Biomedical subjects

Jun Shao

Publications and source records attributed to Jun Shao.

50 records · Page 3Linked to original sources

PubMed2002

Reproducibility probability in clinical trials.

For marketing approval of a new drug product, the United States Food and Drug Administration (FDA) requires that substantial evidence of the effectiveness of the drug product be provided through the conduct of at least two adequate and well-controlled clinical trials. The purpose of conducting the second clinical trial is to study whether the clinical result from the first trial is reproducible in the second trial with the same study protocol. Under certain circumstance, the FDA Modernization Act of 1997 includes a provision to allow data from one adequate and well-controlled clinical trial investigation and confirmatory evidence to establish effectiveness for risk/benefit assessment of drug and biological candidates for approval. In this paper, we introduce the concept of reproducibility probability for a given clinical trial, which is useful in providing important information for regulatory agencies in deciding whether a single clinical trial is sufficient and for pharmaceutical companies in adjusting the sample size in a future clinical trial. Three approaches, the estimated power approach, the method of confidence bounds and the Bayesian approach, are studied in evaluating reproducibility probabilities under several study designs commonly used in clinical trials.

Adult↗

PubMed2002

Testing model fit in longitudinal data analysis against alternatives with omitted covariates.

Several types of common model misspecifications can be re-formulated as problems of omitted covariates. These include situations with unmeasured confounders, measurement errors in observed covariates and informative censoring. Longitudinal data present special opportunities for detecting omitted covariates that are related to the observed ones differently across time than across individuals. This situation arises with period and cohort effects, as well as with usual formulations of classical measurement error in observed covariates. In this article we focus on testing for the existence of omitted covariates in longitudinal data analysis when models are fit by generalized estimation equations. When omitted covariates are present, specification of the correct link function conditionally on only observed covariates under the alternative usually involves complicated numerical integration. We propose a quasi-score test statistic that avoids the need to fit such alternative models. The statistic is asymptotically chi-square distributed under the null hypothesis of no omitted covariates with degrees of freedom determined by the assumed alternative structure. We study the significance level and the power of the quasi-score test in linear and logistic regression models. The test is then applied to an analysis of excessive daytime sleepiness.

Cohort Studies↗

PubMed2002

Individual bioequivalence testing under 2x3 designs.

In recent years, as more generic drug products become available, it is a concern not only whether generic drug products that have been approved based on the regulation of average bioequivalence will have the same quality, safety and efficacy as that of the brand-name drug product, but also whether the approved generic drug products can be used interchangeably. In its recent draft guidance, the U.S. Food and Drug Administration (FDA) recommends that individual bioequivalence (IBE) be assessed using the method proposed by Hyslop, Hsuan, and Holder to address drug switchability. The FDA suggests that a 2x4 cross-over design be considered for assessment of IBE, while a 2x3 cross-over design may be used as an alternative design to reduce the length and cost of the study. Little or no information regarding the statistical procedures under 2x3 cross-over designs is discussed in the guidance. In this paper, a detailed statistical procedure for assessment of IBE under 2x3 cross-over designs is derived. The main purpose of this paper, however, is to derive an IBE test under an alternative 2x3 design and show that the resulting IBE test is better than that under a 2x3 cross-over design and is comparable to or even better than that under a 2x4 cross-over design. Our conclusions are supported by theoretical considerations and empirical results. Furthermore, a method of determining the sample sizes required for IBE tests to reach a given level of power is proposed.

Computer Simulation↗

PubMed2002

Bias adjustment in analysing longitudinal data with informative missingness.

The recent biostatistical literature contains a number of methods for handling the bias caused by 'informative censoring', which refers to drop-out from a longitudinal study after a number of visits scheduled at predetermined intervals. The same or related methods can be extended to situations where the missing pattern is intermittent. The pattern of missingness is often assumed to be related to the outcome through random effects which represent unmeasured individual characteristics such as health awareness. To date there is only limited experience with applying the methods for informative censoring in practice, mostly because of complicated modelling and difficult computations. In this paper, we propose an estimation method based on grouping the data. The proposed estimator is asymptotically unbiased in various situations under informative missingness. Several existing methods are reviewed and compared in simulation studies. We apply the methods to data from the Wisconsin Diabetes Registry Project, a longitudinal study tracking glycaemic control and acute and chronic complications from the diagnosis of type I diabetes.

Bias↗

PubMed2002

Clinical evaluation of 70 degrees and 90 degrees laryngeal telescopes.

OBJECTIVES: Rigid telescopy is widely used in otorhinolaryngology for endolaryngeal visualization. Laryngeal telescopes are made with several angles, including 70 degrees and 90 degrees. In this study, the performances of 70 degrees and 90 degrees telescopes are compared and evaluated on the basis of ability to visualize specific regions of the larynx. METHODS: Each subject (N = 121) received evaluation with both 70 degrees and 90 degrees telescopes. The investigator used the telescopes to attempt to visualize 4 key regions: (1) the subglottic area, (2) the pyriform fossae, (3) the anterior commissure, and (4) the laryngeal surface of the epiglottis. The telescopes were connected to a video camera and videotape recordings were made. The percentage of attempted visualizations that were successful was calculated for both the 70 degrees and the 90 degrees telescopes. RESULTS: The 70 degrees telescope provided successful visualization of the subglottic area in 111 patients (91.7%), of the pyriform fossae in 115 (95.0%), of the anterior commissure in 112 (92.6%), and of the laryngeal surface of the epiglottis in 114 (94.2%). The 90 degrees telescope provided successful visualization of the subglottic area in 103 patients (85.1%), of the pyriform fossae in 112 (92.6%), of the anterior commissure in 100 (82.6%), and of the laryngeal surface of the epiglottis in 102 (84.3%). Differences in rates of visualization were significant for the posterior surface of the epiglottis, the anterior commissure, and the subglottic area. CONCLUSIONS: The 70 degrees telescope provided a significantly higher rate of successful visualization for 3 of the 4 regions studied. This result contributes information that may help the clinical examiner select an instrument of choice.

Adult↗

PubMed2002

A note on statistical methods for assessing therapeutic equivalence.

The two one-sided tests procedure and the confidence interval approach are two commonly used statistical approaches for testing therapeutic equivalence or assessing bioequivalence. However, some confusion arises. For example, what is the difference between the two approaches, given the fact that in some cases the two approaches produce the same test? Should we use level 1-alpha or 1-2alpha when applying the confidence interval approach? When different confidence intervals are available, which confidence interval should be used? The purpose of this paper is to clarify this confusion. It is shown that the approach of using 1-alpha confidence intervals produces level alpha tests, but the sizes of these tests may be smaller than alpha, and that the use of 1-2alpha confidence intervals generally does not ensure that the corresponding test be of level alpha, although there are exceptional cases. The sizes of several tests obtained using different confidence intervals are also evaluated.

Clinical Trials as Topic↗

PubMed2002

Probability lower bounds for USP/NF tests.

In the pharmaceutical industry, a number of tests such as content uniformity and dissolution testing are usually performed at various stages of drug manufacturing process to ensure that the drug product meets standards for identity, strength, quality, purity, and stability of the drug product as specified in the United States Pharmacopedia and National Formulary (USP/NF). The USP/NF provides requirements for sampling plans, testing procedures, and acceptance criteria for these tests. To ensure that there is a high probability of passing the USP/NF tests, the sponsors usually establish in-house specification limits based on some lower bounds of the probabilities of passing USP/NF tests for future samples. In this article, we derive some probability lower bounds for USP/NF tests. It is shown that the proposed probability lower bounds are better than the existing ones and are very close to the true probabilities in a broad range of the population mean and variance of the test sample.

Drug Compounding↗

PubMed2002

On the assessment of similarity for dissolution profiles of two drug products.

The assessment of similarity between dissolution profiles of two drug products is considered. After reviewing some existing approaches, we propose a statistical method of assessing local and global similarities based on a time series model for the ratio of the dissolution results from two drug products and a polynominal model for the mean of the ratio. An example is presented for illustration.

Algorithms↗

PubMed2002

Profile analysis for assessing in vitro bioequivalence.

For locally acting drug products such as nasal aerosols and nasal sprays, therapeutic equivalence between two drug products may be established by in vitro bioequivalence studies based on measurements intended to reflect the rate and extent to which the active ingredient becomes available at the site of action. For cascade impaction or multistage liquid impinger for particle size distribution, profile analysis is required. However, we find that the analysis procedure described in the 1999 FDA guidance lacks statistical justification. In this article, we explain why FDA's approach is incorrect and propose a correct statistical method for profile analysis using the basic ideas in the FDA guidance.

Aerosols↗

PubMed2002

Assessing sensitivity and similarity in bridging studies.

In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry--Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.

Algorithms↗

PubMed2002

A note on sample size calculation for mean comparisons based on noncentral t-statistics.

One-sample and two-sample t-tests are commonly used in analyzing data from clinical trials in comparing mean responses from two drug products. During the planning stage of a clinical study, a crucial step is the sample size calculation, i.e., the determination of the number of subjects (patients) needed to achieve a desired power (e.g., 80%) for detecting a clinically meaningful difference in the mean drug responses. Based on noncentral t-distributions, we derive some sample size calculation formulas for testing equality, testing therapeutic noninferiority/superiority, and testing therapeutic equivalence, under the popular one-sample design, two-sample parallel design, and two-sample crossover design. Useful tables are constructed and some examples are given for illustration.

Algorithms↗

PubMed2002

Tests for inter-subject and total variabilities under crossover designs.

In this paper, we consider statistical tests for inter-subject and total variabilities between treatments under crossover designs. Since estimators of variance components for inter-subject variability and total variability in crossover design are not independent, the usual F-test cannot be applied. Alternatively, we propose a test based on the concept of the extension of the modified large sample method to compare inter-subject variability and total variability between treatments under a 2 x 2 m replicated crossover design. An asymptotic power of the proposed test is derived. A sensitivity analysis is performed based on the asymptotic power to determine how the power changes with respect to various parameters such as inter-subject correlation and intra-class correlation. Also the two methods for sample size calculation for testing total variability under 2 x 4 crossover design are discussed. The method based on the Fisher-Cornish inversion shows better performance than the method based on the normal approximation. Several simulation studies were conducted to investigate the finite sample performance of the proposed test. Our simulation results show that the proposed test can control type I error satisfactorily.

Analysis of Variance↗

PubMed2002

Donor substrate regeneration for efficient synthesis of globotetraose and isoglobotetraose.

Here we describe the efficient synthesis of two oligosaccharide moieties of human glycosphingolipids, globotetraose (GalNAcbeta1-->3Galalpha1-->4Galbeta1-->4Glc) and isoglobotetraose (GalNAcbeta1-->3Galalpha1-->3Galbeta1-->4Glc), with in situ enzymatic regeneration of UDP-N-acetylgalactosamine (UDP-GalNAc). We demonstrate that the recombinant beta-1,3-N-acetylgalactosaminyltransferase from Haemophilus influenzae strain Rd can transfer N-acetylgalactosamine to a wide range of acceptor substrates with a terminal galactose residue. The donor substrate UDP-GalNAc can be regenerated by a six-enzyme reaction cycle consisting of phosphoglucosamine mutase, UDP-N-acetylglucosamine pyrophosphorylase, phosphate acetyltransferase, pyruvate kinase, and inorganic pyrophosphatase from Escherichia coli, as well as UDP-N-acetylglucosamine C4 epimerase from Plesiomonas shigelloides. All these enzymes were overexpressed in E. coli with six-histidine tags and were purified by one-step nickel-nitrilotriacetic acid affinity chromatography. Multiple-enzyme synthesis of globotetraose or isoglobotetraose with the purified enzymes was achieved with relatively high yields.

Bacterial Proteins↗

PubMedDate not supplied

Transepithelial electrical resistance is not a reliable measurement of the Caco-2 monolayer integrity in Transwell.

The significance of monitoring transepithelial electrical resistance (TEER) value during the study on drug absorption through Caco-2 monolayers in Transwells was re-evaluated. TEER value was monitored before, during, and after the absorption of Streptokinase (45 KD). Four enhancers--disodium ethylenediaminetetracetate (disodium EDTA), sodium cholate (NaC), sodium taurocholate (NaTC), and sodium caprate along with alpha-hemolysin (a cell membrane pore-forming toxin)--were used to signify the outcome of this study. Modified trypan blue exclusion technique was used to examine the Caco-2 cell viability throughout the absorption studies. The enhancers at the used concentration exhibited toxic effect on the Caco-2 cells as evident from the trypan blue exclusion studies. This toxic effect was not reflected by the TEER profile because TEER value dropped after the addition of the absorption enhancers. But it came back to its initial value after the cell culture media was replaced by enhancer-free media. This toxic effect was confirmed by the antiproliferation studies on the four enhancers and alpha-hemolysin against Caco-2 cells. Therefore, we concluded that the measurement of TEER is not a reliable method to determine the absorption enhancers toxicity or integrity of the Caco-2 monolayers in the Transwells.

Adjuvants, Pharmaceutic↗