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Sample size calculations with compliance information.

In randomized clinical trials, non-compliance will lead to the loss of power in the standard intention-to-treat analysis and one should account for this in sample size calculations. In this paper a new sample size formula for a binary outcome is proposed in which compliance information is considered. The proposed method is based purely on the treatment randomization. We compare it to the conventional sample size calculation method based on the two independent binomial distributions assumption. We examine 3100 combinations of risks of control group (baseline risks), treatment effects (risk differences), compliances in the test treatment group and the control treatment group, test sizes and powers. We found that, compared to the conventional method, the proposed method gives similar sample sizes for baseline risks 0.4-0.6, larger sample sizes for baseline risks less than 0.4, and smaller sample sizes for baseline risks greater than 0.6 when the true risk difference is negative.

Coronary Disease↗

Blinded sample size reassessment in non-inferiority and equivalence trials.

Even in situations where the design and conduct of clinical trials is highly standardized, there may be a considerable between-study variation in the observed variability of the primary outcome variable. As a consequence, performing a study in a fixed sample size design implies a considerable risk of resulting in a too high or too low sample size. This difficulty can be alleviated by applying a design with internal pilot study. After a provisional sample size calculation in the planning stage, a portion of the planned sample is recruited and the sample size is recalculated on the basis of the observed variability. To comply with the requirement of some regulatory guidelines only blinded data should be used for the reassessment procedure. Furthermore, the effect on the type I error rate should be quantified. The current literature presents analytical results on the actual level in the t-test situation only for superiority trials. In these situations, blinded sample size recalculation does not lead to an inflation of the type I error rate. We extended the methodology to non-inferiority and equivalence trials with normally distributed outcome variable and hypotheses formulated in terms of the ratio and difference of means. Surprisingly, in contrast to the case of testing superiority, we observed actual type I error rates above the nominal level. The extent of inflation depends on the required sample size, the sample size of the internal pilot study, and the standardized equivalence or non-inferiority margin. It turned out that the elevation of the significance level is negligible for most practical situations. Nevertheless, the consequences of sample size reassessment have to be discussed case by case and regulatory concerns with respect to the actual size of the procedure cannot generally be refuted by referring to the fact that only blinded data were used.

Asthma↗

Stopping boundaries adjusted for sample size reestimation and negative stop.

We propose an approach to specify group sequential stopping boundaries adjusted for sample size reestimation and negative stop in interim analyses of a clinical trial. Sample size can be adjusted based on the observed delta at each interim to maintain the targeted power. The calculation of stopping boundaries incorporates possible changes in the type-I error due to sample size reestimation and/or negative stops; hence the overall type-I error is well controlled. This approach combines the advantages of the group sequential and sample size reestimation methods and is more efficient than either one alone. It provides flexibility in clinical trials and still maintains the integrity of these trials. When no early stop is planned, the stopping boundaries will be adjusted only for sample size reestimation. All calculations are given in closed mathematical forms and adjustments in stopping boundaries are based on the exact type-I error change. Therefore, the penalty for the type-I error inflation due to such interim conductions is kept to a minimum.

Algorithms↗

Sample size determination for clinical trials in patients with nonlinear disease progression.

This paper provides explicit sample size determination formulas for planning a long-term trial in patients with chronic disease by using available results from existing short-term studies that may predict long-term disease progression patterns. The sample size calculation formulas are flexible to incorporate different nonlinear disease progression patterns. Various within-patient correlation structures are considered. By using the proposed formulas, sample size sensitivity can be easily explored for possible choices of study duration, assumed nonlinear disease progression patterns, randomization ratio, and expected clinical meaningful difference in the end of study. In addition, sample size calculation formulas are provided when the primary endpoint is change from baseline. Discussions on the relationship among required sample size, study duration, randomization ratio are also included.

Clinical Trials as Topic↗

Determining sample size and power in clinical trials: the forgotten essential.

Estimation of the sample size is a fundamental but usually ignored requirement of the randomized controlled trial (RCT). Indeed, the publication of small trials without consideration of sample size is worrisome from both medical and ethical viewpoints. Type II errors are common, and readers and investigators may reject worthwhile treatments and interventions. Before embarking on an RCT, the investigator must choose an alpha, a beta, and the rates of outcomes anticipated in both treatment groups. This should reflect the characteristics of the condition and its treatment. If limited sample size or available resources pose a problem, the use of continuous outcome measures, paired before-after measurements, and more common outcome measures can minimize sample size requirements. If these approaches are not satisfactory, then a multicenter trial may be in order.

Clinical Trials as Topic↗

On sample size calculation based on odds ratio in clinical trials.

Sample size calculation formulas for testing equality, noninferiority, superiority, and equivalence based on odds ratio were derived under both parallel and one-arm crossover designs. An example concerning the study of odds ratio between a test compound (treatment) and a standard therapy (control) for prevention of relapse in subjects with schizophrenia and schizoaffective disorder is presented to illustrate the derived formulas for sample size calculation for various hypotheses under both a parallel design and a crossover design. Simulations were performed to assess the adequacy of the sample size calculation formulas. Simulation results were given at the end of the paper.

Algorithms↗

[Appropriate sample size and molecular marker loci in the study of genetic diversity of Ocomelania hupensis].

OBJECTIVE: To explore the reasonable sample size and the number of molecular marker loci in the study of amplified fragment length polymorphism (AFLP) being used to analyze the genetic diversity of Ocomelania hupensis. METHODS: The ribbed-shelled snails coming from Yueyang, Hunan province, were selected to analyze the relationship of the number of AFLP molecular marker loci and sample size with the reliability of information on genetic variation for Ocomelania hupensis by AFLP method. RESULTS: Correlations found among the numbers of AFLP molecular marker loci and the sample size with reliable information on genetic variation for Ocomelania hupensis. When sample size was less than 7 individuals, the total number of AFLP loci, the number of polymorphic loci, Nei's gene diversity and Shannon's information index appeared great changes. However, when sample size was bigger than 30 individuals, the values of these indices tended to be stabilized. When the number of AFLP loci was less than 128, the frequency of polymorphic loci, Nei's gene diversity, Shannon's information index and the standard deviation of these two indices changed greatly. Again, when the number of loci was bigger than 338, the values of these indices tended to be stabilized. CONCLUSION: When the genetic diversity of Ocomelania hupensis were analyzed by AFLP method, the sample size coming from each snail population should not be less than 30 individuals and the number of molecular loci analyzed not less than 338.

Amplified Fragment Length Polymorphism Analysis↗

Underpowering in randomized trials reporting a sample size calculation.

OBJECTIVE: The objective of this study was to determine whether standard deviations (SDs) used in sample size calculations are smaller than those found in the resulting study sample, thereby leading to underpowered studies. METHOD: The predicted SD used in the sample size calculation and the actual SD of the study sample were recorded for randomized trials recently published in one of four major journals. RESULTS: Sample SD was greater than predicted SD for 80% of endpoints. About one quarter of trials required five times as many patients as specified in the sample size calculation. CONCLUSION: Trials reporting sample size calculations for continuous endpoints published in the most reputable medical journals are often underpowered. There seems to be insufficient understanding that the SD of a sample of patients is a random variable, associated with imprecision, that cannot easily be extrapolated from one population to another.

Data Interpretation, Statistical↗

Classifier design for computer-aided diagnosis: effects of finite sample size on the mean performance of classical and neural network classifiers.

Classifier design is one of the key steps in the development of computer-aided diagnosis (CAD) algorithms. A classifier is designed with case samples drawn from the patient population. Generally, the sample size available for classifier design is limited, which introduces variance and bias into the performance of the trained classifier, relative to that obtained with an infinite sample size. For CAD applications, a commonly used performance index for a classifier is the area, Az, under the receiver operating characteristic (ROC) curve. We have conducted a computer simulation study to investigate the dependence of the mean performance, in terms of Az, on design sample size for a linear discriminant and two nonlinear classifiers, the quadratic discriminant and the backpropagation neural network (ANN). The performances of the classifiers were compared for four types of class distributions that have specific properties: multivariate normal distributions with equal covariance matrices and unequal means, unequal covariance matrices and unequal means, and unequal covariance matrices and equal means, and a feature space where the two classes were uniformly distributed in disjoint checkerboard regions. We evaluated the performances of the classifiers in feature spaces of dimensionality ranging from 3 to 15, and design sample sizes from 20 to 800 per class. The dependence of the resubstitution and hold-out performance on design (training) sample size (Nt) was investigated. For multivariate normal class distributions with equal covariance matrices, the linear discriminant is the optimal classifier. It was found that its Az-versus-1/Nt curves can be closely approximated by linear dependences over the range of sample sizes studied. In the feature spaces with unequal covariance matrices where the quadratic discriminant is optimal, the linear discriminant is inferior to the quadratic discriminant or the ANN when the design sample size is large. However, when the design sample is small, a relatively simple classifier, such as the linear discriminant or an ANN with very few hidden nodes, may be preferred because performance bias increases with the complexity of the classifier. In the regime where the classifier performance is dominated by the 1/Nt term, the performance in the limit of infinite sample size can be estimated as the intercept (1/Nt= 0) of a linear regression of Az versus 1/Nt. The understanding of the performance of the classifiers under the constraint of a finite design sample size is expected to facilitate the selection of a proper classifier for a given classification task and the design of an efficient resampling scheme.

Computer Simulation↗

A simple computerized program for the calculation of the required sample size necessary to ensure statistical accuracy in medical experiments.

We developed a sample size estimation program (SSEP) with which medical researchers can easily estimate the appropriate sample size for a specific significance level and statistical power using their favorite WWW browsers. SSEP can estimate the sample sizes for six statistical methods by Monte-Carlo simulation: Student's t-test, Welch's t-test, Analysis of variance, Wilcoxon's rank sum test, Kruskal-Wallis test, and the Cochran-Armitage test for linear trends. The SSEP simulation programs were created using the SAS software macro language. Medical researchers can interactively use this program and determine reliable sample sizes when planning new prospective clinical studies and animal experiments.

Computer Simulation↗

Operating characteristics of sample size re-estimation with futility stopping based on conditional power.

Various methods have been described for re-estimating the final sample size in a clinical trial based on an interim assessment of the treatment effect. Many re-weight the observations after re-sizing so as to control the pursuant inflation in the type I error probability alpha. Lan and Trost (Estimation of parameters and sample size re-estimation. Proceedings of the American Statistical Association Biopharmaceutical Section 1997; 48-51) proposed a simple procedure based on conditional power calculated under the current trend in the data (CPT). The study is terminated for futility if CPT < or = CL, continued unchanged if CPT > or = CU, or re-sized by a factor m to yield CPT = CU if CL < CPT < CU, where CL and CU are pre-specified probability levels. The overall level alpha can be preserved since the reduction due to stopping for futility can balance the inflation due to sample size re-estimation, thus permitting any form of final analysis with no re-weighting. Herein the statistical properties of this approach are described including an evaluation of the probabilities of stopping for futility or re-sizing, the distribution of the re-sizing factor m, and the unconditional type I and II error probabilities alpha and beta. Since futility stopping does not allow a type I error but commits a type II error, then as the probability of stopping for futility increases, alpha decreases and beta increases. An iterative procedure is described for choice of the critical test value and the futility stopping boundary so as to ensure that specified alpha and beta are obtained. However, inflation in beta is controlled by reducing the probability of futility stopping, that in turn dramatically increases the possible re-sizing factor m. The procedure is also generalized to limit the maximum sample size inflation factor, such as at m max = 4. However, doing so then allows for a non-trivial fraction of studies to be re-sized at this level that still have low conditional power. These properties also apply to other methods for sample size re-estimation with a provision for stopping for futility. Sample size re-estimation procedures should be used with caution and the impact on the overall type II error probability should be assessed.

Clinical Trials as Topic↗

The PowerAtlas: a power and sample size atlas for microarray experimental design and research.

BACKGROUND: Microarrays permit biologists to simultaneously measure the mRNA abundance of thousands of genes. An important issue facing investigators planning microarray experiments is how to estimate the sample size required for good statistical power. What is the projected sample size or number of replicate chips needed to address the multiple hypotheses with acceptable accuracy? Statistical methods exist for calculating power based upon a single hypothesis, using estimates of the variability in data from pilot studies. There is, however, a need for methods to estimate power and/or required sample sizes in situations where multiple hypotheses are being tested, such as in microarray experiments. In addition, investigators frequently do not have pilot data to estimate the sample sizes required for microarray studies. RESULTS: To address this challenge, we have developed a Microrarray PowerAtlas. The atlas enables estimation of statistical power by allowing investigators to appropriately plan studies by building upon previous studies that have similar experimental characteristics. Currently, there are sample sizes and power estimates based on 632 experiments from Gene Expression Omnibus (GEO). The PowerAtlas also permits investigators to upload their own pilot data and derive power and sample size estimates from these data. This resource will be updated regularly with new datasets from GEO and other databases such as The Nottingham Arabidopsis Stock Center (NASC). CONCLUSION: This resource provides a valuable tool for investigators who are planning efficient microarray studies and estimating required sample sizes.

Algorithms↗

Consideration of covariates and stratification in sample size determination for survival time studies.

Sample size determination for survival time studies is discussed, taking into account stratification. We present formulas and tables which also apply in the case of multicenter clinical trials. In addition, the same method is used to estimate the sample size requirement when a covariate is grouped into strata. Simulation studies compare the results to covariate adjustment by the Cox proportional hazards model.

Follow-Up Studies↗

Methacholine challenge tests: sample sizes required in crossover trials.

OBJECTIVE: Methacholine challenge testing is common for assessing the pharmacodynamic properties of anti-asthma drugs. In order to design studies and to interpret published studies, sample size calculations are essential. Unfortunately, wrong sample sizes were previously reported in the literature. We present correct sample sizes required for the comparison of two treatments based on methacholine challenge testing in a crossover study. METHODS AND RESULTS: Formulas for sample size calculations and the resulting number of subjects required for a specified power are presented for studies designed to show a difference as well as for equivalence and non-inferiority studies. CONCLUSIONS: A much larger sample size is required for methacholine challenge testing than previously reported.

Algorithms↗

Sample size estimation: how many individuals should be studied?

The number of individuals to include in a research study, the sample size of the study, is an important consideration in the design of many clinical studies. This article reviews the basic factors that determine an appropriate sample size and provides methods for its calculation in some simple, yet common, cases. Sample size is closely tied to statistical power, which is the ability of a study to enable detection of a statistically significant difference when there truly is one. A trade-off exists between a feasible sample size and adequate statistical power. Strategies for reducing the necessary sample size while maintaining a reasonable power will also be discussed.

Humans↗

Sample size calculations in studies of test accuracy.

Methods for determining sample size for studies of the accuracy of diagnostic tests are reviewed. Several accuracy indices are considered, including sensitivity and specificity, the full and partial area under the receiver operating characteristic curve, the sensitivity at a fixed false positive rate, and the likelihood ratio. Sample size formulae are presented for studies evaluating a single test and studies comparing the accuracy of tests. Four real examples illustrate the concepts involved in sample size determination. Lastly, various study design issues are discussed, such as sampling methods, choices in format for the test results, and the issue of replicated readings.

Area Under Curve↗

Sample size for K 2x2 tables in equivalence studies using Cochran's statistic.

This paper presents a new sample size formula for Cochran's test that uses additional information on stratum-specific success rates and requires fewer subjects for an equivalence study. Equivalence studies are common in clinical trials, where unlike superiority studies, the goal is to show whether a new drug therapy is as effective as a standard one. Stratification is typically used to adjust for differences among individual clinical trial centers with different success rates. The sample size is derived for a clinical trial design where two independent binomial proportions are compared within each stratum. Implementation of the sample size formula is described when the number of centers is large and the success rates of each individual center are not known exactly. The effect of variability of the success rates on the power of Cochran's test is shown through simulation. The variability of the success rates is measured by the intracluster correlation coefficient, which can be estimated by the ANOVA estimator of Donald and Donner. The simulation results show that the new sample size formula requires fewer subjects than sample size methods, which ignore stratification. The new method provides greater savings as the variability of success rates among centers increases.

Analysis of Variance↗