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Treating postoperative pain improves outcome.

Recent surveys show that many patients still receive inadequate post-surgical analgesia, this problem is international in character. Analgesia techniques like patient-controlled analgesia (PCA) and spinal opioids alone or in combination with local anaesthetics provide superior pain relief compared to intermittent i.m. injections of opioids. Patient satisfaction with these techniques is high; however, reduced pain and suffering or high patient satisfaction is not considered sufficient in this age of diminished health care budgets. There is no overwhelming evidence that effective postoperative pain relief assures good postoperative outcome. Most studies lack sufficient statistical power to detect clinically significant differences. A meta-analysis showed higher patient satisfaction with i.v. PCA compared to i.m. opioid injection. Although PCA still is the standard of care there's little rational or scientific evidence that i.v. PCA improves outcome. A meta-analysis of randomized, controlled trials to assess the effects of seven analgesic therapies on postoperative pulmonary function after various procedures has shown that postoperative epidural pain control can significantly decrease the incidence of pulmonary morbidity. None of the other analgesic techniques had a significant impact on pulmonary outcome. There are few outcome studies with peripheral nerve blocks. Evidence that peripheral nerve blocks are better than PCA and safer than epidural increases. One reason why improved outcome is difficult to demonstrate is that pain management strategies are not integrated with overall perioperative care and postoperative rehabilitation of the patient. The importance of a good APS in developing cost-effective, evidence-based pain treatment strategies for different surgical procedures should not be underestimated.

Analgesia↗

[Topographic selective mapping in patients with disorders of thermoregulation of cerebral origin].

The paper privides the data on topographic selective mapping of electric activity in a state of relaxed consciousness in 11 patients with derangement of thermoregulation of the central genesis compared to a group of patients with vegetative crises. 10 healthy volunteers served as control. On the whole the patients' group was characterized by diffuse augmentation of percentile presentation of the power of slow and regress of rapid ranges. The statistical analysis revealed varying electrophysiological organization in patients with paroxysmal and permanent character of hyperthermia. In the group of patients with paroxysmal temperature rises and vegetative crises, the electrophysiological parameters were identical. In patients with permanent ++sub-febrility, the pattern of spatial electric activity was characterized by qualitative and quantitative differences from the control group.

Action Potentials↗

Detection of changes in the mouse circadian rhythm induced by stress.

Mice were subjected to three types of acute stress (cold, forced swimming and tail hanging) in order to investigate the effects of stress on the motor activity circadian rhythm. This rhythm was studied using the cosinor method and spectral analysis. A statistically significant decrease in the amplitude and the power content of the circadian harmonic was found after stress application. These decreases could be due to a desynchronization of the circadian oscillators which drive the rhythm. The use of the power content of the circadian harmonic is proposed for the detection of the alterations due to stress.

Animals↗

Oxidative metabolism and body weight: inactive, active, and mitochondrial volumes.

In homeotherms, the standardized (basal) metabolic rate should not be expressed per kilogram of body weight (specific metabolic rate), nor per unit of body surface (square meters of body-ambient interface), since both mitochondrial thermogenesis and heat-loss mechanisms (radiation, conduction, convection, evaporation) are not uniform processes. On the contrary, each organism is an heterogeneous bioreactor, which is composed at least of two compartments: 1) a metabolically active volume (aV), where oxidative phosphorylation takes place; and 2) a metabolically inactive volume (iV), where oxygen consumption is negligible. The ratio (aV/iV) is not invariant, since iV increases disproportionately with the scaling up of body size, and as shown by us, when the three main components of iV, i.e., skeleton, fat deposits, and blood volume, are added together, a similar disproportionality is found. The aV was determined by subtracting the iV from the total volume (V) of an organism, or by estimating the volume occupied by all mitochondria, or mitochondrial volume (mtV). For this purpose two procedures are discussed: 1) the stereological or morphometric method; and 2) the oxygen consumption per unit time or physiometric method. The latter procedure is based on the equivalence between an VO2 = 3 ml O2.min-1 and a mtV of 1 ml, whose oxidative phosphorylation yields an approximate power output of 1 watt. The correspondence between oxygen consumption, heat production, and electron flux at the respiratory chain of the mitochondrial cristae, is discussed. From a physical point of view, the metabolic rate is a "power" function (P = M L2T-3), where M = mass, L = length, and T = time. The dimensional analysis and the statistical treatment of the corresponding numerical values of more than 200 allometric equations yields the 3/4 power, law established by Kleiber (1961), for the relationship between basal metabolism and body weight. Instead of expressing the metabolic rate per unit body weight (kg-1) or per unit body surface (m-2) structural and functional criteria should be taken into account as, for instance, the distinction between iV and aV, and particularly by emphasizing the paramount importance of the mtV where oxidative phosphorylation takes place. An allometric equation relating mtV and body weight (W) could be tentatively established for interspecies comparisons.

Adenosine Triphosphate↗

Fetal cells in the maternal circulation. Technical considerations for practical application to prenatal diagnosis.

Recent advances in cell separation technology and DNA analytic techniques leave little doubt as to the presence of fetal cells in the maternal circulation. The potential of using these cells for genetic analysis is compelling. The practical aspects of establishing a universal method utilizing the new capabilities in clinical practice have not been addressed to date. The major hurdles that still need to be traversed before this technology is universally adopted include the identification of appropriate sampling and separation methods yielding fetal cells amenable to genetic analysis by rapid DNA technologies, clinical studies of appropriate statistical power to validate and compare this approach to current genetic testing, and comparison of this approach to other noninvasive paradigms such as triple screening. Despite the tremendous value of noninvasive genetic screening, the rigorous course required to progress from description of scientific capability to validation of a clinical test must not be ignored or rushed for financial considerations.

DNA↗

Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure.

OBJECTIVES: Using a prospective study design, we assessed the value of brain natriuretic peptide (BNP) to identify patients with heart failure who have an increased risk of deterioration of their functional status. Furthermore, we examined the relationship between BNP and various clinical characteristics incorporated into an established survival model used for risk stratification. BACKGROUND: Prediction of the clinical course is a crucial part of the decision-making process about the adequate treatment strategy for patients with advanced congestive heart failure (CHF). Although laborious, multivariable indexes have been established for risk stratification, simple plasma BNP measurements may be as useful as prognostic indicators. METHODS: In 78 patients referred to our heart failure clinic, plasma BNP levels were compared with the results of a multivariable prognostic model. To assess the prognostic power of BNP, the clinical course of this cohort was monitored for a median follow-up period of 398 days. RESULTS: At study entry, plasma BNP and the heart failure survival score (HFSS) showed a significant correlation (r = -0.706). During follow-up, Kaplan-Meier estimates of freedom from clinical events differed significantly for patients above and below the 75th percentile concentrations of plasma BNP (p < 0.0001). Changes in plasma BNP were significantly related to changes in limitations of physical activity, as demonstrated by logistic regression analysis (chi-square statistic = 24.9, p < 0.0001). Proportional hazards analysis confirmed BNP as a powerful predictor of functional status deterioration (p < 0.0001). This prognostic information was as powerful as that derived from the multivariable HFSS. CONCLUSIONS: Measurement of plasma BNP concentrations might provide a useful and cost-effective screening tool that helps reduce the need and frequency for more expensive cardiac tests.

Activities of Daily Living↗

ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.

PURPOSE: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. METHODS: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, >or=48-week treatment duration without forced exit criteria, information on >or=24-week seizure freedom data (efficacy) or >or=48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a <or=20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. RESULTS: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. CONCLUSIONS: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

Adult↗

Controlled trials of therapy in fibromyalgia syndrome.

Many different interventions have been studied in the therapy of fibromyalgia syndrome (Tables 1 and 2). While most have been effective, in general these trials have been short term. Furthermore, important or substantial improvement, when it has been assessed, occurs in only small proportions of patients. Long-term, comparative trials of both efficacy and toxicity are necessary. Trials such as these require large numbers of patients (compared with placebo-controlled trials, which are generally impractical in long-duration trials due to the large numbers of dropouts in the placebo arm) and therefore are expensive and difficult to accomplish. Two other approaches offer potential solutions to the problem of adequate long-term comparative trials: (a) N-of-1 trials and (b) meta-analysis. N-of-1 trials have the advantage of random assignment, double-blinding and multiple potential comparisons in the same patient. Meta-analysis involves combining the results of studies, which individually may have conflicting results and lack adequate statistical power, to reach an overall result with sufficient statistical power to make meaningful conclusions, especially with respect to comparative efficacy. Peluso and colleagues (1993) have performed a recent meta-analysis of available therapies in fibromyalgia syndrome and found that the effect-size (a standardized measure of the efficacy of a given therapy) of several non-medication therapies such as electroacupuncture exceeded that of traditional medication therapies. Unfortunately, lack of uniformity in the use of outcome measures across included trials and the small numbers of comparable non-medication trials makes definitive conclusions regarding relative efficacy of therapies difficult. Nevertheless, application of meta-analytic methods such as these should facilitate future comparisons of different interventions. Ideally, future clinical trials in fibromyalgia syndrome should employ the same outcome measures to permit application of these methods. Few trials have assessed improvement in functional status. Functional status measures such as the HAQ (Fries et al., 1980), the Fibromyalgia Impact Questionnaire (Burckhardt et al, 1991) or similar instruments should be employed in future studies of therapy in fibromyalgia. Given that individual modalities appear to confer relatively modest benefit on average. Combination approaches are reasonable, although randomized, blinded trials to assess these approaches are methodologically complex. Several preliminary studies which have addressed this approach appear promising (see Chapter 12; Goldenberg et al, 1993). Finally, no studies have yet assessed the comparative cost-efficacy of available treatments. Controlled trials which address the cost-efficacy of commonly employed, but unproven treatments such as physiotherapy chiropractic manipulation and injection techniques are urgently needed.

Antidepressive Agents↗

Generalized T2 test for genome association studies.

Recent progress in the development of single-nucleotide polymorphism (SNP) maps within genes and across the genome provides a valuable tool for fine-mapping and has led to the suggestion of genomewide association studies to search for susceptibility loci for complex traits. Test statistics for genome association studies that consider a single marker at a time, ignoring the linkage disequilibrium between markers, are inefficient. In this study, we present a generalized T2 statistic for association studies of complex traits, which can utilize multiple SNP markers simultaneously and considers the effects of multiple disease-susceptibility loci. This generalized T2 statistic is a corollary to that originally developed for multivariate analysis and has a close relationship to discriminant analysis and common measure of genetic distance. We evaluate the power of the generalized T2 statistic and show that power to be greater than or equal to those of the traditional chi2 test of association and a similar haplotype-test statistic. Finally, examples are given to evaluate the performance of the proposed T2 statistic for association studies using simulated and real data.

Algorithms↗

Application of meta-analysis in reviewing occupational cohort studies.

Meta-analysis has been used increasingly in reviewing and summarising epidemiological studies. Reviews incorporating meta-analyses have appeared in medical journals in increasing numbers. Although there are several methodology papers on meta-analysis, most of these papers have been written primarily for discussion among epidemiologists. The present paper considers some of the basic methodological issues, the more practical aspects of meta-analysis, and targets an audience of mainly non-epidemiologists. Thus, the main objective of this paper is to provide some basic guidelines for non-epidemiologists to evaluate meta-analysis in occupational cohort studies. In this methodology paper, the limitations and problems of traditional qualitative reviews are pointed out. Some of these problems can be dealt with by quantitative meta-analysis. The potential limitations and benefits of quantitative meta-analysis are discussed. Rather than replacing traditional qualitative review, quantitative meta-analysis should be made part of the overall assessment. The term "meta-review" is proposed to emphasise the importance of both qualitative and quantitative components in a comprehensive review process. The basic steps in a meta-review are outlined, with a discussion on how to recognise and avoid some of the problems which are likely to occur at each step. A meta-review is useful in selecting studies, and in organising, presenting, and summarising results from individual studies. A meta-review can also be used to detect heterogeneity among studies. Major benefits of conducting a meta-analysis (the quantitative component in a meta-review) include the increase in statistical power and the estimate of a properly weighted summary risk estimate.

Brain Neoplasms↗

Quantified neurophysiology with mapping: statistical inference, exploratory and confirmatory data analysis.

Topographic mapping of brain electrical activity has become a commonly used method in the clinical as well as research laboratory. To enhance analytic power and accuracy, mapping applications often involve statistical paradigms for the detection of abnormality or difference. Because mapping studies involve many measurements and variables, the appearance of a large data dimensionality may be created. If abnormality is sought by statistical mapping procedures and if the many variables are uncorrelated, certain positive findings could be attributable to chance. To protect against this undesirable possibility we advocate the replication of initial findings on independent data sets. Statistical difference attributable to chance will not replicate, whereas real difference will reproduce. Clinical studies must, therefore, provide for repeat measurements and research studies must involve analysis of second populations. Furthermore, Principal Components Analysis can be employed to demonstrate that variables derived from mapping studies are highly intercorrelated and data dimensionality substantially less than the total number of variables initially created. This reduces the likelihood of capitalization on chance. The need to constrain alpha levels is not necessary when dimensionality is low and/or a second data set is available. When only one data set is available in research applications, techniques such as the Bonferroni correction, the "leave-one-out" method, and Descriptive Data Analysis (DDA) are available. These techniques are discussed, clinical and research examples are given, and differences between Exploratory (EDA) and Confirmatory Data Analysis (EDA) are reviewed.

Brain↗

The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study.

BACKGROUND: Many randomized trials involve measuring a continuous outcome - such as pain, body weight or blood pressure - at baseline and after treatment. In this paper, I compare four possibilities for how such trials can be analyzed: post-treatment; change between baseline and post-treatment; percentage change between baseline and post-treatment and analysis of covariance (ANCOVA) with baseline score as a covariate. The statistical power of each method was determined for a hypothetical randomized trial under a range of correlations between baseline and post-treatment scores. RESULTS: ANCOVA has the highest statistical power. Change from baseline has acceptable power when correlation between baseline and post-treatment scores is high;when correlation is low, analyzing only post-treatment scores has reasonable power. Percentage change from baseline has the lowest statistical power and was highly sensitive to changes in variance. Theoretical considerations suggest that percentage change from baseline will also fail to protect from bias in the case of baseline imbalance and will lead to an excess of trials with non-normally distributed outcome data. CONCLUSIONS: Percentage change from baseline should not be used in statistical analysis. Trialists wishing to report this statistic should use another method, such as ANCOVA, and convert the results to a percentage change by using mean baseline scores.

Computer Simulation↗

[Data collection in anesthesia. Experiences with the inauguration of a new information system].

UNLABELLED: In many institutions information systems are used to process off-line anaesthesia data for invoices, statistical purposes, and quality assurance. Information systems are also increasingly being used to improve process control in order to reduce costs. Most of today's systems were created when information technology and working processes in anaesthesia were very different from those in use today. Thus, many institutions must now replace their computer systems but are probably not aware of how complex this change will be. Modern information systems mostly use client-server architecture and relational data bases. Substituting an old system with a new one is frequently a greater task than designing a system from scratch. This article gives the conclusions drawn from the experience obtained when a large departmental computer system is redesigned in an university hospital. METHODS: The new system was based on a client-server architecture and was developed by an external company without preceding conceptual analysis. Modules for patient, anaesthesia, surgical, and pain-service data were included. Data were analysed using a separate statistical package (RS/1 from Bolt Beranek), taking advantage of its powerful precompiled procedures. RESULTS: Development and introduction of the new system took much more time and effort than expected despite the use of modern software tools. Introduction of the new program required intensive user training despite the choice of modem graphic screen layouts. Automatic data-reading systems could not be used, as too many faults occurred and the effort for the user was too high. However, after the initial problems were solved the system turned out to be a powerful tool for quality control (both process and outcome quality), billing, and scheduling. The statistical analysis of the data resulted in meaningful and relevant conclusions. CONCLUSIONS: Before creating a new information system, the working processes have to be analysed and, if possible, made more efficient; a detailed programme specification must then be made. A servicing and maintenance contract should be drawn up before the order is given to a company. Time periods of equal duration have to be scheduled for defining, writing, testing and introducing the program. Modern client-server systems with relational data bases are by no means simpler to establish and maintain than previous mainframe systems with hierarchical data bases, and thus, experienced computer specialists need to be close at hand. We recommend collecting data only once for both statistics and quality control. To verify data quality, a system of random spot-sampling has to be established. Despite the large investments needed to build up such a system, we consider it a powerful tool for helping to solve the difficult daily problems of managing a surgical and anaesthesia unit.

Anesthesia↗

On the power for linkage detection using a test based on scan statistics.

We analyze some aspects of scan statistics, which have been proposed to help for the detection of weak signals in genetic linkage analysis. We derive approximate expressions for the power of a test based on moving averages of the identity by descent allele sharing proportions for pairs of relatives at several contiguous markers. We confirm these approximate formulae by simulation. The results show that when there is a single trait-locus on a chromosome, the test based on the scan statistic is slightly less powerful than that based on the customary allele sharing statistic. On the other hand, if two genes having a moderate effect on a trait lie close to each other on the same chromosome, scan statistics improve power to detect linkage.

Chromosome Mapping↗

Optimal allele-sharing statistics for genetic mapping using affected relatives.

The choice of allele-sharing statistics can have a great impact on the power of robust affected relative methods. Similarly, when allele-sharing statistics from several pedigrees are combined, the weight applied to each pedigree's statistic can affect power. Here we describe the direct connection between the affected relative methods and traditional parametric linkage analysis, and we use this connection to give explicit formulae for the optimal sharing statistics and weights, applicable to all pedigree types. One surprising consequence is that under any single gene model, the value of the optimal allele-sharing statistic does not depend on whether observed sharing is between more closely or more distantly related affected relatives. This result also holds for any multigene model with loci unlinked, additivity between loci, and all loci having small effect. For specific classes of two-allele models, we give the most powerful statistics and optimal weights for arbitrary pedigrees. When the effect size is small, these also extend to multigene models with additivity between loci. We propose a useful new statistic, S(rob dom), which performs well for dominant and additive models with varying phenocopy rates and varying predisposing allele frequency. We find that the statistic S(_#alleles), performs well for recessive models with varying phenocopy rates and varying redisposing allele frequency. We also find that for models with large deviation from null sharing, the correspondence between allele-sharing statistics and the models for which they are optimal may also depend on which method is used to test for linkage.

Alleles↗

Analyses of multinomial mixture distributions: new tests for stochastic models of cognition and action.

Mixture distributions are formed from a weighted linear combination of 2 or more underlying basis distributions [g(x) = sigma j alpha j fj(x); sigma alpha j = 1]. They arise frequently in stochastic models of perception, cognition, and action in which a finite number of discrete internal states are entered probabilistically over a series of trials. This article reviews various distributional properties that have been examined to test for the presence of mixture distributions. A new multinomial maximum likelihood mixture (MMLM) analysis is discussed for estimating the mixing probabilities alpha j and the basis distributions fj(x) of a hypothesized mixture distribution. The analysis also generates a maximum likelihood goodness-of-fit statistic for testing various mixture hypotheses. Stochastic computer simulations characterize the statistical power of such tests under representative conditions. Two empirical studies of mental processes hypothesized to involve mixture distributions are summarized to illustrate applications of the MMLM analysis.

Arousal↗

Cerebrospinal fluid tau protein shows a better discrimination in young old (<70 years) than in old old patients with Alzheimer's disease compared with controls.

Tau protein is consistently reported to be elevated in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF tau alone, however, is not a clinically useful diagnostic marker due to its relatively low diagnostic specificity. Therefore, efforts are under way to combine tau measurements with other criteria in order to improve diagnostic applicability. We investigated whether age could serve as an useful criterion to increase diagnostic accuracy. CSF levels of tau were measured in young old (<70 years) and old old (> or =70 years) patients with probable AD, elderly patients with major depression (MD), and age-matched healthy controls (HC). In AD patients, CSF tau levels were significantly elevated compared with MD patients and HC (P < 0.001). Based on a previously established cut-off of 260 pg/ml, the discriminative power was higher in the young old than in the old old subjects. Similarly, receiver operating characteristics analysis revealed a statistically significant higher correct classification rate in the young old. Our findings indicate that the discriminative power of CSF tau is higher in the young than in the old old. We suggest that the effect of age should be considered in studies investigating CSF tau as a diagnostic marker for neurodegenerative disorders.

Age Distribution↗