Factor Analysis of Cross-Classified Data

This thesis introduces a model hierarchy related to Principal Component Analysis and Factor Analysis, in which vector measurements are linearly decomposed into a relatively small set of hypothetical principal directions, for purposes of dimension reduction. The mathematical specification of unknown parameters in the models is unified. Identifiability of the suitably defined models is proved. The EM algorithm and the Newton-Raphson algorithm based on likelihoods and profile likelihoods are implemented to get computationally effective (maximum likelihood) estimators for the unknown parameters. A restricted model (with some error variances $0$) and a sufficient condition for a local maximum likelihood estimate are established. Score tests are constructed to check whether error variances are $0$, which is shown to be associated with non-identifiability of models. Statistical tests of goodness of fit of the models to data are established in a likelihood ratio testing framework, so that the most parsimoniously parameterized model consistent with the data can be chosen for purposes of description and classification of the experimental settings. The results are applied on a real data set involving coronal cross-sectional ultrasound pictures of the human tongue surface during speech. The likelihood ratio test is used to test the fit of the PARAFAC model on the real coronal tongue data, leading to a finding of inadequacy of the PARAFAC model

Establishing Non-Inferiority of a New Treatment in a Three-Arm Trial: Apply a Step-Down Hierarchical Model in a Papulopustular Acne Study and an Oral Prophylactic Antibiotics Study

Clinical trials comparing a test treatment with an active control therapy have become very popular in drug and medical device development in the last decade. An active controlled trial without a placebo, however, exhibits some major challenges in design, analysis, and interpretation, such as the determination of the non-inferiority margin or the assumption of constancy condition. When there are no ethical concerns, the comparison of a test drug with placebo usually provides the most convincing proof of the efficacy of a new treatment. Therefore, it may be advisable to conduct a three-arm trial — including placebo, active control, and the new treatment - if it is ethically justifiable such as a papulopustular acne study and an oral prophylactic antibiotics study. In this paper, we propose a statistical methodology for a three-arm non-inferiority trial with binary outcomes. We adapt the step-down hierarchical hypotheses and give a three-step testing procedure which is more realistic in conducting a clinical trial. We derived an optimal sample size allocation rule in an ethical and reliable manner to minimize the total sample size and hence to shorten the duration of the trials. Real examples from a papulopustular acne study and an oral prophylactic antibiotics study are used to demonstrate our methodology

A Post-hoc Study of D-Amino Acid Oxidase in Blood as an Indicator of Post-stroke Dementia

Stroke is an important risk factor for dementia. Epidemiological studies have indicated a high incidence of dementia in stroke patients. There is currently no effective biomarker for the diagnosis of post-stroke dementia (PSD). D-amino acid oxidase (DAO) is a flavin-dependent enzyme widely distributed in the central nervous system. DAO oxidizes D-amino acids, a process which generates neurotoxic hydrogen peroxide and leads to neurodegeneration. This study aimed to examine post-stroke plasma DAO levels as a biomarker for PSD. In total, 53 patients with PSD, 20 post-stroke patients without dementia (PSNoD), and 71 age- and gender-matched normal controls were recruited. Cognitive function was evaluated at more than 30 days post-stroke. Plasma DAO was measured using the enzyme-linked immunosorbent assay. White matter hyperintensity (WMH), a neuroimaging biomarker of cerebral small vessel diseases, was determined by magnetic resonance imaging. We found that plasma DAO levels were independently higher in PSD subjects than in PSNoD subjects or the controls and were correlated with the WMH load in stroke patients. Using an area under the curve (AUC)/receiver operating characteristic analysis, plasma DAO levels were significantly reliable for the diagnosis of PSD. The sensitivity and specificity of the optimal cut-off value of 321 ng/ml of plasma DAO for the diagnosis of PSD were 75 and 88.7%, respectively. In conclusion, our data support that plasma DAO levels were increased in PSD patients and correlated with brain WMH, independent of age, gender, hypertension, and renal function. Plasma DAO levels may therefore aid in PSD diagnosis

Optimal Two-Stage Drug Screening Designs Based on Continuous Endpoints

Annual spending on biomedical research nearly doubled in the USA between 1994 and 2003, reaching US$94.3 billions The number of new drugs making it to the market has decline

Translation in Different Diagnostic Procedures—Traditional Chinese Medicine and Western Medicine

Recently, the modernization of traditional Chinese medicines (TCM) for treatment of patients with critical and/or life-threatening diseases has attracted much attention in the pharmaceutical industry. However, there exist essential differences in the evaluation of the efficacy and safety of a TCM as compared with a typical Western medicine (WM), even though they are for the same indication. Therefore, the modernization of a TCM should be based on a scientific evaluation of the safety and effectiveness of the TCM in terms of well-established quantitative criteria. We propose a study design to study the calibration and validation of the Chinese diagnostic procedure for evaluation of a TCM, with respect to a well-established clinical endpoint for evaluation of a WM. Statistical validation of such an instrument is essential to have an accurate and reliable clinical assessment of the performance of the TCM. Similar to the validation of a typical quality of life instrument, some validation performance characteristics such as validity, reliability, and ruggedness are considered. In this article, a design for validation of a standard quantitative instrument to be commonly employed for diagnosis of patient function/activity, performance, disease signs and symptoms, and disease status and severity based on Chinese diagnostic practice is proposed. Methods for statistical validation of the standard instrument are derived. More specifically, for validation of the TCM diagnostic instrument, we consider the following validation performance characteristics (parameters): validity (or accuracy), reliability (or precision), and ruggedness (interrater variability). A numerical example is given to illustrate the proposed methods for validation of the Chinese diagnostic procedure

A Critical Dose of Doxorubicin Is Required to Alter the Gene Expression Profiles in MCF-7 Cells Acquiring Multidrug Resistance

<div><p>Cellular mechanisms of multidrug resistance (MDR) are related to ABC transporters, apoptosis, antioxidation, drug metabolism, DNA repair and cell proliferation. It remains unclear whether the process of resistance development is programmable. We aimed to study gene expression profiling circumstances in MCF-7 during MDR development. Eleven MCF-7 sublines with incremental doxorubicin resistance were established as a valued tool to study resistance progression. MDR marker P-gp was overexpressed only in cells termed MCF-7/ADR-1024 under the selection dose approaching 1024 nM. MCF-7/ADR-1024 and authentic MCF-7/ADR shared common features in cell morphology and DNA ploidy status. MCF-7/ADR-1024 and authentic MCF-7/ADR down regulated repair genes BRCA1/2 and wild type p53, apoptosis-related gene Bcl-2 and epithelial-mesenchymal transition (EMT) epithelial marker gene E-cadherin. While detoxifying enzymes glutathione-S transferase-π and protein kinase C-α were up-regulated. The genes involving in EMT mesenchymal formation were also overexpressed, including N-cadherin, vimentin and the E-cadherin transcription reppressors Slug, Twist and ZEB1/2. PI3K/AKT inhibitor wortmannin suppressed expression of Slug, Twist and mdr1. Mutant p53 with a deletion at codons 127-133 markedly appeared in MCF-7/ADR-1024 and authentic MCF-7/ADR as well. In addition, MCF-7/ADR-1024 cells exerted CSC-like cell surface marker CD44 high/CD24 low and form mammospheres. Overall, results suggest that resistance marker P-gp arises owing to turn on/off or mutation of the genes involved in DNA repair, apoptosis, detoxifying enzymes, EMT and ABC transporters at a turning point (1.024 μM doxorubicin challenge). Behind this point, no obvious alterations were found in most tested genes. Selection for CSC-like cells under this dose may importantly attribute to propagation of the population presenting invasive properties and drug resistance. We thereby suggest two models in the induction of drug resistance. Model 1: Selection for CSC-like cells. Model 2: Mutations for gain-of resistance. Either model 1 or model 2 requires doxorubicin dose approaching 1 μM to alter gene regulation.</p></div

Presence of cancer stem cell-like properties upon doxorubicin selection.

<p>(A) Analysis of mammary stem cell markers in selected MCF-7/ADR-n sublines. Cells were sorted for CD44 high/CD24 low cell surface antigens by flow cytometry. Cell population was distributed in the quadrant. (B) Mammospheres formation of MCF-7/ADR-1024 cells in a three-dimensional culture, followed by a limiting dilution assay. A representative phase-contrast microscopic image shows mammosphere formation of MCF-7/ADR-1024 compared to MCF-7/WT from a total of 50 countable  mammospheres on day 21.</p