Karl E. Peace

YinYang Dynamic Neurobiological Modeling and Diagnostic Analysis of Major Depressive and Bipolar Disorders

Since millions suffer from major depressive and bipolar disorders, the modeling, characterization, classification, and diagnostic analysis of such mental disorders bear great significance in medical and pharmaceutical research. Yin Yang bipolar sets are introduced for neurobiological modeling and diagnostic analysis of such disorders. It is shown that bipolar sets and a bipolar dynamic modus ponens (BDMP) build a technological bridge from a linear, static, and closed world to a nonlinear, dynamic, and open world of equilibria, quasi-equilibria, or nonequilibria and provide a novel model for bipolar neurobiological diagnostic analysis with added rigor to the current standard. It is shown that bipolar inference can help in understanding both the classic manifestations and the counterintuitive symptoms of bipolar disorders with applications in clinical psychopharmacology. Mathematical and visual characterizations of core features of such disorders are presented. A unified diagnosis and outcome model of different treatments are presented for different types of bipolar disorders. The significance and novelty of this work is twofold: 1) it introduces YinYang into biomedicine for the understanding of certain neurobiological disorders and fosters a new standard model for clinical, therapeutic, and pharmacological research and applications; 2) it presents a mathematical basis for the characterization of mood regulation in individuals and/or a cohort of patients with applications in biomedical engineering and potential applications in nanotechnologies for integrated care of major depressive and bipolar disorders.

MentalSquares: A generic bipolar Support Vector Machine for psychiatric disorder classification, diagnostic analysis and neurobiological data mining

MentalSquares (MSQs)--an equilibrium-based dimensional approach is presented for the classification and diagnostic analysis of psychological conditions with Bipolar Disorders (BPDs) as an example. While a Support Vector Machine (SVM) is defined in Hilbert space. A MSQ can be considered as a generic SVM for improved classification. Different from the traditional categorical model of BPDs, the generic approach focuses on the balance of two poles of mental equilibrium. Preliminary results show that this new approach has a number of advantages over existing models. The generic model is analytically illustrated with public domain clinical examples and well-known empirical clinical knowledge. Its clinical and computerised operability is illustrated. Its potential of being a practical method for the classification and analysis of neurobiological patterns and drug effects is discussed.

One-sided or two-sided p values: which most appropriately address the question of drug efficacy?

Whether a one-sided or a two-sided p value should be used for reporting the results of an analysis should be determined by the a priori question the investigation seeks to answer. It is concluded that one-sided p values are appropriate in clinical trials whose objective is to provide definitive, confirmatory evidence of efficacy of pharmaceutical compounds.

The effect of single intravenous doses of cimetidine or ranitidine on gastric secretion

Intravenous Cimetidine, 300 mg or 400 mg, or ranitidine, 50 mg, was administered as a single dose to 36 volunteers in a randomized, crossover fashion. Aspirates of gastric juice were obtained after dosing, and the pH, titratable acidity, gastric fluid volume, and gastric acid output were determined from baseline through 7½ hours for each subject. Each intervention significantly increased pH and suppressed hydrogen ion concentration, gastric fluid volume, and gastric acid output. Both the magnitudes of the changes when compared with baseline and the time of the mean maximum effects were similar in all three drug regimens. The effect of all three interventions on gastric fluid volume and gastric acid output diminished sharply after 6 hours. The data indicate that the gastric secretory response to all three interventions did not differ substantially.

Design, Monitoring, and Analysis Issues Relative to Adverse Events

In the clinical development of new drugs for market approval, it is frequently impossible to design trials to provide definitive information about safety—particularly about adverse events. It is possible, however, to design most trials to provide definitive information about efficacy. Efficacy trials with new drugs should therefore be monitored for safety, and the safety profile described within and across trials. Confidence intervals are recommended as the appropriate statistical methodology for doing this. Such intervals provide an interval estimate on the unknown incidences of adverse experiences among patients who could be treated with each regimen, as well as permit a conclusion that two regimens are different.

Clinical trial data analysis using R

Introduction to R What Is R? Steps on Installing R and Updating R Packages R for Clinical Trials A Simple Simulated Clinical Trial Concluding Remarks Overview of Clinical Trials Introduction Phases of Clinical Trials and Objectives The Clinical Development Plan Biostatistical Aspects of a Protocol Treatment Comparisons in Clinical Trials Data from Clinical Trials Statistical Models for Treatment Comparisons Data Analysis in R Treatment Comparisons in Clinical Trials with Covariates Data from Clinical Trials Statistical Models Incorporating Covariates Data Analysis in R Analysis of Clinical Trials with Time-to-Event Endpoints Clinical Trials with Time-to-Event Data Statistical Models Statistical Methods for Right-Censored Data Statistical Methods for Interval-Censored Data Step-by-Step Implementations in R Analysis of Data from Longitudinal Clinical Trials Clinical Trials Statistical Models Analysis of Data from Longitudinal Clinical Trials Sample Size Determination and Power Calculation in Clinical Trials Prerequisites for Sample Size Determination Comparison of Two Treatment Groups with Continuous Endpoints Two Binomial Proportions Time-to-Event Endpoint Design of Group Sequential Trials Longitudinal Trials Relative Changes and Coefficient of Variation: An Extra Meta-Analysis of Clinical Trials Data from Clinical Trials Statistical Models for Meta-Analysis Meta-Analysis of Data in R Bayesian Analysis Methods in Clinical Trials Bayesian Models R Packages in Bayesian Modeling MCMC Simulations Bayesian Data Analysis Analysis of Bioequivalence Clinical Trials Data from Bioequivalence Clinical Trials Bioequivalence Clinical Trial Endpoints Statistical Methods to Analyze Bioequivalence Step-by-Step Implementation in R Analysis of Adverse Events in Clinical Trials Adverse Event Data from a Clinical Trial Statistical Methods Step-by-Step Implementation in R Analysis of DNA Microarrays in Clinical Trials DNA Microarray Breast Cancer Data Bibliography Index Concluding Remarks appear at the end of each chapter.

Statistical methods for a three-period crossover design in which high dose cannot be used first

Design and analysis methods for the three-period crossover trial defined by the sequences: (D0, D1, D2), (D1, D0, D2), and (D1, D2, D0), where D0 is a placebo, and D1 and D2 are a low dose and a high dose of a drug, respectively, are developed. This design may be used when investigators are unwilling to administer a higher dose of a new drug to a patient before administering a lower dose. In using this design, patients should be randomized to sequences in blocks that are integer multiples of 3. Both parametric and non-parametric analysis methods are based on contrasts that capture intrapatient variability only and provide unbiased estimates and hypothesis tests of pairwise differences between carryover, direct dose, and period effects. The design and methods are illustrated with data reflecting the cognitive component of the Alzheimers disease assessment scale collected in a large clinical trial of Tacrine at doses of 0, 40, and 80 mg/day.

The Alternative Hypothesis: One-Sided or Two-Sided?

The appropriateness of a one-sided alternative hypothesis rather than the more conservative, boiler-plate, two-sided hypothesis is discussed and examples provided. It is concluded that confirmatory efficacy clinical trials of pharmaceutical compounds should always be viewed within the one-sided alternative hypothesis testing framework.

Clinical Trial Methodology

Overview of Clinical Trial Methodology Clinical Trials Clinical Trial Methodology Summary of Clinical Trial Methodology Overview of the Drug Development Process and Regulation of Clinical Trials Introduction The Drug Development Process History of Drug Regulation Principles of Adequate and Controlled Investigations Content and Format of the IND Content and Format of the NDA Organizational Structure of the FDA The FDA Review Process Labeling and the Package Insert Pharmaceutical Company Organization and Role of the Biostatistician Ethical Considerations in the Design and Conduct of Clinical Trials Introduction History and Evolution of Ethical Considerations in Clinical Trials: Key Milestones Independent Review Boards Clinical Trial Ethics: Who Should Practice? Informed Consent, Sample Size, and Power Common Ethical Principles of Various Codes and Regulations Sample Size Considerations in Clinical Trials Pre-Market Approval Introduction Phases of Clinical Trials and Objectives The Clinical Development Plan: Pre-Market Approval Sample Size Requirements Examples Philosophical Issues Sequential, Group Sequential, Stochastic Curtailment, and Adaptive Design Procedures in Clinical Trials Introduction Sequential Procedures Group Sequential Procedures Stochastic Curtailment Adaptively Designed Clinical Trials Biostatistical Aspects of the Protocol The Background or Rationale Objective Plan of Study Statistical Analysis Section Administration Protocol References Section The Statistical Analysis Plan Introduction Protocol Objective Efficacy Data Collected and Protocol Schema Primary and Secondary Efficacy Endpoints Objectives, Translated as Statistical Hypotheses Protocol Design Features Statistical Analyses Pooling of Data from Multicenter Clinical Trials Introduction Multicenter Clinical Trial Experimental Setting Pre-Study Planning Multicenter Clinical Trial Conduct Biostatistical Analysis Validity of Statistical Inference Introduction Planning the Investigation Conducting the Investigation Statistical Analyses, Interpretation, and Inference Reporting Results of Investigations Bioequivalence Clinical Trials Introduction Absorption, Distribution, Metabolism, and Excretion (ADME) Bioavailability Factors That Affect Bioavailability Blood Level Clinical Trials Bioequivalence Design of Bioequivalence Trials Analysis of Bioequivalence Trials Analysis of Ratios Pharmacokinetic Models Support of Bioequivalence Trials in the Pharmaceutical Industry Examples Dose and Frequency Determination from Phase II Clinical Trials in Stress Test-Induced Angina Introduction Overview of Response Surface Methodology Full Quadratic Response Surface Model Phase II Clinical Trial Program in Stress Test-Induced Angina Confirmation of Clinically Optimal Dosing in the Treatment of Duodenal Ulcers: A Phase III Dose Comparison Trial Introduction Background Objective Designing and Planning the Investigation Conducting the Investigation Statistical Analyses Other Considerations Innovative Aspects of the Clinical Trial Program Pivotal Proof-of-Efficacy Clinical Trials in the Prevention of NANSAID-Induced Gastric Ulceration Introduction Rationale The Protocols Monitoring and Data Management FDA Meeting Clinical Trials in the Treatment of Alzheimers Disease Based upon Enrichment Designs Introduction Enrichment Design Clinical Trials Objective Primary Efficacy Endpoints Sample Size Determination Statistical Methods Results A Clinical Trial to Establish Reduction of CHD Risk Introduction Objective Designing and Planning the Investigation Conducting the Investigation Data Management Statistical Analyses Results Summary Pivotal Proof-of-Efficacy Clinical Trials in the Treatment of Panic Disorder Introduction Design of Pivotal Proof-of-Efficacy Trials Traditional Statistical Analysis Methods Overview of Efficacy Results of the Two Trials Alternative Design and Analysis Strategies Combination Clinical Trials Introduction Two-by-Two Factorial Design Effectiveness of the Combination Contribution of Components to the Effectiveness of the Combination Factorial Designs in Other Clinical Development Areas Example 1: Actifed in the Treatment of SAR Following DESI Review Example 2: Crossover Trial of Actifed in the Treatment of SAR Example 3: Parallel Trial of Actifed in the Treatment of the Common Cold Monitoring Clinical Trials for Adverse Events Introduction Designing for Safety: Antibiotic Rash Example Designing for Safety: Hypokalemia Example Designing for Safety: Hypertensive Rebound Example Premarket Approval Trials: Designed for Efficacy Premarket Approval Trials: Quality of Adverse Event Information Monitoring for Safety Statistical Methodology: Individual Trial Example Statistical Methodology: Across Trials Index References appear at the end of each chapter.

The effect of tacrine and lecithin in Alzheimer's disease

Tacrine, a cholinesterase inhibitor, has beneficial effects on cognition and global status in patients with Alzheimers disease. These effects have been demonstrated in clinical trials by double-blind comparisons with placebo. Tacrine dosages have been studied in 5 protocols that used either enrichment or parallel designs.We have used a population pharmacodynamic model to describe the response to tacrine and placebo in the 3 trials that used the enrichment design. The time-course of the response and its relation to tacrine dosage obtained from the enrichment design analysis were used to define the parallel design.The effects of tacrine on cognition and global status was estimated separately from each trial. Analysis of the 2 trials using the parallel design confirmed the predictions from the enrichment design. By combining the data from all 5 trials it was possible to show that tacrine potency was similar in all studies, but that the placebo response was different in some. The effect of tacrine was linearly proportional to dosage from 40 to 160 mg per day.One of the enrichment design trials included a subgroup treated with lecithin, a choline precursor. The potency of lecithin was equivalent to about 40 mg per day of tacrine. Using the combined data from all 5 trials it was possible to distinguish a responder population, approximately one-third of all patients, with a 4-fold greater effect compared with poor responders.Tacrine has beneficial effects on cognitive status in patients with Alzheimers disease. Lecithin has a small additional benefit independent of tacrine. The pharmacodynamic model predicts a 1.94 year delay in disease progression at a dose of 160 mg per day for patients who are similar to the responders in the 5 clinical trials.