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Study design in clinical research: sample size estimation and power analysis.

The purpose of this review is to describe the statistical methods available to determine sample size and power analysis in clinical trials. The information was obtained from standard textbooks and personal experience. Equations are provided for the calculations and suggestions are made for the use of power tables. It is concluded that sample size calculations and power analysis can be performed with the information provided and that the validity of clinical investigation would be improved by greater use of such analyses.

Clinical Trials as Topic↗

Stagewise, group sequential experimental designs for quantal responses. one-sample and two-sample comparisons.

The use of stagewise, group sequential experimental designs with dichotomous responses in toxicity or drug screening programs is discussed. Such designs represent a compromise between the standard, fixed sample size designs and fully sequential designs. Stagewise group sequential designs place specified numbers of animals on test at each stage, up to a maximum number of stages. The greatest increases in sample size efficiency occur with small numbers of stages, particularly when going from one stage to two. Two-stage designs can result in a 15 to 20 percent reduction in average sample size. Five-stage designs can result in a 30 to 40 percent reduction in average sample size, with no appreciable decrease in Type 1 error or power. Examples of the efficiencies that arose in actual screening programs are given. This paper demonstrates that the routine use of stagewise, group sequential designs in standardized screening protocols can result in substantial savings in animal use with virtually no sacrifice of statistical sensitivity.

Animals↗

An overview of the National Survey of SSI Children and Families and related products.

The National Survey of SSI Children and Families (NSCF) is the first nationally representative survey since 1978 of noninstitutionalized children and young adults who currently receive or formerly received Supplemental Security Income (SSI). Over 8,500 interviews were completed between July 2001 and June 2002. The primary objective of the NSCF is to provide data to support research and policy evaluation on the current cross section of children (ages 0 to 17) and young adults (ages 18 to 23) receiving SSI. Following that objective, the survey was designed to answer questions such as those presented below. What are the general characteristics of children and young adults receiving SSI and their families? What are the patterns of access to and utilization of health care among children and young adults receiving SSI? What services are utilized by children and young adults receiving SSI? What are the unmet health care and service needs of children and young adults receiving SSI? What costs are associated with caring for a disabled child? What is the impact on the family of having a disabled child? What is the status of young adults with disabilities as they make the transition to adulthood? How well are they prepared for that transition? In addition, the NSCF questionnaire and sample were designed to be comprehensive enough and large enough to address numerous additional policy issues as they emerge. The NSCF fills a gap in the data available to policy analysts by addressing a wide range of topics that cannot be addressed with SSI administrative data and by providing a large sample in contrast to major national survey databases that cover this target population fairly sparsely. A companion article to this overview describes general characteristics of SSI beneficiary children and their families (see Rupp and others 2005/2006, pages 21-48 of this issue). Other topics being examined include disability-related expenditures for SSI children and young adults and labor force participation of the parents of SSI children. The NSCF data files are accompanied by a detailed User's Manual, which includes a detailed codebook and information about the NSCF sample design, questionnaire design and content, data collection procedures, variable construction, editing, and variance estimation procedures. In order to facilitate research, the Social Security Administration published the NSCF Public-Use File and survey documentation on its Web site. These products are available at http://www.socialsecurity.gov/disabilityresearch/nscf.htm. The NSCF is an outstanding tool for conducting research and policy analysis regarding children and young adults receiving SSI.

Adolescent↗

Schistosoma mansoni in the Nile Delta, Egypt. A large scale epidemiological study in Kafr El Sheikh Governorate.

This is an early descriptive report of the 'Epidemiology 123' project in Egypt which makes use of large probability sampling methods. These results focus on Schistosoma mansoni infection in the northern Nile Delta Governorate of Kafr El Sheikh. A probability sample of 18,777 persons, representing the rural population of the entire Governorate, was drawn. The sample was designed not to exclude villages based on location or presence of health care facilities and to include representation of the smaller ezbas or hamlets. The objective was to obtain detailed estimates on age and sex specific patterns of S. mansoni infection, and to provide a baseline for prospective studies. Stool specimens were examined by the Kato method. The estimated prevalence of S. monsoni infection in the rural population was 39.3% (SE +/- 3.3) in 44 villages and ezbas after weighing for the effects of the sample design. The estimated geometric mean egg count per gram stool (GMEC) was 72.9 (SE +/- 7.3). Prevalence and GMEC varied considerably by village and ezba, with ezbas having a significantly higher prevalence. Villages and ezba specific prevalence was strongly associated with GMEC (r2 = 0.61, p < 0.001). The prevalence of S. mansoni infection increased by age to 55.4% (SE +/- 3.2) at age 16, without significant change in the adult ages. There was no gender difference until age six, after which males were consistently higher until middle age, when the differences converged. The age and sex specific pattern of GMEC varied widely, however, when the GMEC data were collapsed into five year age groups, GMEC peaked at 81.5 (SE / + - 12.1) epg in the 10 to 14 year age group. These estimates provide the basis for evaluating control measures for reducing prevalence, intensity of infection, and transmission.

Adolescent↗

The epidemiology of schistosomiasis in Egypt: patterns of Schistosoma mansoni infection and morbidity in Kafer El-Sheikh.

This is a descriptive report of the Epidemiology 1, 2, 3 project in Egypt that made use of large probability sampling methods. These results focus on Schistosoma mansoni infection in the northern Nile Delta governorate of Kafr El Sheikh. A probability sample of 18,777 persons, representing the rural population of the entire governorate, was drawn. The sample was designed not to exclude villages based on location or presence of health care facilities and to include representation of the smaller ezbas or hamlets. The objective was to obtain detailed estimates on age- and sex-specific patterns of S. mansoni infection, and to provide a baseline for prospective studies. Stool specimens were examined by the Kato method. The estimated mean +/- SE prevalence of S. mansoni infection in the rural population was 39.3 +/- 3.3% in 44 villages and ezbas after weighing for the effects of the sample design. The estimated mean +/- SE geometric mean egg count per gram of stool (GMEC) was 72.9 +/- 7.3. Prevalence and GMEC varied considerably by village and ezba, with ezbas having a significantly higher prevalence. Villages and ezba-specific prevalence was strongly associated with GMEC (r2 = 0.61, P < 0.001). The prevalence of S. mansoni infection increased by age to 55.4 +/- 3.2% at age 16 without a significant change in the adult ages. There were no gender differences until age 6, after which males were consistently higher until middle age, when the differences converged. The age- and sex-specific pattern of GMEC varied widely; however, when the GMEC data were collapsed into 5-year age groups, the GMEC peaked at 81.5 +/- 12.1 eggs/g in the 10-14-year-old age group. These estimates provide the basis for evaluating control measures for reducing prevalence, intensity of infection, and transmission.

Adolescent↗

Using biased image analysis for improving unbiased stereological number estimation - a pilot simulation study of the smooth fractionator.

The smooth fractionator was introduced in 2002. The combination of a smoothing protocol with a computer-aided stereology tool provides better precision and a lighter workload. This study uses simulation to compare fractionator sampling based on the smooth design, the commonly used systematic uniformly random sampling design and the ordinary simple random sampling design. The smooth protocol is performed using biased information from crude (but fully automatic) image analysis of the fields of view. The different design paradigms are compared using simulation in three different cell distributions with reference to sample size, noise and counting frame position. Regardless of clustering, sample size or noise, the fractionator based on a smooth design is more efficient than the fractionator based on a systematic uniform random design, which is more efficient than a fractionator based on simple random design. The fractionator based on a smooth design is up to four times more efficient than a simple random design.

Journal Article↗

Analysis of epidemiologic case-base studies for binary data.

Recent developments in statistical methods for epidemiology have revived the application of sampling techniques in the design and analysis of cohort studies. The 'case-base' design involves sampling of both the cases and the cohort base of the study. This paper reviews some data-analytic imperfections of the approaches to risk ratio estimation, and modifies and advances a consistent likelihood-based procedure-analogous to Miettinen and Nurminen's proposal for a full cohort design--for interval estimation (and also point estimation and significance testing) in the context of binary case-base data. First, the procedure avoids the use of Taylor-series approximations to derive variance estimators for non-linear functions of parameters. Second, the asymptotic condition effects a simple computational expression for the chi-square function of risk ratios that is universally applicable to small samples. The statistical modelling underlying the method allows inferences about risk ratios without the assumption of rare disease either for the general population or for a particular base. The paper also extends the analysis to encompass stratified data. Finally, a numerical evaluation evinced the accurate small-sample properties of the proposed method.

Binomial Distribution↗

Determination of power and sample size in the design of clinical trials with failure-time endpoints and interim analyses.

An important but difficult task in the design of a clinical trial to compare time to failure between two treatment groups is determination of the number of patients required to achieve a specified power of the test. Because patients typically enter the trial serially and are followed until they fail or withdraw from the study or until the study is terminated, the power of the test depends on the accrual pattern, the noncompliance rate, and the withdrawal rate in addition to the actual survival distributions of the two groups. Incorporating interim analyses and the possibility of early stopping into the trial increases its complexity, and although normal approximations have been developed for computing the significance level of the test when the log-rank or other rank statistics are used, there are no reliable analytic approximations for evaluating the power of the test. This article presents methods, based on Monte Carlo simulations and recent advances in group sequential testing with time-to-event responses, to choose appropriate test statistics, compute power and sample size at specified alternatives, check the adequacy of commonly used normal approximations of the type I error probability, and assess the performance of different interim analysis strategies. It also presents two computer programs implementing these methods.

Adrenergic beta-Antagonists↗

Serum levels of prolactin, LH and LH-RH after ablation of the medial basal hypothalamus.

4 weeks after surgical ablation (MHA) of the medial basal hypothalamus (MBH) in adult male rats, serum levels of prolactin, LH, and LH-RH were determined by radioimmunoassay. Blood samples were obtained by jugular venipuncture under ether anesthesia (designated 'stress' samples) and 30 min after the ether stress by rapid decapitation (designated 'resting samples). 30 min after ether, serum levels of prolactin, LH, and LH-RH in MHA rats were comparable to those of intact and sham-operated controls. Among intact and sham-operated rats, ether elicited an initial increased in prolactin but not in LH or LH-RH. In the MHA group, prolactin levels were also acutely increased, although the increment was not as great as in control groups. The data indicate that considerable basal prolactin and LH secretion persists after MHA, and that this continued secretion may be regulated by neurohoromones such as LH-RH which arise from areas outside the MBH.

Animals↗

Single point aerosol sampling: evaluation of mixing and probe performance in a nuclear stack.

Alternative reference methodologies have been developed for sampling of radionuclides from stacks and ducts, which differ from the methods previously required by the United States Environmental Protection Agency. These alternative reference methodologies have recently been approved by the U.S. EPA for use in lieu of the current standard techniques. The standard EPA methods are prescriptive in selection of sampling locations and in design of sampling probes whereas the alternative reference methodologies are performance driven. Tests were conducted in a stack at Los Alamos National Laboratory to demonstrate the efficacy of some aspects of the alternative reference methodologies. Coefficients of variation of velocity, tracer gas, and aerosol particle profiles were determined at three sampling locations. Results showed that numerical criteria placed upon the coefficients of variation by the alternative reference methodologies were met at sampling stations located 9 and 14 stack diameters from the flow entrance, but not at a location that was 1.5 diameters downstream from the inlet. Experiments were conducted to characterize the transmission of 10 microns aerodynamic diameter liquid aerosol particles through three types of sampling probes. The transmission ratio (ratio of aerosol concentration at the probe exit plane to the concentration in the free stream) was 107% for a 113 L min-1 (4-cfm) anisokinetic shrouded probe, but only 20% for an isokinetic probe that follows the existing EPA standard requirements. A specially designed isokinetic probe showed a transmission ratio of 63%. The shrouded probe performance would conform to the alternative reference methodologies criteria; however, the isokinetic probes would not.

Aerosols↗

A new approach to sample size calculation for reference interval studies.

A new criterion is proposed for determining the sample size required for a study performed for the purpose of establishing reference intervals. The basic idea behind the criterion is to compare the empirical coverage (i.e. the probability content) of the reference region obtained from the sample with its target value (e.g. 95 per cent) and to set suitable limits delta1, delta2 to the difference between both quantities which must not be exceeded with sufficiently large probability beta (e.g. beta=90 per cent). For the most frequently used parametric and distribution-free methods of estimating univariate reference limits, implicit formulae are derived relating the sample size to the design parameters delta1, delta2 and beta. For symmetric specification of (delta1, delta2), explicit approximation formulae for the computation of n are given. Exact values obtained by means of suitable numerical techniques are presented in a set of tables covering specifications of delta1, delta2 and beta which can be recommended for real applications. The tables can be used both for one- and two-sided reference intervals.

Alanine Transaminase↗

Stopping a clinical trial early: frequentist and Bayesian approaches applied to a CALGB trial in non-small-cell lung cancer.

In May 1984, the Cancer and Leukemia Group B (CALGB) opened a phase III clinical trial for patients with stage III non-small-cell lung cancer (NSCLC). The experimental design entailed randomization of 240 patients equally to one of two treatments: radiotherapy alone or chemotherapy followed by radiotherapy. The original design was a fixed sample size design with the intent to analyse the results after 190 deaths. Shortly after the trial began, it was decided to apply group sequential concepts by using a truncated O'Brien-Fleming stopping rule, implemented via a Lan-DeMets alpha-spending function. A study monitoring committee was established to review the analyses as they were produced. The study was stopped at the fifth interim analysis in May 1987 after 155 eligible patients had been entered. This paper reviews the statistical and other considerations leading to this decision and presents later follow-up information on these patients. Some Bayesian alternatives to the standard frequentist approaches are also explored and it is demonstrated how these alternatives provide a natural way to address many of the issues raised in monitoring clinical trials.

Bayes Theorem↗

Use of poly-l-lysine-coated slides in clinical bronchoalveolar lavage fluid samples.

OBJECTIVE: Polylysine coating of microscope slides provides superior cell adhesion. We compared poly-l-lysine-coated (PLC) slides to conventional slides in cytocentrifuged bronchoalveolar lavage (BAL) fluid samples. STUDY DESIGN: Twenty BAL fluid samples with representative numbers of alveolar macrophages, lymphocytes and polymorphonuclear neutrophils were cytocentrifuged on uncoated slides and on PLC slides (2 slides each). Cell density, differential cell counts and cytomorphology were assessed on May-Grünwald-Giemsa-stained preparations. Reliability of cell differentiation was expressed as a phi value, which measures combined reproducibility and agreement. Statistical significance of differences between slides was calculated with ANOVA. Clinical relevance was assessed using a validated computer program predicting the most probable diagnosis. RESULTS: Although not statistically significant, cell recovery was lower on PLC slides as compared to uncoated slides. PLC slides held significantly fewer lymphocytes as compared to uncoated slides (mean value +/- SD: 25.89% +/- 28.26 versus 28.34% +/- 29.96, respectively). Counts of alveolar macrophages, lymphocytes and polymorphonuclear neutrophils displayed excellent phi values for both uncoated and PLC slides. No discrepancies in the computer-generated diagnoses were found. CONCLUSION: For BAL fluid cytology on cytocentrifuged preparations, PLC slides are not superior to conventional slides.

Bronchoalveolar Lavage↗

Knowledge of heart disease risk among spanish speakers with diabetes: the role of interpreters in the medical encounter.

OBJECTIVE: To investigate heart disease risk knowledge among Spanish speakers with diabetes. DESIGN: Single sample cross-sectional design. SETTING: A Spanish-language diabetes health fair in an inner-city community center in Connecticut. PARTICIPANTS: Ninety-four Spanish-speaking adults participated. They were predominantly from Puerto Rico, had less than high school education, and were economically disadvantaged. Most had type 2 diabetes (96%) for an average of 10 years. Most had health insurance and a primary care provider. A sizable minority relied on ad hoc interpreters (friends or family members) during clinic visits, but most would prefer to use a professional medical interpreter. MEASURES AND RESULTS: Knowledge of risk for heart disease was measured by a Spanish version of the Heart Disease Fact Questionnaire (HDFQ). Knowledge of heart disease was low (mean score 17.5 [out of 25], SD=5.0), and lack of knowledge was found for the risks of diabetes, high-fat foods, cholesterol, physical activity, hypertension, family history of heart disease, sex, and whether one is necessarily cognizant of having heart disease. Regression analyses showed that bank account status and use of ad hoc interpreters contributed significantly to the prediction of HDFQ scores. Having a bank account and not using family or friends as interpreters in visits with the primary care provider predicted higher HDFQ scores. CONCLUSION: Heart disease risk knowledge was low in Spanish speakers with diabetes. Providing professional medical interpretation instead of relying on ad hoc interpreters is recommended for this high-risk group.

Aged↗

Strong feature sets from small samples.

For small samples, classifier design algorithms typically suffer from overfitting. Given a set of features, a classifier must be designed and its error estimated. For small samples, an error estimator may be unbiased but, owing to a large variance, often give very optimistic estimates. This paper proposes mitigating the small-sample problem by designing classifiers from a probability distribution resulting from spreading the mass of the sample points to make classification more difficult, while maintaining sample geometry. The algorithm is parameterized by the variance of the spreading distribution. By increasing the spread, the algorithm finds gene sets whose classification accuracy remains strong relative to greater spreading of the sample. The error gives a measure of the strength of the feature set as a function of the spread. The algorithm yields feature sets that can distinguish the two classes, not only for the sample data, but for distributions spread beyond the sample data. For linear classifiers, the topic of the present paper, the classifiers are derived analytically from the model, thereby providing an enormous savings in computation time. The algorithm is applied to cancer classification via cDNA microarrays. In particular, the genes BRCA1 and BRCA2 are associated with a hereditary disposition to breast cancer, and the algorithm is used to find gene sets whose expressions can be used to classify BRCA1 and BRCA2 tumors.

Breast Neoplasms↗

Electrochemical cells for voltammetry, coulometry, and protein activity assays of small-volume biological samples.

Cell designs, experimental protocols, and results for electrochemical investigation of small quantitites of biological materials under anaerobic conditions are reported. Three types of electrochemical experiments are considered: (i) cyclic voltammetry of 20- to 100-microliters samples; (ii) direct coulometry of 0.5- to 1.5-ml samples; and (iii) an electrochemically initiated protein activity assay which includes provision for analysis of gaseous reaction products and correlation with electron flux. The first two procedures are illustrated by measurement of the formal electrode potential (E0') and number of electrons transferred (n) in redox reactions of small quantities of biological and inorganic materials. The third procedure is illustrated by assaying the activity of the MoFe protein plus Fe protein complex from Azotobacter vinelandii nitrogenase for reduction of C2H2 to C2H4.

Acetylene↗