Biomedical subjects

Joel Pounds

Publications and source records attributed to Joel Pounds.

4 recordsLinked to original sources

PubMed2006

Testing for additivity at select mixture groups of interest based on statistical equivalence testing methods.

Several assumptions, defined and undefined, are used in the toxicity assessment of chemical mixtures. In scientific practice mixture components in the low-dose region, particularly subthreshold doses, are often assumed to behave additively (i.e., zero interaction) based on heuristic arguments. This assumption has important implications in the practice of risk assessment, but has not been experimentally tested. We have developed methodology to test for additivity in the sense of Berenbaum (Advances in Cancer Research, 1981), based on the statistical equivalence testing literature where the null hypothesis of interaction is rejected for the alternative hypothesis of additivity when data support the claim. The implication of this approach is that conclusions of additivity are made with a false positive rate controlled by the experimenter. The claim of additivity is based on prespecified additivity margins, which are chosen using expert biological judgment such that small deviations from additivity, which are not considered to be biologically important, are not statistically significant. This approach is in contrast to the usual hypothesis-testing framework that assumes additivity in the null hypothesis and rejects when there is significant evidence of interaction. In this scenario, failure to reject may be due to lack of statistical power making the claim of additivity problematic. The proposed method is illustrated in a mixture of five organophosphorus pesticides that were experimentally evaluated alone and at relevant mixing ratios. Motor activity was assessed in adult male rats following acute exposure. Four low-dose mixture groups were evaluated. Evidence of additivity is found in three of the four low-dose mixture groups. The proposed method tests for additivity of the whole mixture and does not take into account subset interactions (e.g., synergistic, antagonistic) that may have occurred and cancelled each other out.

Animals↗

PubMed2006

Whole-body lifetime occupational lead exposure and risk of Parkinson's disease.

BACKGROUND: Several epidemiologic studies have suggested an association between Parkinson's disease (PD) and exposure to heavy metals using subjective exposure measurements. OBJECTIVES: We investigated the association between objective chronic occupational lead exposure and the risk of PD. METHODS: We enrolled 121 PD patients and 414 age, sex, and race, frequency-matched controls in a case-control study. As an indicator of chronic Pb exposure, we measured concentrations of tibial and calcaneal bone Pb stores using 109Cadmium excited K-series X-ray fluorescence. As an indicator of recent exposure, we measured blood Pb concentration. We collected occupational data on participants from 18 years of age until the age at enrollment, and an industrial hygienist determined the duration and intensity of environmental Pb exposure. We employed physiologically based pharmacokinetic modeling to combine these data, and we estimated wholebody lifetime Pb exposures for each individual. Logistic regression analysis produced estimates of PD risk by quartile of lifetime Pb exposure. RESULTS: Risk of PD was elevated by > 2-fold [odds ratio = 2.27 (95% confidence interval, 1.13-4.55); p = 0.021] for individuals in the highest quartile for lifetime lead exposure relative to the lowest quartile, adjusting for age, sex, race, smoking history, and coffee and alcohol consumption. The associated risk of PD for the second and third quartiles were elevated but not statistically significant at the alpha = 0.05 level. CONCLUSIONS: These results provide an objective measure of chronic Pb exposure and confirm our earlier findings that occupational exposure to Pb is a risk factor for PD.

Age Distribution↗

PubMed2005

Overview of the HUPO Plasma Proteome Project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly-available database.

HUPO initiated the Plasma Proteome Project (PPP) in 2002. Its pilot phase has (1) evaluated advantages and limitations of many depletion, fractionation, and MS technology platforms; (2) compared PPP reference specimens of human serum and EDTA, heparin, and citrate-anti-coagulated plasma; and (3) created a publicly-available knowledge base (www.bioinformatics.med.umich.edu/hupo/ppp; www.ebi.ac.uk/pride). Thirty-five participating laboratories in 13 countries submitted datasets. Working groups addressed (a) specimen stability and protein concentrations; (b) protein identifications from 18 MS/MS datasets; (c) independent analyses from raw MS-MS spectra; (d) search engine performance, subproteome analyses, and biological insights; (e) antibody arrays; and (f) direct MS/SELDI analyses. MS-MS datasets had 15 710 different International Protein Index (IPI) protein IDs; our integration algorithm applied to multiple matches of peptide sequences yielded 9504 IPI proteins identified with one or more peptides and 3020 proteins identified with two or more peptides (the Core Dataset). These proteins have been characterized with Gene Ontology, InterPro, Novartis Atlas, OMIM, and immunoassay-based concentration determinations. The database permits examination of many other subsets, such as 1274 proteins identified with three or more peptides. Reverse protein to DNA matching identified proteins for 118 previously unidentified ORFs. We recommend use of plasma instead of serum, with EDTA (or citrate) for anticoagulation. To improve resolution, sensitivity and reproducibility of peptide identifications and protein matches, we recommend combinations of depletion, fractionation, and MS/MS technologies, with explicit criteria for evaluation of spectra, use of search algorithms, and integration of homologous protein matches. This Special Issue of PROTEOMICS presents papers integral to the collaborative analysis plus many reports of supplementary work on various aspects of the PPP workplan. These PPP results on complexity, dynamic range, incomplete sampling, false-positive matches, and integration of diverse datasets for plasma and serum proteins lay a foundation for development and validation of circulating protein biomarkers in health and disease.

Algorithms↗

PubMed2003

Methodologies to examine the importance of host factors in bioavailability of metals.

Bioavailability provides a link between intrinsic toxicity and the ability to produce that toxic effect in an organism. Biomonitoring tools are essential to assess the health of ecosystems and their component parts, including humans. While field and laboratory data are available, two critical issues to our understanding of bioavailability are often missing: 1) knowing the relationship between dose and tissue concentrations, and 2) species extrapolations. Understanding of high to low dose extrapolation is also critical. Methods to understand the importance of host factors in bioavailability of metals must assess gender, age, nutritional status, individual variability, temporal changes, and critical habitat effects. Methods to examine these variables include correlational, observational, experimental, epidemiological, and modeling studies, or a combination of these. Data gaps include developing more representative studies of human and animal populations, better analytical tools for rapid determination of metal content in the field, improved analytical characterization of metal bioavailability, and concurrent studies of different metals.

Animals↗