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Diet quality and cancer incidence in Nova Scotia, Canada.

Cancer rates in the province of Nova Scotia, Canada, are among the highest in the country and coincide with elevated rates of risk factors such as smoking, poor diet, and obesity. To investigate the importance of diet on cancer, using data from the 1990 Nova Scotia Nutrition Survey, we developed a diet quality score reflecting compliance with 17 nutrient recommendations. The survey data were subsequently linked with the provincial cancer registry, and the relationship between diet quality and cancer was quantified using logistic regression. Our results support an inverse relationship between diet quality and cancer, although limited statistical power resulting from our small study sample did not reveal any statistically significant relationships. We estimated that cancer incidence could potentially be reduced by approximately 35% through improved diet quality. On the basis of poor diet, nutrition-related factors (high body mass index), our estimates of the preventable fraction of cancer, and the high provincial cancer rates, we recommend health promotion strategies aimed at improving diet quality in Nova Scotia.

Adolescent↗

[Spectral analysis of heart period variability in anorexia nervosa].

The aim of this study was to investigate the response of autonomic cardiac control to postural change using spectral analysis, in patients with anorexia nervosa. Spectral components of total variability as well as of low and high frequencies were analyzed for 17 anorexic patients with mean body mass index (14.9 +/- 1.9) kg/m2 and for 9 healthy age-matched women with body mass index (20.3 +/- 1.7) kg/m2 , in supine and standing postures. During standing posture, increased heart rate in all subjects was accompanied by the decrease in total variability and high frequency spectral powers. In supine posture, anorexic patients demonstrated the reduced low frequency spectral power. Compared to control women, during standing posture anorexic patients showed higher heart rate, reduced total variability and high frequency spectral powers. Statistically significant correlation was noticed between body mass index and spectral power of low frequency in both supine and standing posture. Alterations in autonomic cardiac control induced by anorexia nervosa could be estimated by spectral analysis of heart period variability.

Adult↗

Strategic issues in the design and interpretation of studies on metabolic polymorphisms and cancer.

This chapter describes in a simple way the most important issues of epidemiological design, with emphasis on studies on metabolic polymorphisms. Different options are offered to the researcher who approaches a molecular epidemiology study. Case-control studies and cohort studies have different and sometimes complementary advantages and disadvantages. The sources of bias and the choice of controls, with specific problems in the context of investigations on metabolic polymorphisms, are key issues. Confounding is an issue that needs further clarification in the field, partly because of the lack of complete biological knowledge on the complex relationships between exposure, markers of susceptibility, and cancer. Metabolic polymorphisms are correctly interpreted as effect modifiers of the exposure-disease relationship. This interpretation implies that studies should be planned in order to have sufficient statistical power and that an interactive term should be modelled in the statistical analysis.

Bias↗

The relationship of health-promoting behaviour to health locus of control: analysis of one baccalaureate nursing class.

This study established a health-promoting lifestyle profile in one first year baccalaureate nursing class using the Health-Promoting Lifestyle Profile (HPLP) scale (Walker, Sechrist, & Pender, 1987). Students also completed the Multidimensional Health Locus of Control Scale. Pearson correlation coefficients were run to determine the relationship between perceived health locus of control and each of the categories in the HPLP scale. The only significant, albeit low, correlations were between: stress management and internal health locus of control (r = .39, p = .01); and, interpersonal support and powerful others locus of control (r = .33, p = .03). Although low statistical power (n = 34) may have contributed to these findings, the value of health locus of control as an antecedent to health promoting behaviour is questioned. The students in the current study did engage in health-promoting behaviours as measured by the HPLP scale, with behaviours in the categories self-actualization and interpersonal support receiving the highest scores. As a group, the students displayed a high perceived internal locus of control. There was virtually no relationship between perceived health locus of control and the health-promoting lifestyle profile categories. However, the significant relationship between internal locus of control and the dimension, stress management, and the powerful others locus of control and the dimension, interpersonal support, may indicate that people with a differing locus of control have different coping strategies.

Education, Nursing, Baccalaureate↗

An interactive power analysis tool for microarray hypothesis testing and generation.

MOTIVATION: Human clinical projects typically require a priori statistical power analyses. Towards this end, we sought to build a flexible and interactive power analysis tool for microarray studies integrated into our public domain HCE 3.5 software package. We then sought to determine if probe set algorithms or organism type strongly influenced power analysis results. RESULTS: The HCE 3.5 power analysis tool was designed to import any pre-existing Affymetrix microarray project, and interactively test the effects of user-defined definitions of alpha (significance), beta (1-power), sample size and effect size. The tool generates a filter for all probe sets or more focused ontology-based subsets, with or without noise filters that can be used to limit analyses of a future project to appropriately powered probe sets. We studied projects from three organisms (Arabidopsis, rat, human), and three probe set algorithms (MAS5.0, RMA, dChip PM/MM). We found large differences in power results based on probe set algorithm selection and noise filters. RMA provided high sensitivity for low numbers of arrays, but this came at a cost of high false positive results (24% false positive in the human project studied). Our data suggest that a priori power calculations are important for both experimental design in hypothesis testing and hypothesis generation, as well as for the selection of optimized data analysis parameters. AVAILABILITY: The Hierarchical Clustering Explorer 3.5 with the interactive power analysis functions is available at www.cs.umd.edu/hcil/hce or www.cnmcresearch.org/bioinformatics. CONTACT: jseo@cnmcresearch.org

Algorithms↗

Improving on ETDRS acuities: design and results for a computerised thresholding device.

AIMS: All visual acuity data are subject to test-retest variability (TRV). This measurement error obscures true clinical change and reduces the statistical power of clinical trials using acuity as a primary outcome measure. This study was designed to assess whether a computerised system can reduce TRV by taking repeated acuity measurements and averaging them. A computerised system (PC-test) was developed for this purpose and compared in terms of TRV with the current Gold Standard ETDRS logMAR chart. METHODS: A total of 19 subjects with a mean acuity of +0.16 logMAR (range +0.49 to -0.10 logMAR) were recruited. The performance of two computerised tests (one averaging 10 repeats and one five) was compared with that of the ETDRS logMAR chart in terms of TRV and agreement of acuity data. Results The 10 and five repeat computerised tests (PC-tests) produced a TRV of +/-0.11 and +/-0.10 logMAR, respectively, compared with +/-0.18 logMAR for the ETDRS chart. No significant bias was observed between PC-test and ETDRS acuities. CONCLUSIONS: A computerised system that takes repeated acuity measurements and averages them is subject to less TRV than a single ETDRS acuity measurement. A reduced TRV of visual acuity data allows earlier detection of true clinical change in individual patients. It also allows smaller differences between groups to be detected in clinical trials for a given degree of statistical confidence and power.

Diagnosis, Computer-Assisted↗

Multireader receiver operating characteristic studies: a comparison of study designs.

RATIONALE AND OBJECTIVES: Traditionally, multireader receiver operating characteristic (ROC) studies have used a "paired-case, paired-reader" design. The statistical power of such a design for inferences about the relative accuracies of the tests was assessed and compared with alternative designs. METHODS: The noncentrality parameter of an F statistic was used to compute power as a function of the reader and patient sample sizes and the variability and correlation between readings. RESULTS: For a fixed-power and Type I error rate, the traditional design reduces the number of verified cases required. A hybrid design, in which each reader interprets a different sample of patients, reduces the number of readers, total readings, and reading required per reader. The drawback is a substantial increase in the number of verified cases. CONCLUSION: The ultimate choice of study design depends on the nature of the tests being compared, limiting resources, a priori knowledge of the magnitude of the correlations and variability and logistic complexity.

Analysis of Variance↗

Analyzing multivariate neurobehavioral outcomes in occupational studies: a comparison of approaches.

Neurobehavioral studies often employ test batteries and confront issues of multiple testing and comparability between batteries. We have organized our battery of 12 tests into areas of neurobehavioral function to reduce the number of reported results, provide greater statistical power, and improve interpretability of the results. We explored several different organizational and statistical methods of creating summary scores including a priori groupings based upon clinical experience and factor analysis. We compared the sensitivity of these summary scores to performance changes associated with exposure to styrene in the manufacture of reinforced plastics. Our results demonstrated dramatic increases in power to detect exposure related changes compared to using individual test scores. Furthermore, the various methods provided generally compatible and comparable results. We encourage other neurobehavioral investigators to pursue and refine this approach.

Adolescent↗

Sib-pair linkage tests for disease susceptibility loci: common tests vs. the asymptotically most powerful test.

Several statistical tests for linkage between a disease susceptibility locus and a marker locus for sib-pair data are examined analytically. Two common statistics, a test based on the mean number of marker alleles shared identical by descent by sib-pairs, and a test based on the proportion of sib-pairs sharing exactly two marker alleles, are shown to be special cases of a more general statistic. We use this more general statistic to derive the asymptotically most powerful statistic for a given genetic alternative hypothesis, and then compare this statistic with the "mean" statistic and the "proportion" statistic. Results indicate that the "mean" statistic generally compares well with the most powerful statistic. However, in some instances the "mean" statistic may lose power, relative to the most powerful. To guard against this, a new statistic (the maximum of the "mean" and "proportions" statistics) is considered and its asymptotic distribution is derived. Results indicate that this new statistic performs well.

Alleles↗

Paired versus two-sample design for a clinical trial of treatments with dichotomous outcome: power considerations.

For the same number of observations in a small-sample clinical trial with dichotomous outcome, the statistical power associated with a two-sample design, analyzed by Fisher's exact test, is slightly greater than that associated with a matched design, analyzed by McNemar's test, and hence of the matched design, is monotone increasing in the within-pair correlation between the treatment responses. Power curves are presented which demonstrate that positive within-pair correlation, even when quite small, can result in a superiority in power for the matched design. Conversely, in the rare situations where there is a negative within-pair correlation, choice of a two-sample design can result in a substantial gain in power.

Clinical Trials as Topic↗

Association of sperm, vaginal cytology, and reproductive organ weight data with results of continuous breeding reproduction studies in Swiss (CD-1) mice.

In continuous breeding reproduction studies in which an adverse effect on fertility was detected over an 18-week treatment period, a crossover mating trial was then conducted to determine the affected sex. Results of 25 crossover breeding studies conducted using Swiss (CD-1) mice were compared with results of sperm morphology and vaginal cytology examinations (SMVCEs) conducted at the conclusion of the mating trial. SMVCE endpoints include sperm concentration, motility, and morphology, vaginal cytology, and male reproductive organ weights. In most SMVCE studies multiple endpoints were adversely affected. For male reproductive toxicants, sperm motility was decreased in 89% of the studies, and absolute right epididymis and right testis weights were affected less frequently (80% each). Among studies with no detectable reduction in male breeding performance, 87% exhibited no detectable decrease in epididymis weight. Eighty-two percent had no change in cauda epididymis weight and 80% had no significant change in sperm concentration. An increase in female cycle length was associated (100%) with an effect on breeding due to female dysfunction. Overall accuracy, defined as correct identification of toxicants and nontoxicants, was highest for epididymis weight (84%), followed by cauda epididymis weight and sperm motility (79% each), and sperm concentration (76%). Female cycle length was so variable that the overall accuracy of the parameter in 13 studies was 69%. With the variety of chemicals used in this analysis, the association of abnormal sperm morphology with reproductive outcome was 71%. Control data (mean, 95% confidence interval around the mean, median, and statistical sensitivity) for each male endpoint (parent, and offspring at 10 weeks of age following a single breeding) were summarized from each of the two laboratories that conducted the studies. For several endpoints, statistical power was dependent on the laboratory conducting the studies. In general, the statistical sensitivity was relatively high for reproductive organ weights, although it was less for smaller organs such as the prostate. On the basis of both the biological and statistical analyses, it is recommended that multiple SMVCE endpoints, including sperm measures, be included in screens for reproductive toxicants.

Animals↗

Discovering statistically significant pathways in expression profiling studies.

Accurate and rapid identification of perturbed pathways through the analysis of genome-wide expression profiles facilitates the generation of biological hypotheses. We propose a statistical framework for determining whether a specified group of genes for a pathway has a coordinated association with a phenotype of interest. Several issues on proper hypothesis-testing procedures are clarified. In particular, it is shown that the differences in the correlation structure of each set of genes can lead to a biased comparison among gene sets unless a normalization procedure is applied. We propose statistical tests for two important but different aspects of association for each group of genes. This approach has more statistical power than currently available methods and can result in the discovery of statistically significant pathways that are not detected by other methods. This method is applied to data sets involving diabetes, inflammatory myopathies, and Alzheimer's disease, using gene sets we compiled from various public databases. In the case of inflammatory myopathies, we have correctly identified the known cytotoxic T lymphocyte-mediated autoimmunity in inclusion body myositis. Furthermore, we predicted the presence of dendritic cells in inclusion body myositis and of an IFN-alpha/beta response in dermatomyositis, neither of which was previously described. These predictions have been subsequently corroborated by immunohistochemistry.

Algorithms↗

Methodological and statistical problems in sleep apnea research: the literature on uvulopalatopharyngoplasty.

A comprehensive review of the literature on the surgical treatment of sleep apnea found 37 appropriate papers (total n = 992) on uvulopalatopharyngoplasty (UPPP). Methodological and statistical problems in these papers included the following: 1) There were no randomized studies and few (n = 4) with control groups. 2) Median sample size was only 21.5; thus statistical power was low and clinically important associations were routinely classified as "not statistically significant". 3) Only one paper presented the confidence bounds that might distinguish between statistical and clinical significance. 4) Because of short follow-up time and infrequent repeat follow-ups, little is known about whether UPPP results deteriorate with time. 5) In at least 15 papers, bias caused by retrospective designs and nonrandom loss to follow-up raised questions about the generalizability of results. 6) Few papers associated polysomnographic data with patient-based quality of life measures. 7) Missing data and missing and inconsistent definitions were common. 8) Baseline measures were often biased because the same assessment was inappropriately but routinely used for both screening and baseline. We conclude that because of these and other problems, there is much that is needlessly unknown about UPPP. It is the responsibility of the research and professional communities to define training, editorial and review procedures that will raise the methodological and statistical quality of published research.

Humans↗

Methodological issues in case-control studies: validity and power of various design/analysis strategies.

Computer stimulations have been used to estimate the efficiency, as measured by the statistical power, of various combinations of design and analysis strategies for case-control studies. Conditions under which the various forms of analysis yield consistent relative risk estimators are derived for the general model. The results indicate that the loss of efficiency resulting from the use of a less than optimum design or analysis strategy in many real life situations is small. Practical considerations are of more importance than theoretical statistical ones in deciding upon appropriate strategies. It is concluded that matching is rarely, if ever, justified in most case-control studies of chronic diseases.

Adult↗

Calculation of power for matched pair studies when randomization is by group.

A formula is given for the calculation of the statistical power of paired intervention trials in which the units of randomization are groups rather than individuals. Factors affecting the power of such trials are also investigated and an example is given where the power of group randomization is compared to that of individual randomization.

Humans↗

Meta-analyses of cluster randomization trials. Power considerations.

A commonly cited purpose for conducting a meta-analysis of randomized trials is to increase the statistical power for detecting the effect of an intervention on a specified set of endpoints. At the same time, it also has been noted by several authors that many large-scale cluster randomization trials have not had the power to detect small or even moderate effect sizes. The loss of efficiency associated with cluster randomization relative to individual randomization, and the frequent failure of investigators to take this loss of efficiency into account at the planning stage of a trial, undoubtedly contributes to this problem. In this article, the authors present an approach that may be used to estimate the power of a planned meta-analysis that includes trials that are cluster randomized. Two examples are presented.

Cluster Analysis↗

How many replicates of arrays are required to detect gene expression changes in microarray experiments? A mixture model approach.

BACKGROUND: It has been recognized that replicates of arrays (or spots) may be necessary for reliably detecting differentially expressed genes in microarray experiments. However, the often-asked question of how many replicates are required has barely been addressed in the literature. In general, the answer depends on several factors: a given magnitude of expression change, a desired statistical power (that is, probability) to detect it, a specified Type I error rate, and the statistical method being used to detect the change. Here, we discuss how to calculate the number of replicates in the context of applying a nonparametric statistical method, the normal mixture model approach, to detect changes in gene expression. RESULTS: The methodology is applied to a data set containing expression levels of 1,176 genes in rats with and without pneumococcal middle-ear infection. We illustrate how to calculate the power functions for 2, 4, 6 and 8 replicates. CONCLUSIONS: The proposed method is potentially useful in designing microarray experiments to discover differentially expressed genes. The same idea can be applied to other statistical methods.

Animals↗

On power and sample size for studying features of the relative odds of disease.

Estimates of sample size and statistical power are essential ingredients in the design of epidemiologic studies. Once an association between disease and exposure has been demonstrated, additional studies are often needed to investigate special features of the relation between exposure, other covariates, and risk of disease. The authors present a general formulation to compute sample size and power for case-control and cohort studies to investigate more complex patterns in the odds ratios, such as to distinguish between two different slopes of linear trend, to distinguish between two possible dose-response relations, or to distinguish different models for the joint effects of two important exposures or of one exposure factor adjusting for another. Such special studies of exposure-response relations may help investigators to distinguish between plausible biologic models and may lead to more realistic models for calculating attributable risk and lifetime disease risk. The sample size formulae are applied to studies of indoor radon exposure and lung cancer and suggest that epidemiologic studies may not be feasible for addressing some issues. For example, if the risk estimates from underground miners' studies are, in truth, not applicable to home exposures and overestimate the gradient of risk from home exposure to radon by, for example, a factor of 2, then enormously large numbers of subjects would be required to detect the difference. Furthermore, if the true interaction between smoking and radon exposure is less than multiplicative, only the largest investigations will have sufficient power to reject additivity. For the simple case of testing for no exposure effect, when exposure is either dichotomous or continuous, these methods yield well-known formulae.

Aged↗