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Proper experimental design, involving the correct number of animals, should be a basic skill for any scientist working with animals. The authors describe a university-developed and freely available tutorial program and an interactive computer-assisted learning program, both of which guide students through the steps necessary for designing animal experiments and estimating optimal sample sizes.
This study describes a fully automated procedure using alkaline hydrolysis and headspace (HS) solid-phase microextraction (SPME) followed by on-fiber derivatization and gas chromatographic (GC)-mass spectrometric (MS) detection of amphetamine, methamphetamine, methylendioxyamphetamine, methylendioxymethamphetamine, methylendioxyethylamphetamine, methylendioxyphenylbutanamine, and methylmethylendioxyphenylbutanamine in human hair samples. Ten milligrams of hair is washed with deionized water, petroleum ether, and dichloromethane. After the addition of deuterated internal standards the sample is hydrolyzed with sodium hydroxide and directly submitted to HS-SPME. After the absorption of analytes for an on-fiber derivatization procedure the fiber is directly placed into the HS of a second vial containing N-methyl-bis(trifluoroacetamide) before GC-MS analysis. The limits of detection are determined between 0.01 and 0.17 ng/mg. Absolute analyte recoveries are in the range between 0.3% and 7.5%. Linearity is proven over a range from 0.1 to 50 ng/mg with coefficients of correlation from 0.998 to 1. In comparison with conventional methods of hair analysis, this fully automated HS-SPME-GC-MS procedure is substantially faster and easier to perform without using solvents. It uses minimal sample amounts and has the same degree of sensitivity and reproducibility.
In some studies that relate covariates to times of failure it is not feasible to observe all covariates for all subjects. For example, some covariates may be too costly in terms of time, money, or effect on the subject to record for all subjects. This paper considers the relative efficiencies of several designs for sampling a portion of the cohort on which the costly covariates will be observed. Such designs typically measure all covariates for each failure and control for covariates of lesser interest. Control subjects are sampled either from "risk sets" at times of observed failures or from the entire cohort. A new design in which the sampling probability for each individual depends on the amount of information that the individual can contribute to estimated coefficients is shown to be superior to other sampling designs under certain conditions. Primary focus of our designs is on time-invariant covariates, but some methods easily generalize to the time-varying setting. Data from a study conducted by the AIDS Clinical Trials Group are used to illustrate the new sampling procedure and to explore the relative efficiency of several sampling schemes.
"Five types of multipopulation surveys are defined and described: periodic surveys; multidomain designs; multinational survey designs; cumulated and combined samples; and controlled observations or quasi- experimental designs. I emphasize the deliberate designs of these surveys, not the mere post hoc or ad hoc utilization of survey results. Most importantly, I emphasize a sharp distinction between seven listed aspects. Similarity and standardization of the survey aspects (definitions, methods, measurements) are essential to avoid biases in comparisons, though admittedly difficult. In contrast, flexibility in sampling designs and sizes, to reduce variances, is permissible, also desirable to reduce variances and costs." (SUMMARY IN FRE)
Limited research exists to guide the development of continental-scale field sampling approaches. We developed a method to compare different sampling schemes designed for continental-scale environmental analysis. Using simulated annealing, we produced hypothetical soil property surfaces for the conterminous United States. The surfaces exhibited varying degrees of polygonality and conditioning by existing soil datasets. Differences in mean between a gridded sample and a polygon-centered sample were evaluated using randomization and other statistical tests. We saw a weak evidence in support of the hypothesis that if a polygonal structure exists in a surface being sampled, then it should be utilized during the actual sampling routine. We saw a somewhat stronger evidence for the hypothesis that differences in local sample density across a continental trend surface can lead to significant sampling bias. Ultimately, the success of different sampling strategies designed for use in continental-scale environmental analysis will largely depend on the ability to anticipate the spatial variability of the variable being measured.
The bolus injection technique is widely used for assessing plasma clearance rates of substances and is based on multiexponential data analysis of multiple concentration measurements. This approach can be simplified to a monoexponential description with only two measurements if intercompartmental mixing occurs at a much faster rate than elimination, i.e. with low plasma clearance rates. In this context initial transients must be ignored because the first measurement time instant affects the accuracy of clearance estimates if mixing is still incomplete. Moreover, measurement noise affects estimation precision which can be optimized by suitable choice of the sampling schedule and of the injected test dose. The aim of this study is to design two-sample bolus injection tests for measuring low plasma clearance rates with preassigned precision and with minimum amount of injected test substance. This paper provides equations for evaluating whether plasma clearance is sufficiently low to allow a monoexponential description of the plasma disappearance curve and for choosing the first sampling time instant. Closed form equations are proposed for determining the optimal test dose and the second sampling time. Result are derived for a particular heteroscedastic measurement noise description, and the problem of robustness with respect to interpatient variability of kinetic parameters is addressed.
The design of sampling and sample processing has a tremendous effect on the analytical results from which conclusions are drawn with respect to the quality of the environment and any possible impact on human health. Large scale environmental surveys need rigorous planning and extensive screening experiments to evaluate their boundary conditions. Representativeness and sample homogeneity are highlighted here in the context of a long-term biological monitoring survey for trace elements using spruce shoots. Several aspects concerning the selection of samples, amount of material, material processing and sample preparation prior to chemical characterisation are illustrated by selected examples.
In fixed sample size designs, precise knowledge about the magnitude of the outcome variable's variance in the planning phase of a clinical trial is mandatory for an adequate sample size determination. Wittes and Brittain introduced the internal pilot study design that allows recalculation of the sample size during an ongoing trial using the estimated variance obtained from an interim analysis. However, this procedure requires the unblinding of the treatment code. Since unblinding of an ongoing trial should be avoided whenever possible, there should be some benefit of this design compared with blinded sample size recalculation procedures to justify the unveiling of the treatment code. In this paper, we compare several sample size recalculation procedures with and without unblinding. The simulation results indicate that the procedures behave similarly. In particular, breaking of the blind is not required for an efficient sample size adjustment. We also compare these pure sample size adaptation procedures with study designs which additionally allow for early stopping. Evaluation of the cumulative distribution function of the resulting sample sizes shows that the option for early stopping may lead to lower expectation but generally to a higher variability. The procedures are illustrated by an example of a trial in the treatment of depression.
Research interest in microbial biodiversity over the past 25 years has increased markedly as microbiologists have become interested in the significance of biodiversity for ecological processes and as the industrial, medical, and agricultural applications of this diversity have evolved. One major challenge for studies of microbial habitats is how to account for the diversity of extremely large and heterogeneous populations with samples that represent only a very small fraction of these populations. This review presents an analysis of the way in which the field of microbial biodiversity has exploited sampling, experimental design, and the process of hypothesis testing to meet this challenge. This review is based on a systematic analysis of 753 publications randomly sampled from the primary scientific literature from 1975 to 1999 concerning the microbial biodiversity of eight habitats related to water, soil, plants, and food. These publications illustrate a dominant and growing interest in questions concerning the effect of specific environmental factors on microbial biodiversity, the spatial and temporal heterogeneity of this biodiversity, and quantitative measures of population structure for most of the habitats covered here. Nevertheless, our analysis reveals that descriptions of sampling strategies or other information concerning the representativeness of the sample are often missing from publications, that there is very limited use of statistical tests of hypotheses, and that only a very few publications report the results of multiple independent tests of hypotheses. Examples are cited of different approaches and constraints to experimental design and hypothesis testing in studies of microbial biodiversity. To prompt a more rigorous approach to unambiguous evaluation of the impact of microbial biodiversity on ecological processes, we present guidelines for reporting information about experimental design, sampling strategies, and analyses of results in publications concerning microbial biodiversity.
This is the first of two articles concerning the techniques of critical appraisal of controlled clinical trials. It presents an overview of the delicate points of the following issues: operational questions; definition of primary and secondary variables, classification of the trial as pragmatic or explanatory, selection of the population sample, study design and its appropriateness to the goals, sample size and overall statistical analysis. Particular attention is given to the value of randomisation and blinding for the prevention of bias.
Over the last decade, considerable interest has focused on sample size estimation in the design of clinical trials. The resulting literature is scattered over many textbooks and journals. This paper presents these methods in a single review and comments on their application in practice.
This paper describes the steps taken by the British Medical Research Council (MRC) in developing the MRC RE01 trial, a randomized clinical trial for patients with metastatic renal cancer; we discuss the reasons for adopting a triangular sequential design and the impact that this has upon the monitoring of the trial. It had been suggested to the MRC that a trial of biological agents for metastatic renal carcinoma should be initiated. The Cancer Therapy Committee (CTC) of the MRC, through its associated site specific working parties, is responsible for designing and co-ordinating randomized trials of alternative treatments in cancer in solid tumours. Since no MRC working party for renal carcinoma existed at that time, development began by the formation of an ad hoc group set up under the auspices of the CTC. They assessed, by means of a postal questionnaire, U.K. interest in the trials of, and modalities utilized for, treatment of renal cancer. The responses focused attention on the important questions to ask and indicated the level of potential collaboration. These responses and related clinical and statistical issues suggested a protocol to compare medroxy-progesterone acetate (MPA) against alpha-interferon (alpha-IFN). In view of the special problems of comparing an expensive and potentially toxic therapy with an inexpensive and non-toxic standard, a sequential design was used rather than a fixed sample size design. Statistical issues raised and solutions provided are described. The method of establishing the trial data monitoring committee and a brief review of mortality from renal carcinoma in England and Wales are also included. The trial opened to patient recruitment on 1 January 1992. The formal statements regarding statistical issues that appear in the formal trial protocol (RE01) are set out in the Appendix.
Buprenorphine and methadone are the two established substitution drugs licensed in many countries for the treatment of opioid dependence. Little is known, however, about how these two drugs are applied and how they work in clinical practice. In this paper we present the aims, methods, design and sampling issues of a collaborative multi-stage epidemiological study (COBRA) to address these issues. Based on a nationally representative sample of substitution physicians, the study is designed as an observational, naturalistic study, consisting of three major parts. The first part was a national survey of substitution doctors (prestudy, n = 379 doctors). The second part was a cross-sectional study (n = 223 doctors), which consisted of a target-week assessment of 2,694 consecutive patients to determine (a) the severity and problem profiles and treatment targets; (b) the choice and dosage scheme of the substitution drug; (c) past and current interventions, including treatment of comorbid hepatitis C; and (d) cross-sectional differences between the two drugs with regard to comorbidity, clinical course, acceptance/compliance and social integration. The third part consists of a prospective-longitudinal cohort study of 48 methadone-treated and 48 buprenorphine-treated patients. The cohort is followed up over a period of 12 months to investigate whether course and outcome of the patients differ by type or treatment received in terms of clinical, psychosocial, pharmaco-economic and other related measures. The response rate among substitution doctors was 57.1%; that among eligible patients was 71.7%. Comparisons with the federal registers reveal that the final samples of doctors and patients may be considered nationally representative with regard to regional distribution, training, type of setting as well as the frequency of patients treated with buprenorphine or methadone. The COBRA study provides a unique comprehensive database, informing about the natural allocation and intervention processes in routine care and about the course and outcome of patients treated with buprenorphine or methadone.
OBJECTIVE: To understand how the prevalence of anemia, human immunodeficiency virus (HIV), and syphilis in a sample of out-of-treatment drug users affected delivery of care in a managed care model. STUDY DESIGN: A snowball sampling design with multiple zero order contacts was used in targeted census tracts with a high incidence of illicit drug use and sexually transmitted diseases. PATIENTS AND METHODS: Out-of-treatment drug users were recruited as part of a national multisite study of HIV risk behaviors in this population. Subjects were recruited using targeted community-based sampling. RESULTS: The rate of individuals who tested positive for both syphilis and HIV was 2.5 times greater than those who tested positive for syphilis only and 2.8 times greater than those who tested positive for HIV only. Of the men, 16.1% were anemic, and 33.3% of women were anemic. Rates of HIV (10.7%) and syphilis (19.8%) were found to be high among both male and female drug users. These statistics, coupled with the prevalence of anemia, indicate that drug users have many more problems other than drug use, a conclusion which can have an impact on how managed care plans approach drug users. CONCLUSION: A multipronged interdisciplinary approach may be warranted for both the patient and the managed care organization.
This is a discussion of the paper' Sample size recalculation in internal pilot study designs' by Tim Friede and Meinhard Kieser, appearing in this special issue on adaptive designs.
SETTING: As an alternative to biochemical analysis, microplate DNA-DNA hybridization was applied for rapid diagnosis of mycobacterial infection. OBJECTIVE: To assess how rapidly and correctly the microplate hybridization method can progress from clinical sample to final species identification of mycobacteria. DESIGN: Clinical samples (pooled sputa or bronchial lavage fluid) were obtained from patients. Depending on the estimated bacterial amounts, genetic identification was performed either directly or following primary culture. Extracted DNA labeled by photobiotin was hybridized in microdilution wells with type-strain DNAs from 4 species (Mycobacterium tuberculosis, M. avium, M. intracellulare, and M. kansasii), the identified on the basis of genetic relatedness, which was quantitated by colorimetric detection. RESULTS: With samples containing more than 10(8) colony-forming units [CFU] (5 cases), species identification was successfully performed on the day of sample preparation. With samples of not more than 10(7) CFU (14 cases), although 4-21 days' primary culture were necessary, species were also correctly identified by the microplate method. Furthermore, M. avium and M. intracellulare were distinctly identified. All the results precisely corresponded to those of biochemical analysis, which took 4-12 weeks to complete identification. CONCLUSION: We consider that microplate DNA-DNA hybridization is a dependable technique for rapid diagnosis of mycobacterial infection.
PRIMARY OBJECTIVE: To examine the role of selective attention and visual perception in medicating inattentional blindness in a severe traumatic brain injured sample. RESEARCH DESIGN: Cross-sectional design with age and education matched control sample. METHODS AND PROCEDURES: Twenty participants with severe traumatic brain injury (n = 10) and matched controls (n = 10) completed a series of tests of focused attention (Stroop test), divided attention (Trail Making Test), visual perception (Visual Object and Space Perception Battery) and two tasks of inattentional blindness. MAIN OUTCOMES AND RESULTS: The group with severe TBI were significantly slower on the Stroop test and TMT and displayed significantly elevated Stroop interference and TMT ratio scores. On the inattentional blindness tasks, fewer TBI participants identified a distracting stimulus. CONCLUSION: The results indicate severe TBI is associated with deficits to focused and divided attention with the finding of a potentially more debilitating impairment arising from reduced distractibility following severe TBI.
In this article, we present a simple method to calculate sample size and power for a simulation-based multiple testing procedure which gives a sharper critical value than the standard Bonferroni method. The method is especially useful when several highly correlated test statistics are involved in a multiple-testing procedure. The formula for sample size calculation will be useful in designing clinical trials with multiple endpoints or correlated outcomes. We illustrate our method with a quality-of-life study for patients with early stage prostate cancer. Our method can also be used for comparing multiple independent groups.
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