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At least 1,261 records · Page 70Linked to original sources
PubMed2002

Placebo response in studies of major depression: variable, substantial, and growing.

CONTEXT: Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. OBJECTIVE: To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. DATA SOURCES AND STUDY SELECTION: We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. DATA EXTRACTION: Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. DATA SYNTHESIS: The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. CONCLUSIONS: The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.

Adult↗
PubMed1966

World biomedical journals, 1951-60: a study of the relative significance of 1,388 titles indexed in Current List of Medical Literature.

This study is an application of the relationship of serial articles published to serial articles cited, developed in theory in the author's "Statistical Bibliography in the Health Sciences" (Bulletin 50: 450-461, July 1962). A ranked list of the indexes of significance of most of the serials indexed in Current List of Medical Literature was derived and erected from 21,000 citations secured in a random sampling of 1962 and 1961 biomedical journals regularly received in the Yale Medical Library. The author measures the gross indexing effectiveness of Current List against his indexes of significance, offers his method and results as means to reach objective standards for indexing and abstracting, and projects his results as measures of general value of the serials analyzed.

Abstracting and Indexing↗
PubMedDate not supplied

Statistical principles for clinical trials.

If a trial is to be well designed, and the conclusions drawn from it valid, a thorough understanding of the benefits and pitfalls of basic statistical principles is required. When setting up a trial, appropriate sample-size calculation is vital. If initial calculations are inaccurate, trial results will be unreliable. The principle of intent-to-treat in comparative trials is examined. Randomization as a method of selecting patients to treatment is essential to ensure that the treatment groups are equalized in terms of avoiding biased allocation in the mix of patients within groups. Once trial results are available the correct calculation and interpretation of the P-value is important. Its limitations are examined, and the use of the confidence interval to help draw valid conclusions regarding the clinical value of treatments is explored.

Clinical Trials as Topic↗
PubMed2006

Systematic reviews and meta-analysis for the surgeon scientist.

BACKGROUND: Understanding of data-reporting methods is imperative for correct interpretation of the medical literature as well as for proper performance of future clinical research. Recent developments in biostatistics have greatly changed the types of statistical analyses used and the minimum quality standards that must be maintained. METHOD: Different types of review are described, including systematic review with and without meta-analysis. Minimum reporting standards, sources of bias, both quantitative and qualitative, and references are discussed. RESULTS AND CONCLUSION: Meta-analysis has become a clearly defined technique, with reporting standards for both randomized controlled trials and observational studies. It is assuming a wider role in the surgical literature. Although many sources of bias exist, there are clear reporting standards and readers should be aware of these when studying the literature.

General Surgery↗
PubMedDate not supplied

Do HMOs affect educational disparities in health care?

BACKGROUND: We wanted to examine how membership in a health maintenance organization (HMO) is related to delivery of preventive clinical services to patients with different educational levels. METHODS: We conducted a cross-sectional analysis of the 1996-1997 Community Tracking Study Household Survey among adults aged 18 to 64 years with private or Medicaid health insurance. We examined interactions between respondent educational level and HMO membership for the following measures: having a regular source of care and, in the past year, having had a physician visit, a mental health visit, a mammogram (women > or = 50 years), an influenza vaccination (ages > or = 55 years), or smoking cessation counseling (smokers). RESULTS: After adjustment for sociodemographic factors, community size, insurance type, physical and mental health status, and smoking, respondents with less education were significantly less likely to have had a physician visit or mental health visit, mammogram, or influenza vaccination in the past year. Disparities in receipt of preventive care by educational level were smaller among HMO members. Differences in disparities between HMO members and non-HMO members reached statistical significance for influenza vaccination and showed a trend for mental health visits (P = .06). Moreover, HMO members with less than 12 years of education received services at levels comparable to non-HMO members with more education. CONCLUSIONS: There are appreciable disparities in receipt of preventive care by education among nonelderly insured persons. HMO membership is associated with smaller disparities for some services. Those with the lowest levels of education appeared to benefit the most from HMO membership.

Adolescent↗
PubMed1994

Monitoring pairwise comparisons in multi-armed clinical trials.

This paper proposes a method for monitoring multi-armed clinical trials on the basis of pairwise comparisons between arms. The set of pairwise test statistics is examined during the course of the trial in order to make decisions about hypotheses, continuation of treatment arms, and continuation of the trial. Strong control of the Type I error rate is achieved by modifying two-armed group sequential procedures of Pocock (1977, Biometrika 64, 191-199), O'Brien and Fleming (1979, Biometrics 35, 549-556), and Lan and DeMets (1983, Biometrika 70, 659-663) to multi-armed trials. In the fixed-sample situation, these methods reduce to either Dunnett's or Tukey's procedure for multiple comparisons. A simpler, more flexible approximation based on the Bonferroni inequality is suggested, as well as an analogue to a sequentially rejective procedure.

Clinical Trials as Topic↗
PubMed1994

The early termination of clinical trials: causes, consequences, and control. With special reference to trials in the field of arrhythmias and sudden death. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology.

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations because of the inherent difficulty of a prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a Task Force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial.

Anti-Arrhythmia Agents↗
PubMedDate not supplied

The importance of effect mechanism in the design and interpretation of clinical trials: the role of magnesium in acute myocardial infarction.

The design and interpretation of randomized clinical trials and of meta-analyses of trials should be informed by a biologically plausible hypothesis of treatment effect. Without some insight on likely mechanism, trial conditions may not be optimum to allow a true treatment effect to be detected. Judgments on mechanism underpin decisions on the appropriateness of pooling studies in meta-analysis. Where statistical heterogeneity of trial results is found, the possibility of true biological effect modification can only be assessed by considering potential treatment mechanisms. These can then be tested in carefully designed laboratory models. Meta-analysis of 12 randomized controlled trials of intravenous Mg(2+) in acute myocardial infarction gives a null effect (odds ratio 1.02, 95% CI 0.96 to 1.08) with a fixed effects model, but with strong evidence of heterogeneity (P <.0001) due to a single large study in which Mg(2+) was generally given late and after fibrinolytic treatment. A random effects model gives a pooled odds ratio 0.61 (95% CI 0.43 to 0.87, P = 0.006). Laboratory models show that timing of Mg(2+) administration before or after reperfusion critically determines whether myocardial protection occurs.

Humans↗
PubMed1995

The problem of the type II statistical error.

OBJECTIVE: To determine if type II statistical errors (also known as beta errors) are a common problem in published clinical research. METHODS: Type II statistical errors occur when sample sizes are too small to show an effect of treatment, even when an effect truly exists. Searching the Medline data base, we identified ten meta-analyses published during 1986-1994 in the American Journal of Obstetrics and Gynecology, Obstetrics and Gynecology, and The Journal of Reproductive Medicine. Meta-analyses were used as sources of component or individual studies for the following reason: When small component studies have negative findings that differ from the overall conclusions of the meta-analysis, the component studies may have type II statistical errors. RESULTS: We found that only 6.5% (15 of 231) of component studies provided any documentation that power calculations to determine sample sizes had been done a priori (before) the research began. Thus, many of these component studies with findings of no treatment effect may have had type II errors because of too-small sample sizes. When stratifying the component studies by year of publication, we found that 7.9% (14 of 178) of studies published in the 1980s and 1990s had any documented evidence of a priori power calculations. In the 1960s and 1970s, only one of 53 component studies had documented evidence of power calculations. CONCLUSION: To ensure that truly effective treatments are introduced into clinical practice as quickly as possible, we believe that a priori power calculations should always be done in quantitative clinical research.

Meta-Analysis as Topic↗
PubMed2001

Can placebo controls reduce the number of nonresponders in clinical trials? A power-analytic perspective.

BACKGROUND: There is ongoing debate regarding the ethics of placebo-controlled clinical trials when a moderately effective standard treatment exists. One aspect of the debate--the number of nonresponders--tends to be overlooked. A larger between-group effect size is expected in placebo-controlled trials than in trials with an active comparator. For that reason, substantially fewer subjects need to be enrolled in placebo-controlled trials; consequently, there tend to be far fewer nonresponders in placebo-controlled trials. OBJECTIVE: This analysis was undertaken to illustrate that the use of placebo as a control can reduce the number of subjects who are unnecessarily exposed to delayed treatment. METHODS: Statistical power analyses were used to estimate the sample size required to detect various population treatment differences and the resulting number of nonresponders for 2-tailed chi-square tests. RESULTS: Empiric evidence of the phenomenon is provided for a wide range of rates of response to placebo, investigational, and comparator treatments. For example, 24 subjects (ie, 12 per group) are needed to detect differences between placebo (10% response rate) and an investigational drug (70% response); 15 of these would not respond. In contrast, if the investigational drug (70% response) is initially compared with a standard therapy (60% response), 752 subjects would be required, 263 of whom would not respond. CONCLUSIONS: This paper shows empirically that placebo controls can reduce the number of nonresponders in a randomized controlled trial. The number of subjects who are exposed to unproven, albeit promising, investigational drugs should be kept to a minimum until placebo-controlled trials support their use.

Clinical Trials as Topic↗
PubMed2001

Achieving graphical excellence: suggestions and methods for creating high-quality visual displays of experimental data.

Graphics are an important means of communicating experimental data and results. There is evidence, however, that many of the graphics printed in scientific journals contain errors, redundancies, and lack clarity. Perhaps more important, many graphics fail to portray data at an appropriate level of detail, presenting summary statistics rather than underlying distributions. We seek to aid investigators in the production of high-quality graphics that do their investigations justice by providing the reader with optimum access to the relevant aspects of the data. The depiction of by-subject data, the signification of pairing when present, and the use of symbolic dimensionality (graphing different symbols to identify relevant subgroups) and small multiples (the presentation of an array of similar graphics each depicting one group of subjects) to portray stratification are stressed. Step-by-step instructions for the construction of high-quality graphics are offered. We hope that authors will incorporate these suggestions when developing graphics to accompany their manuscripts and that this process will lead to improvements in the graphical literacy of scientific journals. We also hope that journal editors will keep these principles in mind when refereeing manuscripts submitted for peer review.

Data Display↗
PubMed1990

Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS)

OBJECTIVE: To determine whether oral corticosteroids can prevent early deterioration in patients with acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia. DESIGN: Prospective, double-blind, placebo-controlled, randomized trial. METHODS: Included patients were having their first P. carinii pneumonia episode, had no other known active pulmonary pathology, had no contraindications for corticosteroids, received no anti-P. carinii pneumonia medications for more than 48 hours, and had oxygen saturation by pulse oximetry of 85% or more and less than 90% at rest or a 5-percentage-point decrease in oxygen saturation with exercise while breathing room air. Consenting subjects were randomly assigned to prednisone, 60 mg/d for 7 days, followed by a progressive tapering over 14 days or to an identical placebo. Early deterioration, the endpoint of the trial, was defined as a 10% decrease in baseline oxygen saturation on day 3 or thereafter. The cases of patients developing early deterioration were considered to be failures of treatment; the code was then broken, and the patient's treatment was left to the judgment of the treating physician. Sequential analysis was done with the primary variable being development of early deterioration. RESULTS: The trial was terminated 5 April 1989 on the basis of the sequential analysis when a total of nine episodes of early deterioration had occurred in the first 37 patients at an overall significance level of P = 0.0136. A total of 8 of 19 placebo-treated patients (42.1%) developed early deterioration compared with only 1 of 18 patients (5.6%) treated with corticosteroids. Baseline characteristics were not statistically different between the two treatment groups. The adjusted odds ratio for the treatment effect was 5.87 (95% CI, 1.27 to 27.4). The adjusted point estimates for the probability of early deterioration in the placebo and corticosteroid groups were 43% and 12%, respectively. All 8 patients in the placebo group developing early deterioration recovered rapidly with addition of corticosteroid treatment. The single patient with early deterioration in the corticosteroid group died on day 6 from overwhelming P. carinii pneumonia, as documented at autopsy. The corticosteroid group had an increased exercise tolerance on day 7 that persisted at day 30. CONCLUSION: Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with moderately severe AIDS-related P. carinii pneumonia.

Acquired Immunodeficiency Syndrome↗
PubMed2004

[Statistical notes. From superiority to non-inferiority clinical trials: a leap in the dark?].

In these "statistical notes", equivalence and non-inferiority randomized controlled clinical trials (RCCT) are considered. Equivalence trials are designed to confirm the absence of a meaningful difference between the effect of two treatments. Non-inferiority trials are designed to prove that the new treatment is no less effective than an existing one: it may be more effective or it may have a similar effect. In this note the attention is addressed to suitable criteria for the choice of the tolerance margin epsilon, i.e. the largest difference which is clinically acceptable, so that a difference bigger than that would matter in practice. In particular, the procedures for the determination of the margin epsilon, used by the authors of the non-inferiority RCCT COBALT and INJECT, are presented and discussed in detail. The ethical implications of equivalence and non-inferiority RCCT are here considered and the reader is repeatedly invited to consider the appropriateness of the basic arguments asserted by the supporters of this kind of studies.

Algorithms↗
PubMed2003

Estimating the efficacy of interventions to prevent mother-to-child transmission of human immunodeficiency virus in breastfeeding populations: comparing statistical methods.

Postnatal transmission of human immunodeficiency virus infection through breastfeeding complicates evaluating the efficacy of interventions aimed to reduce mother-to-child transmission risk. Results from trials in Africa evaluating either peripartum antiretroviral therapy or refraining from breastfeeding show an estimated long-term efficacy at 15-24 months of age between 25 and 50 percent. Differences in statistical methods, duration of follow-up, and age at weaning hinder direct comparison between trials. The authors recently outlined theoretically preferred statistical methods for evaluating interventions aimed to reduce risk of mother-to-child transmission of human immunodeficiency virus. When multiple test results and/or supplementary information is available, the more sophisticated methods account for the fact that exact age at infection is unknown, that risk for infection ends at weaning, or that censoring due to death may be informative. The authors apply these methods to four scenarios, using data from four randomized trials carried out in Africa between 1995 and 2000. The authors' findings suggest that, to estimate the cumulative proportion infected at age 6 weeks, a standard Kaplan-Meier approach is likely to give valid results. For estimation of this proportion at age 18 months, more sophisticated methods, such as the extension of the Kaplan-Meier procedure to interval-censored data and competing risks, would be preferred.

Adult↗
PubMed2006

Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data.

RATIONALE: Up to 60% of children with attention-deficit/hyperactivity disorder (ADHD) suffer from comorbid affective or behavioral impairments, the most common condition being oppositional defiant disorder (ODD), which occurs in 40-60% of children with ADHD. OBJECTIVES: This post hoc meta-analysis was performed to determine the effect of the presence of comorbid ODD symptoms on clinical outcomes among pediatric and adolescent subjects being treated for ADHD. METHODS: Acute-phase data were analyzed from three randomized, double-blind, placebo-controlled studies in outpatients aged 6-16 and meeting the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for ADHD. Subjects received placebo or atomoxetine (max 1.8 mg/kg/day, daily) for 6-8 weeks. Patients were diagnosed with comorbid ODD on structured diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-aged Children-Present and Lifetime Versions). RESULTS: Of the 512 subjects studied, 158 were diagnosed with comorbid ODD. Relative to placebo, atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects irrespective of the comorbidity with ODD. ADHD subjects also showed significant improvements from baseline on most of the psychosocial measures of the child health questionnaire irrespective of the comorbidity with ODD. Reduction in ODD symptoms was highly related to the magnitude of ADHD response. CONCLUSIONS: Atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects to similar extents, indicating that the presence of comorbid symptoms of oppositionality does not affect clinical outcomes of treatment of ADHD with atomoxetine.

Adolescent↗
PubMed1990

Statistical analysis of the clinical trial of a therapy for Alzheimer's disease. Univariate tests and logistic regression.

A placebo controlled, randomized, double blind, multicentric clinical trial was carried out in Italy to test the effectiveness of a drug in the therapy of Alzheimer's disease. Informed consensus was gained for the inclusion of 130 patients, whose mental performance was assessed before allocation and after 3, 6, 12 months of continuing assumption of treatment. 14 different outcome variables were used. The main analysis was performed on measures adjusted for baseline, using both univariate and multivariate techniques for each of the three assessing times. The former is mainly descriptive in its scope and allows an analytical view of the results; the latter protects from a too high type I error probability, without implying the loss of power produced by the Bonferroni correction. The techniques are respectively Mann-Whitney test, and analysis of deviance of logistic models, which was suggested by Cupples et al. (1984). In the latter we used the allocation of the patients as response variable, and compared the predictor containing all outcome measures with that having just a constant term. It is shown that a significant difference of fit implies that treatment significantly affects outcome. For the 3 and 6 month follow-up assessment, univariate tests do not show clearcut trends (only 1 outcome measure is significantly better for the drug, none is for the placebo). After 12 months, a trend shows: 13 out of 14 variables are in favour of the drug and 4 of them are significant. Of the three multivariate test carried out, that relative to the 12-month follow-up is significant at the 0.05 level, which is consistent with the univariate results.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed2006

Randomization in substance abuse clinical trials.

BACKGROUND: A well designed randomized clinical trial rates as the highest level of evidence for a particular intervention's efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA)-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial. RESULTS: Comparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large. CONCLUSION: We develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn randomization schemes and other highly adaptive designs. In many instances, simple or blocked randomization with stratification on a major covariate or two will accomplish the same objectives as an urn or adaptive design, and it can do so with more simply implemented schedules and without the dangers of overmatching. Furthermore, the proper analysis, fully accounting for the stratified design, can be conducted.

Humans↗
PubMed1991

Randomized dose-searching phase ILE/II trials of fractionation in radiation therapy for cancer.

This article describes a new design, phase ILE/II dose searching, used in four prospective, randomized, multicenter clinical trials of escalating total doses of hyperfractionated radiation. This design combines an experimental protocol with a statistical application of ranking and selection theory. Its purpose was to identify (within a certain margin of error) a dose that achieved the highest rate of clinical response from a set of doses that were tolerable in terms of both acute (within 90 days) and late (more than 90 days) toxic effects (LE). We calculated the number of patients required to reliably test toxicity under various assumptions. To determine the maximum tolerated total dose for hyperfractionated radiation, we randomly assigned patients with tumors that responded to radiation therapy in a dose-dependent manner from four body sites (lung, upper respiratory and digestive tract, bladder, and brain) to one of three regimens receiving total doses (D1, D2, or D3) differing by increments of 4.8 Gy. All patients received two fractions of 1.2 Gy each (separated by 4-6 hours) daily 5 days a week. The lowest total dose was set at the level considered tolerable with standard once-a-day radiation therapy. We tested tumor responses and late toxic effects of higher doses by assigning patients to these three regimens until acute effects and early estimates of late effects were found to be acceptable for the highest dose D3; thereafter, regimen D1 was closed, and additional patients were assigned to D2, D3, and D4 (an escalated total dose greater than D3 by an increment of 4.8 Gy). The assignment of patients was performed in a weighted manner (1:1:2), so that greater numbers were assigned to the highest dose regimen (whether D3 or D4) to allow rapid evaluation of the feasibility of the highest dose.

Clinical Trials as Topic↗