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Suicide & Life-threatening Behavior Feb 2021Categorical data analysis is relevant to suicide risk and prevention research that focuses on discrete outcomes (e.g., suicide attempt status). Unfortunately, results... (Review)
Review
OBJECTIVE
Categorical data analysis is relevant to suicide risk and prevention research that focuses on discrete outcomes (e.g., suicide attempt status). Unfortunately, results from these analyses are often misinterpreted and not presented in a clinically tangible manner. We aimed to address these issues and highlight the relevance and utility of categorical methods in suicide research and clinical assessment. Additionally, we introduce relevant basic machine learning methods concepts and address the distinct utility of the current methods.
METHOD
We review relevant background concepts and pertinent issues with references to helpful resources. We also provide non-technical descriptions and tutorials of how to convey categorical statistical results (logistic regression, receiver operating characteristic [ROC] curves, area under the curve [AUC] statistics, clinical cutoff scores) for clinical context and more intuitive use.
RESULTS
We provide comprehensive examples, using simulated data, and interpret results. We also note important considerations for conducting and interpreting these analyses. We provide a walk-through demonstrating how to convert logistic regression estimates into predicted probability values, which is accompanied by Appendices demonstrating how to produce publication-ready figures in R and Microsoft Excel.
CONCLUSION
Improving the translation of statistical estimates to practical, clinically tangible information may narrow the divide between research and clinical practice.
Topics: Area Under Curve; Data Analysis; Humans; Logistic Models; ROC Curve; Suicide, Attempted
PubMed: 33624878
DOI: 10.1111/sltb.12670 -
GigaScience Jun 2019Chemicals induce compound-specific changes in the transcriptome of an organism (toxicogenomic fingerprints). This provides potential insights about the cellular or...
BACKGROUND
Chemicals induce compound-specific changes in the transcriptome of an organism (toxicogenomic fingerprints). This provides potential insights about the cellular or physiological responses to chemical exposure and adverse effects, which is needed in assessment of chemical-related hazards or environmental health. In this regard, comparison or connection of different experiments becomes important when interpreting toxicogenomic experiments. Owing to lack of capturing response dynamics, comparability is often limited. In this study, we aim to overcome these constraints.
RESULTS
We developed an experimental design and bioinformatic analysis strategy to infer time- and concentration-resolved toxicogenomic fingerprints. We projected the fingerprints to a universal coordinate system (toxicogenomic universe) based on a self-organizing map of toxicogenomic data retrieved from public databases. Genes clustering together in regions of the map indicate functional relation due to co-expression under chemical exposure. To allow for quantitative description and extrapolation of the gene expression responses we developed a time- and concentration-dependent regression model. We applied the analysis strategy in a microarray case study exposing zebrafish embryos to 3 selected model compounds including 2 cyclooxygenase inhibitors. After identification of key responses in the transcriptome we could compare and characterize their association to developmental, toxicokinetic, and toxicodynamic processes using the parameter estimates for affected gene clusters. Furthermore, we discuss an association of toxicogenomic effects with measured internal concentrations.
CONCLUSIONS
The design and analysis pipeline described here could serve as a blueprint for creating comparable toxicogenomic fingerprints of chemicals. It integrates, aggregates, and models time- and concentration-resolved toxicogenomic data.
Topics: Animals; Computational Biology; Drug-Related Side Effects and Adverse Reactions; Models, Biological; Risk Assessment; Toxicogenetics; Transcriptome; Zebrafish
PubMed: 31140561
DOI: 10.1093/gigascience/giz057 -
BMC Bioinformatics Oct 2020Metabolomics data analyses rely on the use of bioinformatics tools. Many integrated multi-functional tools have been developed for untargeted metabolomics data...
BACKGROUND
Metabolomics data analyses rely on the use of bioinformatics tools. Many integrated multi-functional tools have been developed for untargeted metabolomics data processing and have been widely used. More alternative platforms are expected for both basic and advanced users.
RESULTS
Integrated mass spectrometry-based untargeted metabolomics data mining (IP4M) software was designed and developed. The IP4M, has 62 functions categorized into 8 modules, covering all the steps of metabolomics data mining, including raw data preprocessing (alignment, peak de-convolution, peak picking, and isotope filtering), peak annotation, peak table preprocessing, basic statistical description, classification and biomarker detection, correlation analysis, cluster and sub-cluster analysis, regression analysis, ROC analysis, pathway and enrichment analysis, and sample size and power analysis. Additionally, a KEGG-derived metabolic reaction database was embedded and a series of ratio variables (product/substrate) can be generated with enlarged information on enzyme activity. A new method, GRaMM, for correlation analysis between metabolome and microbiome data was also provided. IP4M provides both a number of parameters for customized and refined analysis (for expert users), as well as 4 simplified workflows with few key parameters (for beginners who are unfamiliar with computational metabolomics). The performance of IP4M was evaluated and compared with existing computational platforms using 2 data sets derived from standards mixture and 2 data sets derived from serum samples, from GC-MS and LC-MS respectively.
CONCLUSION
IP4M is powerful, modularized, customizable and easy-to-use. It is a good choice for metabolomics data processing and analysis. Free versions for Windows, MAC OS, and Linux systems are provided.
Topics: Area Under Curve; Chromatography, High Pressure Liquid; Cluster Analysis; Data Mining; Gas Chromatography-Mass Spectrometry; Humans; Mass Spectrometry; Metabolome; Metabolomics; ROC Curve; User-Computer Interface
PubMed: 33028191
DOI: 10.1186/s12859-020-03786-x -
Current Drug Metabolism Nov 2012The prevalence of obesity continues to rise throughout the world. Increasingly, bariatric surgery is used for those with morbid obesity as a pivotal approach to achieve... (Review)
Review
UNLABELLED
The prevalence of obesity continues to rise throughout the world. Increasingly, bariatric surgery is used for those with morbid obesity as a pivotal approach to achieve weight loss. Along with substantial weight loss, malabsorption of essential vitamins, minerals, and drugs also occurs. Therefore, more than ever, a better understanding of the physiology and mechanisms by which these deficiencies occur is essential. We review the normal physiology of vitamin, mineral, and drug absorption. This is followed by a description of currently performed bariatric surgeries in the United States. A detailed review of specific nutrient and mineral deficiency states is presented, based on the most significant studies published in the last two decades. Of note, screening and supplementation recommendations have been included. Drug absorption data after these procedures is presented and discussed. Studies were identified by searching the Cochrane Registry and MEDLINE using relevant search terms, as well as through review of the reference section of included manuscripts.
CONCLUSIONS
Bariatric surgery can be effectively used to achieve sustainable weight-loss in morbidly obese patients. It simultaneously brings forth important functional consequences on nutrient deficiencies and drug absorption that clinician's must be aware of. Further prospective, randomized research on specific procedures and deficiencies is required.
Topics: Animals; Bariatric Surgery; Humans; Intestinal Absorption; Minerals; Obesity, Morbid; Pharmaceutical Preparations; Vitamins
PubMed: 22746302
DOI: 10.2174/138920012803341339 -
Actas Dermo-sifiliograficas Nov 2014Scarce scientific evidence is available to define the precise effects that certain drugs might have on embryonic and fetal development if taken by pregnant women with... (Review)
Review
Scarce scientific evidence is available to define the precise effects that certain drugs might have on embryonic and fetal development if taken by pregnant women with psoriasis, given the ethical concerns that preclude enrolling such women in clinical trials. The little information on the use of biologics during gestation that has been published is based on retrospective and observational studies, and experience with these drugs in this context in psoriasis is still very limited. The literature seems to suggest that biologic therapy is safe during pregnancy, but there is no certainty. This detailed review of accumulated experience with biologic therapy during pregnancy relies mainly on descriptions of the management of other types of rheumatic disease, although the use of these agents in psoriasis is growing steadily.
Topics: Abnormalities, Drug-Induced; Animals; Antirheumatic Agents; Biological Products; Female; Fetus; Humans; Infant, Newborn; Milk, Human; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Psoriasis; Risk Assessment; Tumor Necrosis Factor-alpha
PubMed: 24314892
DOI: 10.1016/j.ad.2013.06.005 -
Molecules (Basel, Switzerland) Jan 2013Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of... (Review)
Review
Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins, so we also argue that it is good starting point for multi-target drugs. This review is primarily addressed to the description of the recent advances in the biological activity studies of evodiamine, with a focus on pharmacological mechanism. The present review also includes the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine in an attempt to provide a direction for further multi-target drug design.
Topics: Animals; Humans; Ligands; Models, Molecular; Proteins; Quinazolines
PubMed: 23434865
DOI: 10.3390/molecules18021826 -
Environmental Health Perspectives Mar 2021There is a great concern on potential adverse effects of exposure to perfluorooctane sulfonate (PFOS) in sensitive subpopulations, such as pregnant women, fetuses, and...
Development of a Gestational and Lactational Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctane Sulfonate (PFOS) in Rats and Humans and Its Implications in the Derivation of Health-Based Toxicity Values.
BACKGROUND
There is a great concern on potential adverse effects of exposure to perfluorooctane sulfonate (PFOS) in sensitive subpopulations, such as pregnant women, fetuses, and neonates, due to its reported transplacental and lactational transfer and reproductive and developmental toxicities in animals and humans.
OBJECTIVES
This study aimed to develop a gestational and lactational physiologically based pharmacokinetic (PBPK) model in rats and humans for PFOS to aid risk assessment in sensitive human subpopulations.
METHODS
Based upon existing PBPK models for PFOS, the present model addressed a data gap of including a physiologically based description of basolateral and apical membrane transporter-mediated renal reabsorption and excretion in kidneys during gestation and lactation. The model was calibrated with published rat toxicokinetic and human biomonitoring data and was independently evaluated with separate data. Monte Carlo simulation was used to address the interindividual variability.
RESULTS
Model simulations were generally within 2-fold of observed PFOS concentrations in maternal/fetal/neonatal plasma and liver in rats and humans. Estimated fifth percentile human equivalent doses (HEDs) based on selected critical toxicity studies in rats following U.S. Environmental Protection Agency (EPA) guidelines ranged from 0.08 to . These values are lower than the HEDs estimated in U.S. EPA guidance () using an empirical toxicokinetic model in adults.
CONCLUSIONS
The results support the importance of renal reabsorption/excretion during pregnancy and lactation in PFOS dosimetry and suggest that the derivation of health-based toxicity values based on developmental toxicity studies should consider gestational/lactational dosimetry estimated from a life stage-appropriate PBPK model. This study provides a quantitative tool to aid risk reevaluation of PFOS, especially in sensitive human subpopulations, and it provides a basis for extrapolating to other per- and polyfluoroalkyl substances (PFAS). All model codes and detailed tutorials are provided in the Supplemental Materials to allow readers to reproduce our results and to use this model. https://doi.org/10.1289/EHP7671.
Topics: Alkanesulfonic Acids; Animals; Breast Feeding; Female; Fluorocarbons; Humans; Lactation; Pregnancy; Rats
PubMed: 33730865
DOI: 10.1289/EHP7671 -
Journal of Pharmacokinetics and... Jun 2021The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release...
The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone). Unfortunately, standard non-linear mixed effects population pharmacodynamic models such as turnover and precursor response models (with or without a cosinor component) are unable to quantify these complex secretion profiles over time. In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12 h post-dose on simulated dense concentration-time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the deconvolution-analysis informed approach reached a statistical power of more than 80% with a sample size of less than 200 subjects per cohort. Furthermore, the use of this deconvolution-analysis-informed modelling approach improved the description of the observations on an individual level and enabled the quantification of a drug effect to be used for subsequent clinical trial simulations.
Topics: Area Under Curve; Biological Variation, Individual; Biological Variation, Population; Biomarkers; Circadian Rhythm; Clinical Trials as Topic; Cohort Studies; Healthy Volunteers; Human Growth Hormone; Humans; Insulin; Luteinizing Hormone; Male; Models, Biological; Monte Carlo Method
PubMed: 33660229
DOI: 10.1007/s10928-021-09743-2 -
Drug Metabolism and Disposition: the... Jan 2021Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes...
Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes and nuclear factor erythroid 2-related factor 2 (NRF2) genes in human livers were examined via QuantiGene multiplex suspension array (226 samples) and quantitative polymerase chain reaction (qPCR) (247 samples) to profile the expression of nuclear receptors, cytochrome P450s, conjugation enzymes, transporters, bile acid metabolism, and NRF2-regulated genes. Sex differences were found in expression of about half of the genes, but in general the differences were not large. For example, females had higher transcript levels of catalase glutamate-cysteine ligase catalytic subunit () heme oxygenase 1 () Kelch-like ECH-associated protein 1 () superoxide dismutase 1, and thioredoxin reductase-1 compared with males via qPCR. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit () and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor () but higher expression of , Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of , small heterodimer partner, and bile salt export pump. An examination of 34 diseased and control human liver samples showed that compared with disease-free livers, fibrotic livers had higher NAD(P)H-quinone oxidoreductase 1 (), and ; hepatocellular carcinoma had higher transcript levels of and ; and steatotic livers had lower , , and expression. In summary, in drug-processing gene and NRF2 genes, sex differences were the major findings, and there were no apparent age differences, and race/ethnicity differences occurred for a few genes. These descriptive findings could add to our understanding of the sex-, age-, and race/ethnicity-dependent differences in drug-processing genes as well as NRF2 genes in normal and diseased human livers. SIGNIFICANCE STATEMENT: In human liver drug-processing and nuclear factor erythroid 2-related factor 2 genes, sex differences were the main finding. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit, and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor () but higher expression of heme oxygenase 1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of small heterodimer partner, and bile salt export pump.
Topics: Adult; Age Factors; Aged; Child; Cytochrome P-450 Enzyme System; Female; Gene Expression Profiling; Hepatobiliary Elimination; Humans; Liver; Liver Diseases; Male; Membrane Transport Proteins; NF-E2-Related Factor 2; Pharmaceutical Preparations; Pharmacogenomic Testing; Pharmacokinetics; Race Factors; Receptors, Cytoplasmic and Nuclear; Sex Factors
PubMed: 33162398
DOI: 10.1124/dmd.120.000181 -
Toxicological Sciences : An Official... Jan 2011Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human... (Review)
Review
Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment.
Topics: Administration, Oral; Animals; Carcinogens, Environmental; Chromium; Guidelines as Topic; Humans; Intestinal Neoplasms; Mice; Models, Theoretical; Research Design; Risk Assessment; United States; United States Environmental Protection Agency
PubMed: 20947717
DOI: 10.1093/toxsci/kfq320