Biomedical subjects

J E Overall

Publications and source records attributed to J E Overall.

At least 37 records · Page 2Linked to original sources

PubMed1995

Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study.

OBJECTIVE: To assess critically the efficacy and safety of lithium and replicate earlier findings in a larger sample of aggressive children with conduct disorder and to assess the utility of the Profile of Mood States (POMS) in this population. METHODS: Children hospitalized for treatment-refractory severe aggressiveness and explosiveness and with diagnosed conduct disorder were subjects in this double-blind, placebo-controlled clinical trial. After a 2-week placebo baseline period, children were randomly assigned to lithium or placebo treatment for 6 weeks of placebo. The main outcome measures were the Global Clinical Judgments (Consensus) Scale, Children's Psychiatric Rating Scale, Conners Teacher Questionnaire, Parent-Teacher Questionnaire, and the POMS. RESULTS: Fifty children (mean age 9.4 years) completed this study. The mean optimal daily dose of lithium was 1,248 mg and the mean serum level was 1.12 mEq/L. Lithium was superior to placebo, although the effects on some measures were more modest than in a previous study. CONCLUSIONS: Lithium appears to be an effective treatment for some severely aggressive children with conduct disorder. Although the POMS appeared to be reliable, it did not detect any response to lithium.

Aggression↗

PubMed1994

Issues in the design and analysis of controlled clinical trials.

Several issues that pertain to the analysis of data from repeated measurements designs are addressed. The necessity for an assumption concerning uniformity of correlations (symmetry) can be avoided by calculating linear and/or nonlinear trend scores. In the usual repeated measurements ANOVA the baseline covariate does not affect within-subject sums of squares, such as that for the groups x times interaction. However, the separately calculated trend scores have the advantage of accounting for most of that interaction and permitting covariance-correction for baseline differences. Chance baseline differences in a repeated measurements design otherwise can contribute materially to probabilities of erroneous conclusions. A conservative criterion for use of one-sided tests of significance is proposed.

Data Interpretation, Statistical↗

PubMed1994

Estimating sample sizes for repeated measurement designs.

Formulas for estimating sample sizes that are required to provide specified power for analysis of variance (ANOVA) tests of significance in a two-group repeated measurements design are presented and evaluated. Power and sample size requirements depend on the pattern of treatment effects and the pattern of correlations among the repeated measurements, as well as on parameters common to sample size estimation for cross-sectional comparisons of treatment effects in simple randomized designs. Simplifying assumptions permit generation of these numerous parameter estimates from predictions of the magnitude of the standardized "effect size" at end of trial and the single correlation between the baseline and endpoint measurements. Monte Carlo methods are used to verify the actual power of different tests of significance for treatment effects in repeated measurement designs using sample sizes estimated by the formulas. The sample size implications of different patterns of treatment effects, levels of correlation, and numbers of repeated measurements are evaluated.

Analysis of Variance↗

PubMed1994

Implications of chance baseline differences in repeated measurement designs.

Datasets representing randomized, parallel-groups designs were analyzed by repeated measurements ANOVA and linear trend analysis with and without baseline values being covaried. ANOVA tests for the between-groups main effect, groups X times interaction, and differences in linear trends across time periods are shown to be seriously conservative or seriously nonconservative, depending on the direction and significance of chance baseline mean difference. Inclusion of baseline scores as a covariate in the repeated measurements ANOVA provides appropriate correction for the between-groups (average) effect across time, but the covariate provides no correction for the within-subject effects that are concerned with differences in the rates or patterns of change across time. If one desires to evaluate differences between patterns of treatment-induced change, tests of significance for differences in group means on composite trend scores with covariance correction for baseline are recommended. If covariance correction is not or cannot be employed, the potentially "favorable" or "unfavorable" influence of chance baseline differences on tests of significance needs to be explicitly recognized.

Analysis of Variance↗

PubMed1994

A comment on the importance of numerical evaluation of analytic solutions involving approximations.

An analytic solution proposed by Senn (1) for removing the effects of covariate imbalance in controlled clinical trials was subjected to Monte Carlo evaluation. For practical applications of his derivation, Senn proposed substitution of sample statistics for parameters of the bivariate normal model. Unfortunately, that substitution produces severe distortion in the size of tests of significance for treatment effects when covariate imbalance is present. Numerical verification of proposed substitutions into analytic models is recommended as a prudent approach.

Analysis of Variance↗

PubMed1994

Recovery of brain glucose metabolism in detoxified alcoholics.

OBJECTIVE: To differentiate withdrawal-related abnormalities in brain glucose metabolism among alcoholics from abnormalities that may be irreversible or antedate alcohol use, the authors evaluated metabolic recovery during alcohol detoxification. METHOD: Regional brain glucose metabolism was measured with positron emission tomography and 2-deoxy-2-[18F]fluoro-D-glucose in 10 male alcoholics at 8-15 days, 16-30 days, and 31-60 days after last use of alcohol. The alcoholics' metabolic values were compared with those of 10 age-matched male healthy volunteers. RESULTS: Brain metabolism increased significantly during detoxification. There were significant differences in global and regional measures between the first and last time points but not between the second and third points, suggesting that recovery occurred predominantly within 16-30 days. Regional increases in metabolism were greater in the frontal regions. Whereas during the first evaluation the alcoholics showed significantly lower metabolism in various brain regions than the comparison group, at the end of detoxification the alcoholics showed significantly lower absolute and relative metabolic values in the basal ganglia and lower relative metabolic values in the parietal cortex. Among the alcoholics, but not the comparison group, metabolism in the frontal, parietal, and left temporal cortexes was negatively correlated with years of alcohol use and with age. CONCLUSIONS: This study shows significant increases in brain metabolism during alcohol withdrawal and documents persistent low metabolic levels in the basal ganglia of detoxified alcoholics.

Adult↗

PubMed1993

Factor structure and scoring of the SKT test battery.

The SKT (Syndrom Kurztest) has been used in the assessment of treatment responses in numerous clinical trials for treatment of dementia in German-speaking Europe. Data from 265 patients with mild to moderate Alzheimer's disease in a study conducted in the U.S. were analyzed to evaluate factor structure, common and specific subtest content, reliability, and concurrent validity. Results confirm the presence of two primary factors of memory and attention. Test-retest reliability of the factor scores was estimated to be .75 and .93. Test-retest reliability of the composite SKT total score was .90. The correlations between the SKT memory and attention factor scores and the MMSE and ADAS measurements of dementia also support validity with regard to the broader construct of cognitive dysfunction.

Aged↗

PubMed1993

Population recovery capabilities of 35 cluster analysis methods.

Comparative evaluation of population recovery capabilities of 35 cluster analysis methods defined by different combinations of 5 profile similarity measures and 7 agglomeration rules was undertaken using artificial data that represented duplicate mixture samples from 4 latent populations. The latent population mean profiles differed primarily in elevation or in pattern parameters. Latent population sampling variances were controlled to provide two different levels of realistic overlap. The within-population distributions were multivariate normal with diagonal covariance structure. Across all conditions examined, complete linkage and Ward's minimum variance methods, used with Euclidian or city block interprofile distance measures, performed best. Single linkage, median, and centroid methods were substantially inferior for clustering individuals in accordance with true population memberships.

Analysis of Variance↗

PubMed1993

Computer simulation of alternative sampling strategies to estimate risk of infection from Cryptosporidium.

Estimation of acceptably safe levels of biological contaminants in drinking water requires fitting a mathematical model to infection rates observed in small samples of human subjects. Because of obvious constraints on exposing human subjects to infective conditions, it is not feasible to compare the utilities of alternative sampling strategies and research designs using data from real experiments. Computer simulation methods were used to generate sample data having known probabilities of infection determined by an exponential or log-linear infectivity model. Experimental conditions that were examined included variations in the total available sample size, strategies for allocating subjects among different test concentrations, and methods for fitting a prediction model to the observed data. Results confirmed that data obtained by exposing most subjects to a concentration that produces an infection rate approximating 50% and calculating the sample regression coefficient for the log-linear model as the average infectivity-to-concentration ratio provided the best estimates of safe concentration. Exposing a single subject to each successively higher test level until an initial infection is observed, and exposing all remaining subjects at that level, or an adjacent log-concentration level is a tactic supported by the empirical results.

Animals↗

PubMed1993

Neuroleptic-related dyskinesias and stereotypies in autistic children: videotaped ratings.

Tardive dyskinesia, an involuntary abnormal movement disorder, is a serious untoward effect of neuroleptic treatment. Certain patient populations likely to be treated with neuroleptics have an increased rate of abnormal movements--or stereotypies (ST)--at baseline that may be difficult to differentiate from neuroleptic-related dyskinesias. The objective of the present study was to ascertain whether blind raters could differentiate dyskinesias from ST on videotapes of autistic children and to compare ratings on the Abnormal Involuntary Movement Scale (AIMS) of patients seen live with ratings of patients seen on videotapes. Blind raters of videotapes could only differentiate dyskinesias from ST 59.3 percent of the time. Mean AIMS scores were higher for children with dyskinesias than for children with ST. A discriminant function based on AIMS Items 1 (muscles of facial expression), 2 (lips and perioral area), 6 (lower extremities), and 7 (neck, shoulders, hips) correctly classified all 9 children with dyskinesias and 8 of the 9 children with ST.

Antipsychotic Agents↗

PubMed1993

Selecting an interim analysis procedure.

Motivations for undertaking interim analyses differ, as do the methods proposed by different authors. This article evaluates five interim analysis procedures with regard to different requirements. The five procedures differ with respect to concern for the presence or absence of a true treatment effect. One provides interim criteria only for accepting Ho (terminating due to insufficient evidence of a true treatment effect), two provide criteria only for rejecting H(o), and the others provide criteria for either accepting or rejecting H(o). A computer program was developed to simulate applications of the interim analyses to sampling data. Actual Type I error probabilities, power, probabilities of early termination, and expected sample sizes resulting from the different interim analysis procedures are compared. One-sided and two-sided tests, equal and unequal interim sample segments, and interim alterations in the sample size or research design are considered. Results should be helpful in selecting a method that satisfies particular interests.

Humans↗

PubMed1992

Directional baseline differences and type I error probabilities in randomized clinical trials.

Adequate correction for baseline differences that occur in the same or opposite direction from inferred treatment effects in a simple randomized experimental design is addressed by Monte Carlo simulation. Results confirm that the analysis of covariance (ANOVA) can provide appropriate correction whether baseline means differ significantly by chance in the same or opposite direction from the inferred treatment effect. The results from analysis of simple pre-post difference scores are highly dependent on the direction of chance baseline deviations in relation to the directional treatment effect that would be inferred from rejection of the null hypothesis. The attempt to correct for baseline differences by expressing outcome as percentage of baseline entails directional bias that depends on the location of the zero point, the direction of change, and the level of correlation between baseline and follow-up measurements.

Analysis of Variance↗

PubMed1992

Baseline correction in a two-way randomized blocks design.

Randomized blocks designs are used in clinical psychopharmacology research to test the hypothesis that relative effectiveness of different drug treatments depends on the type of patient being treated. Monte Carlo methods were used to evaluate the adequacies of different approaches to statistical control over baseline differences in such a design with special concern for the treatments x blocks interaction effect. Given the usual assumptions, analysis of covariance (ANCOVA) was shown to provide adequate baseline correction with consequent unbiased tests for the treatments x blocks interaction, as well as the main effect for the randomized treatments. Tests relying on simple pre-post difference scores and percentage change scores evidenced seriously conservative or nonconservative bias in the test for treatments x blocks interaction effect, a bias that depended on the direction of the corresponding interaction effect observed in the baseline measurements alone. This is discussed as a serious matter because the interaction effect in a randomized blocks design is a common basis for the claim of specific indications of drug treatments for particular types of patients.

Humans↗

PubMed1992

Verapamil versus lithium in acute mania.

Twenty acutely manic patients were studied in a double-blind randomized trial comparing verapamil with lithium. The Petterson Mania Scale, the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impression (CGI) were administered before treatment and weekly during 4 weeks of treatment to evaluate response to verapamil and lithium. Both treatment groups improved significantly, and there were no significant overall differences between treatments.

Acute Disease↗

PubMed1992

Comparison of a two-stage and three-stage interim-analysis procedure.

A statistical model for combining p values from multiple tests of significance is used to define rejection and acceptance regions for two-stage and three-stage sampling plans. Type I error rates, power, frequencies of early termination decisions, and expected sample sizes are compared. Both the two-stage and three-stage procedures provide appropriate protection against Type I errors. The two-stage sampling plan with its single interim analysis entails minimal loss in power and provides substantial reduction in expected sample size as compared with a conventional single end-of-study test of significance for which power is in the adequate range. The three-stage sampling plan with its two interim analyses introduces somewhat greater reduction in power, but it compensates with greater reduction in expected sample size. Either interim-analysis strategy is more efficient than a single end-of-study analysis in terms of power per unit of sample size.

Bias↗

PubMed1991

Factor analysis of the Diagnostic Inventory of Personality and Symptoms.

The Diagnostic Inventory of Personality and Symptoms (DIPS; Vincent, 1985) is a self-rating instrument that yields 14 clinical scale scores and a validity scale score. The scale scores present diagnostic classification information derived from major DSM-III diagnostic categories. This study replicates and extends a previous factor study by Vincent and Duthie (1986). DIPS data were collected from 170 psychiatric inpatients and outpatients. Both a principal components analysis and an oblique, cluster-oriented, marker variable factor analysis of the 14 clinical scale scores resulted in four factors, the first three of which reproduced the pattern of factor loadings found by Vincent and Duthie (1986). The results support the existing distinction between DSM-III Axis I psychotic and neurotic disorders, and Axis II characterological disorders.

Adolescent↗

PubMed1991

A comment concerning one-sided tests of significance in new drug applications.

One-sided tests provide actual type I error probabilities that are consistent with specified alpha levels in situations where differences in only one direction will ever be the basis for a consequential claim of significance. A drug-placebo comparison presented to the FDA in support of a new drug application is clearly a case in point. It is important to use the correct one-sided tests in all cases where they are appropriate in order to avoid the suspicion that they are only used to relax criteria so that marginal results can be reported as significant. The choice of a one-sided test should be a design consideration with consequent reduction in sample sizes commensurate with greater power against consequential alternatives.

Drugs, Investigational↗

PubMed1991

Statistical efficiencies that the FDA should encourage.

The Food and Drug Administration (FDA) has a dual responsibility to the public of protecting against unsafe or ineffective drugs while efficiently licensing new drugs that are safe and effective. Balancing these two responsibilities requires correct safeguards that are also efficient in minimizing time, cost, and patient exposure to ineffective or unsafe experimental conditions. Reliance on statistical probabilities that do not relate to the question being asked, conservatively biased tests of significance, statistically inconsequential interim-analysis procedures, and largely superfluous active control groups in three-arm designs are discussed as problems. In each of these cases, design and analysis methods that are both correct and more efficient are available. Their use can reduce sample-size requirements and enhance power for documenting meaningful treatment effects.

Drug Industry↗