkage between Na(+),K(+)-ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old-order Amish.

Previous studies provide evidence for a genetic component for susceptibility to bipolar affective disorder (BPAD) in the old-order Amish population. El-Mallakh and Wyatt [1995: Biol Psychiatry 37:235-244] have suggested that the Na(+),K(+)-ATPase may be a candidate gene for BPAD. This study examines the relationship between BPAD in the old-order Amish cohort and the Na(+),K(+)-ATPase alpha1 and beta3 subunit genes (ATP1A3, ATP1B3). A total of 166 sibling pairs were analyzed for linkage via nonparametric methods. Suggestive levels of statistical significance were not reached in any stratification model for affective illness. Overall, the results do not support linkage of bipolar disorder to the Na(+),K(+)-ATPase alpha subunit gene (ATP1A3) and beta subunit gene (ATP1B3) in these old-order Amish families and they show that these Na(+),K(+)-ATPase subunit genes are not major effect genes (>or=fourfold increased genetic risk of disease) for BPAD in the old-order Amish pedigrees. We cannot exclude other genetic variants of the Na(+),K(+)-ATPase hypothesis for BPAD, whereby other loci may modifying Na(+),K(+)-ATPase activity.

Bipolar Disorder↗

Linkage analysis with sequential imputation.

Multilocus calculations, using all available information on all pedigree members, are important for linkage analysis. Exact calculation methods in linkage analysis are limited in either the number of loci or the number of pedigree members they can handle. In this article, we propose a Monte Carlo method for linkage analysis based on sequential imputation. Unlike exact methods, sequential imputation can handle large pedigrees with a moderate number of loci in its current implementation. This Monte Carlo method is an application of importance sampling, in which we sequentially impute ordered genotypes locus by locus, and then impute inheritance vectors conditioned on these genotypes. The resulting inheritance vectors, together with the importance sampling weights, are used to derive a consistent estimator of any linkage statistic of interest. The linkage statistic can be parametric or nonparametric; we focus on nonparametric linkage statistics. We demonstrate that accurate estimates can be achieved within a reasonable computing time. A simulation study illustrates the potential gain in power using our method for multilocus linkage analysis with large pedigrees. We simulated data at six markers under three models. We analyzed them using both sequential imputation and GENEHUNTER. GENEHUNTER had to drop between 38-54% of pedigree members, whereas our method was able to use all pedigree members. The power gains of using all pedigree members were substantial under 2 of the 3 models. We implemented sequential imputation for multilocus linkage analysis in a user-friendly software package called SIMPLE.

Genetic Linkage↗

Alcohol neurolysis of the sciatic nerve in the treatment of hemiplegic knee flexor spasticity: clinical outcomes.

OBJECTIVE: To study clinical outcomes after 50% to 100% alcohol neurolysis of the sciatic nerve in the treatment of chronic hemiplegic knee flexor spasticity. DESIGN: Case series using a convenience sample. SETTING: Rehabilitation teaching hospital. PATIENTS: Eight patients (mean age, 55.1 +/- 12.1 yr; mean duration to block, 4.4 +/- 3.7 mo) with chronic hemiplegia and severe spasticity (modified Ashworth scale [MAS] score < 2) secondary to cerebrovascular accidents (n = 5) and traumatic brain injuries (n = 3). Two patients were ambulant, 6 were wheelchair-bound. INTERVENTIONS: Fifty percent to 100% alcohol neurolysis of the sciatic nerve using repetitive electric stimulation to localize the sciatic nerve. MAIN OUTCOME MEASURES: MAS score, gain in knee range of motion (ROM), and visual inspection of gait at 0, 1, and 6 months postneurolysis. Nonparametric tests were used in statistical analysis. RESULTS: The mean preinjection MAS score was 2.8 +/- 0.7, which improved to 1.4 +/- 0.7 at 1 month (p = .005), and 1.8 +/- 0.9 (p = .01) and 1.9 +/- 1.1 (p = .02) at 3 and 6 months postinjection, respectively. The mean gain in knee ROM was 34.4 degrees +/- 15.7 degrees at 1 month postinjection and was maintained at 6 months postinjection. Improvements in gait were noted in both ambulant patients, and improved positioning in 3 of 6 wheelchair-bound patients. The incidence of dysesthetic pain was 0%. CONCLUSION: Fifty percent to 100% alcohol neurolysis of the sciatic nerve is a safe and effective method for treatment of hemiplegic knee flexor spasticity, with therapeutic effects lasting 6 months.

Adult↗

Outcomes of open versus closed treatment of mandibular subcondylar fractures.

OBJECTIVES: The purpose of this study was to compare the long-term treatment results of open reduction and rigid internal fixation (ORIF) with closed reduction and maxillomandibular fixation (CRMMF) for subcondylar fractures when guided by specific indications and contraindications. PATIENTS AND METHODS: A protocol for the treatment of condylar process fractures was developed that included absolute and relative indications and contraindications as well as a technique regimen. To evaluate the results of this protocol, 10 patients treated with CRMMF and 10 treated by ORIF were recalled after a minimum of 6 months and examined for gender, race, diagnosis, age at injury, time since operation, and cause of the fracture. Each group was assessed by 2 blinded investigators for maximum interincisal opening, right lateral excursion, left lateral excursion, protrusive movement, deviation on opening, scar perception, motor function, sensory perception, contour perception, occlusion, and perception of pain. Nonparametric data were compared for statistical significance with a chi-square analysis and parametric data with an independent samples t-test (P < .05). RESULTS: No statistically significant differences existed between the ORIF and CRMMF groups for gender, race, diagnosis, or cause. Moreover, no differences existed for age at injury, maximum interincisal opening, right lateral excursion, left lateral excursion, protrusive movement, deviation on opening, or occlusion. Differences were noted between groups for time since operation, scar perception, and perception of pain. Using the protocol outlined, there were no differences between the ORIF and CRMMF groups for ranges of motion, occlusion, contour, and motor or sensory function. The ORIF group was associated with perceptible scars. The CRMMF group was associated with chronic pain. CONCLUSIONS: Using a treatment protocol, there were few differences in outcomes between patients treated with CRMMF and ORIF for subcondylar fractures.

Adult↗

Serum ceruloplasmin and ferroxidase activity are not decreased in hepatic failure related to alcoholic cirrhosis: clinical and pathophysiological implications.

BACKGROUND: A decrease in serum ceruloplasmin (Cp), a protein involved in iron metabolism through its ferroxidase activity, is classically claimed to be observed in severe hepatic failure of non-wilsonian chronic liver disease and therefore to be a confounding factor for the diagnosis of Wilson's disease. Moreover, a simultaneous decrease in ferroxidase activity could be hypothesized as playing a role in the development of the hepatic siderosis frequently observed in advanced chronic liver diseases. The aim of this study was to test the validity of these two statements. METHODS: This study investigated Cp, determined by immunonephelometry, and its ferroxidase 1 activity determined by Erel's method in 33 male patients with severe alcoholic cirrhosis compared with 66 healthy male volunteers, selected on strict criteria. Each patient was age-matched with two controls. Nonparametric tests were used for statistical analysis. RESULTS: The mean values of Cp were significantly higher in cirrhotic patients as compared with control subjects. A significant elevation of Cp was also observed in the subgroup of 11 cirrhotic patients who had normal serum C-reactive protein levels. The mean values of ferroxidase 1 activity were similar to those obtained in control subjects. CONCLUSIONS: Low serum Cp should not be expected in severe hepatic cirrhosis of non-wilsonian origin. Hepatic siderosis in advanced chronic liver disease is likely to be unrelated to decreased ferroxidase activity.

Adult↗