Dingzhou Li - Academia.edu (original) (raw)

Papers by Dingzhou Li

Pharmaceutical statistics, Jun 11, 2024

Diagnostic and Prognostic Research

A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder ... more A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample si...

Statistics in Biopharmaceutical Research, Mar 21, 2022

Journal of Pharmacological and Toxicological Methods, Sep 1, 2019

Journal of Pharmacological and Toxicological Methods, Sep 1, 2008

Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its ... more Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity. Fractal analysis is a novel and efficient tool to explore the adrenergic blockade effect on HRV. This paper applies the detrended fluctuation analysis (DFA) and multifractal DFA (MF-DFA) methods in an attempt to understand the effect of adrenergic blockade on cardiac dynamics in conscious beagle dogs. DFA and MF-DFA analysis are conducted on RR interval data generated from telemetry instrumented dogs receiving a combination of 15 mg/kg nadolol and 5 mg/kg phenoxybenzamine orally administered at the 22nd and 34th hour in a parallel design (n=12). All dogs had approximately 48 h of beat-to-beat heart rate measurements recorded in the left ventricle. Complexity measures for heartbeat series are compared between the blocker and vehicle group. We also compute traditional statistics for HRV and spectral parameters and examine their correlation with fractal analysis. When compared to the vehicle group, the adrenergic blocker group had: 1) longer RR intervals (p=0.02) and lower beat-to-beat variability (p=0.04); 2) decreased low frequency (LF) and high frequency (HF) power (p=0.03), and higher LF-to-HF ratio; 3) larger middle-range scaling exponents (p&amp;amp;amp;amp;amp;amp;amp;lt;0.01); 4) broader multifractal spectra (p=0.03) with higher dominant singularity indices (p=0.02). Our results show that 1) adrenergic blockade alters the sympathovagal balance; 2) adrenergic blockers enhance the complexity of the cardiac dynamics; 3) the adrenergic blockade effect on cardiac dynamics is primarily the attenuation of small fluctuations in RR intervals. Fractal analysis also has the potential to be applied to early QT diagnosis.

Environmental and Molecular Mutagenesis, May 26, 2023

Historical negative control data (HCD) have played an increasingly important role in interpreting... more Historical negative control data (HCD) have played an increasingly important role in interpreting the results of genotoxicity tests. In particular, Organisation for Economic Co‐operation and Development (OECD) genetic toxicology test guidelines recommend comparing responses produced by exposure to test substances with the distribution of HCD as one of three criteria for evaluating and interpreting study results (referred to herein as “Criterion C”). Because of the potential for inconsistency in how HCD are acquired, maintained, described, and used to interpret genotoxicity testing results, a workgroup of the International Workshops for Genotoxicity Testing was convened to provide recommendations on this crucial topic. The workgroup used example data sets from four in vivo tests, the Pig‐a gene mutation assay, the erythrocyte‐based micronucleus test, the transgenic rodent gene mutation assay, and the in vivo alkaline comet assay to illustrate how the quality of HCD can be evaluated. In addition, recommendations are offered on appropriate methods for evaluating HCD distributions. Recommendations of the workgroup are: When concurrent negative control data fulfill study acceptability criteria, they represent the most important comparator for judging whether a particular test substance induced a genotoxic effect. HCD can provide useful context for interpreting study results, but this requires supporting evidence that (i) HCD were generated appropriately, and (ii) their quality has been assessed and deemed sufficiently high for this purpose. HCD should be visualized before any study comparisons take place; graph(s) that show the degree to which HCD are stable over time are particularly useful. Qualitative and semi‐quantitative assessments of HCD should also be supplemented with quantitative evaluations. Key factors in the assessment of HCD include: (i) the stability of HCD over time, and (ii) the degree to which inter‐study variation explains the total variability observed. When animal‐to‐animal variation is the predominant source of variability, the relationship between responses in the study and an HCD‐derived interval or upper bounds value (i.e., OECD Criterion C) can be used with a strong degree of confidence in contextualizing a particular study's results. When inter‐study variation is the major source of variability, comparisons between study data and the HCD bounds are less useful, and consequentially, less emphasis should be placed on using HCD to contextualize a particular study's results. The workgroup findings add additional support for the use of HCD for data interpretation; but relative to most current OECD test guidelines, we recommend a more flexible application that takes into consideration HCD quality. The workgroup considered only commonly used in vivo tests, but it anticipates that the same principles will apply to other genotoxicity tests, including many in vitro tests.

Journal of Computational Neuroscience, Nov 1, 2003

Journal of Pharmacological and Toxicological Methods

Environmental and Molecular Mutagenesis

Statistics in Biopharmaceutical Research, 2022

Journal of Pharmacological and Toxicological Methods, 2018

Biomarkers in Medicine, 2010

Certain compounds that induce liver injury clinically are not readily identified from earlier pre... more Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase) – the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance cre...

Journal of Pharmacological and Toxicological Methods, 2008

Journal of Computational Neuroscience, 2003

Journal of Medical Primatology

BackgroundThe cynomolgus macaque has become the most used non‐human primate species in nonclinica... more BackgroundThe cynomolgus macaque has become the most used non‐human primate species in nonclinical safety assessment during the past decades.MethodsThis review summarizes the biological data and organ system development milestones of the cynomolgus macaque available in the literature.ResultsThe cynomolgus macaque is born precocious relative to humans in some organ systems (e.g., nervous, skeletal, respiratory, and gastrointestinal). Organ systems develop, refine, and expand at different rates after birth. In general, the respiratory, gastrointestinal, renal, and hematopoietic systems mature at approximately 3 years of age. The female reproductive, cardiovascular and hepatobiliary systems mature at approximately 4 years of age. The central nervous, skeletal, immune, male reproductive, and endocrine systems complete their development at approximately 5 to 9 years of age.ConclusionsThe cynomolgus macaque has no meaningful developmental differences in critical organ systems between 2 an...

Journal of Pharmacological and Toxicological Methods, 2011

Page 1. Pfizer Global Research & Development Groton, CT Pfizer Global Research & Developm... more Page 1. Pfizer Global Research & Development Groton, CT Pfizer Global Research & Development Groton, CT Global Safety Pharmacology CoE Drug Safety Research and Development Global Safety Pharmacology CoE Drug Safety Research and Development ...

Journal of Pharmacological and Toxicological Methods, 2007

Veterinary Clinical Pathology

Epilepsy Research, 2006

It has recently been shown that differences between the marginal predictability associated with s... more It has recently been shown that differences between the marginal predictability associated with scalp electrodes adjacent to and remote from the site of a seizure focus are able to distinguish between epochs temporally distant from and just prior to (within about 20 min) the onset of a seizure in patients with temporal lobe epilepsy. The purpose of this paper is to show that these differences of marginal predictability intervals are independent of the state of consciousness of the patient. Methods: We have studied a data set encompassing 33 preictal epochs (within 1 h prior to a seizure) and 61 interictal epochs (defined as at least 1 h away from any seizure) from 14 patients. Each 30 s interval of each epoch was categorized into one of seven different states of consciousness. Statistical models were used to search for relationships (in aggregated data) between the values of differences of marginal predictabilities and state of consciousness. Results: It was not possible to reject the null hypothesis of no relationship between differences of marginal predictabilities and state of consciousness. Conclusions: The values of the differences between marginal predictabilities on aggregated data are apparently insensitive to the state of consciousness. This conclusion, coupled with the fact that the differences between marginal predictabilities do depend on time to seizure, suggests the potential utility of these measures as the basis for ambulatory, non-invasive methods of seizure anticipation. However, the development of a practical non-invasive method for seizure anticipation requires further extensive study on disaggregated data from individual patients.

This chapter provides a survey of key nonclinical safety assays. For each study type, we discuss ... more This chapter provides a survey of key nonclinical safety assays. For each study type, we discuss the typical study designs employed, including a summary of the type of endpoints collected. We then provide an overview of common statistical approaches in each setting. There are some general themes that are common across the study types (e.g., trend testing). At the same time, the different study types may have features that require special consideration (e.g., cross-over designs for safety pharmacology studies, intra-litter correlation in reproductive toxicology studies). While some of the design aspects of these studies are to some extent “fixed” by precedent across the industry, we do address sample size and power considerations, as this information can be valuable to understanding how statistical results can contribute to the overall interpretation of these studies. Finally, for any discussion of statistical approaches, there are likely to be multiple reasonable approaches. We’ve a...