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Biomedical subjects

Jun Shao

Publications and source records attributed to Jun Shao.

At least 19 recordsLinked to original sources
PubMed2003

Last observation carry-forward and last observation analysis.

Drop-out often occurs in clinical trials with multiple visits and drop-out is often informative in the sense that the population of patients who dropped out is different from the population of patients who completed the study. To handle data with informative drop-out, an intention-to-treat analysis, which evaluates treatment effects over the population of all randomized patients with at least one post-treatment evaluation, is often required by the regulatory agencies. As a popular and simple intention-to-treat analysis, the last observation carry-forward (LOCF) analysis of variance (ANOVA) performs a statistical test for treatment effects by treating the last observation prior to drop-out as the observation from the last visit. Although discussions, examples and limited empirical results about the LOCF analysis can be found, its theoretical property is unclear. We find that the LOCF one-way ANOVA test is actually asymptotically valid (that is, its asymptotic size is equal to the nominal size) in the special but important case where only two treatments are compared and the two treatment groups have the same number of patients, regardless of whether drop-out is informative or not. In other cases, however, the asymptotic size of the LOCF test is different from the nominal size and is often too small when drop-out is informative, which results in a loss in power of detecting treatment effects, a disadvantage to drug companies. We propose an asymptotically valid test for comparing the global means over subpopulations, where each subpopulation contains patients dropping out after a particular visit. Some simulation results are presented to study the finite sample performance of the LOCF test and our proposed test.

Analysis of Variance↗
PubMed2003

In vitro bioequivalence testing.

A statistical test is proposed for in vitro bioequivalence testing between drug products such as nasal aerosols and nasal sprays. The proposed test generalizes the one recommended in the FDA 1999 guidance to the situation where replicated observations obtained from each sampled canister or bottle of the drug product are available. The technique developed by Hyslop, Hsuan and Holder is used so that the proposed test is asymptotically accurate. The type I error probability and power of the proposed test are investigated through a simulation study. A method for determining the required sample size to achieve a desired power is also proposed. A numerical example is given for illustration.

Administration, Intranasal↗
PubMed2003

Evaluating the agreement of two quantitative assays with repeated measurements.

A common task in assay validation is to show the agreement between an assay under investigation and a reference assay. Hence, in the hypothesis setup, we should choose nonagreement as the null hypothesis so that when the null hypothesis is rejected at 5% level of significance, we have a 95% statistical assurance to claim the agreement between two assays. In this paper, we propose a statistical test with nonagreement as the null hypothesis. The calculation of sample size is also given. Some simulation results are provided for illustration.

Biometry↗
PubMed2003

Stability analysis with discrete responses.

We consider the estimation of shelf life of a drug product when the stability data are discrete. When there is no batch-to-batch variation, the proposed shelf life estimator is an approximate 95% lower confidence bound of the true shelf life. In the presence of batch-to-batch variation, the proposed shelf life estimator is an approximate 95% lower prediction bound of the shelf life of future batches. As a result, the proposed shelf life is applicable to all future batches of the same drug product. Testing for batch-to-batch variation based on discrete responses is also discussed.

Confidence Intervals↗
PubMed2003

Enhanced production of alpha-galactosyl epitopes by metabolically engineered Pichia pastoris.

A metabolically engineered Pichia pastoris strain was constructed that harbored three heterologous enzymes: an S11E mutated sucrose synthase from Vigna radiata, a truncated UDP-glucose C4 epimerase from Saccharomyces cerevisiae, and a truncated bovine alpha-1,3-galactosyltransferase. Each gene has its own methanol-inducible alcohol oxidase 1 promoter and transcription terminator on the chromosomal DNA of P. pastoris strain GS115. The proteins were coexpressed intracellularly under the induction of methanol. After permeabilization, the whole P. pastoris cells were used to synthesize alpha-galactosyl (alpha-Gal) trisaccharide (Galalpha1,3Galbeta1,4Glc) with in situ regeneration of UDP-galactose. Up to 28 mM alpha-Gal was accumulated in a 200-ml reaction. The Pichia system described here is simple and flexible. This work demonstrates that recombinant P. pastoris is an excellent alternative to Escherichia coli transformants in large-scale synthesis of oligosaccharides.

Animals↗
PubMed2002

[Incidence of senile dementia and depression in elderly population in Xicheng District, Beijing, an epidemiologic study].

OBJECTIVE: To investigate the incidence of senile dementia and depression in the elderly and the factors correlative with these disorders. METHODS: All the non-case subjects investigated in a survey of prevalence of senile dementia and depression conducted among the elderly population in Xicheng District, Beijing in 1997 were followed up in 1999. The investigation procedure, instruments and diagnostic criteria were identical with those used in 1997 survey. RESULTS: The annual incidence rates of senile dementia was 0.89% in those aged 60 and over. The incidence rate of old males and that of the old females were not significantly different. The annual incidence rate of senile dementia in groups aged 60 approximately 64, 64 approximately 69, 70 approximately 74 75 approximately 79 80 approximately 84 85 approximately 89, and 90 and over were 0.15% 0.68 % 0.44% 1.32% 2.41% 5.72% and 5.13% respectively. The incidence rate in the elderly over 90 was lower than that in the group aged 85 approximately 89. The minimum annual incidence rate of depression in the elderly aged 60 and over was 1.28%. The incidence rate of depression was higher in the group with poorer health than in the group with better health. The incidence rates of moderate and severe dementia were not significantly different from those in 1989. CONCLUSION: The incidence rate of senile dementia in the elderly remains rather stable during this period of 10 years in Beijing city. The incidence rate of senile dementia is closely correlated with age. The incidence rate of depression in the elderly is remarkably correlated with health status. Senile dementia and depression may coexist in the same person.

Aged↗
PubMed2002

Overexpression and biochemical characterization of beta-1,3-N-acetylgalactosaminyltransferase LgtD from Haemophilus influenzae strain Rd.

The lipopolysaccharide of capsule deficient Haemophilus influenzae strain Rd contains an N-acetylgalactosamine residue attached to the terminal globotriose moiety in the Hex5 glycoform. Genome analysis identified an open reading frame HI1578, referred to as lgtD, whose amino acid sequence shows significant level of similarity to a number of bacterial glycosyltransferases involved in lipopolysaccharide biosynthesis. To investigate its function, overexpression and biochemical characterization were performed. Most of the protein was obtained in a highly soluble and active form. By using standard glycosyltransferase assay and HPLC, we show that LgtD is an N-acetylgalactosaminyltransferase with high donor substrate specificity and globotriose is a highly preferred acceptor substrate for the enzyme. The K(m) for UDP-GalNAc and globotriose are 58 microM and 8.6 mM, respectively. The amino acid sequence of the enzyme shows the conserved features of family II glycosyltransferases. This is the first N-acetylgalactosaminyltransferase identified from H. influenzae, which shows potential application in large-scale synthesis of globo-series oligosaccharides.

Amino Acid Sequence↗
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↗