Browsing by Author "Margolick, Joseph B"
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Item Open Access Common genetic variation and the control of HIV-1 in humans.(PLoS Genet, 2009-12) Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T; Urban, Thomas J; Zhang, Kunlin; Gumbs, Curtis E; Smith, Jason P; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M; Obel, Niels; Wolinsky, Steven M; Martinson, Jeremy J; Detels, Roger; Margolick, Joseph B; Jacobson, Lisa P; Descombes, Patrick; Antonarakis, Stylianos E; Beckmann, Jacques S; O'Brien, Stephen J; Letvin, Norman L; McMichael, Andrew J; Haynes, Barton F; Carrington, Mary; Feng, Sheng; Telenti, Amalio; Goldstein, David B; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.Item Open Access Comparison of interlaboratory variation in absolute T-cell counts by single-platform and optimized dual-platform methods.(Cytometry B Clin Cytom, 2010-05) Hultin, Lance E; Chow, Marianne; Jamieson, Beth D; O'Gorman, Maurice RG; Menendez, Frederick A; Borowski, Luann; Denny, Thomas N; Margolick, Joseph BBACKGROUND: Previous studies have reported that the adoption of a single-platform flow cytometry cell counting method resulted in lower interlaboratory variation in absolute T cell counts as compared to predicate dual-platform flow cytometry methods which incorporate independent automated lymphocyte counts (Schnizlein-Bick et al., Clin Diagn Lab Immunol 2000;7:336-343; Reimann et al., Clin Diagn Lab Immunol 2000;7:344-351). In the present study, we asked whether use of a single-platform method could reduce variation in absolute cell counts across the laboratories in the Multicenter AIDS Cohort Study (MACS) (n = 4), as suggested by the studies cited. METHODS: Identical study samples were shipped overnight to the MACS laboratories either by the National Institute of Allergy and Infectious Diseases, Division of AIDS Immunology Quality Assessment (NIAID- IQA) proficiency-testing program (n = 14), or by the Los Angeles site of the MACS (n = 10). For each sample, two tubes of blood were received; one was used for an automated complete blood count and differential, and the other for flow cytometry. The latter was performed using both our current dual-platform method (three-color CD45 gating and automated hematology) and the single-platform method (with TruCOUNT beads to generate the absolute counts). RESULTS: The median percent coefficients of variation (%CVs) for the dual-platform and single-platform methods were 6.6 and 9.9, respectively, for CD4 T cell counts, and 5.9 and 8.5, respectively, for CD8 T cell counts (n = 24). These differences were not statistically significant. The differences in absolute T-cell counts between the MACS sites and the median of all laboratories participating in the NIAID-IQA were smaller for the dual-platform than for single-platform absolute count method. CONCLUSION: In contrast to previous reports, we did not observe lower interlaboratory variation across the MACS sites for single-platform absolute lymphocyte subset counting relative to dual-platform methods. This result may be at least partly explained by the lower interlaboratory variation with the optimized dual-platform method in this study relative to the previous reports.Item Open Access Multiplex assay reliability and long-term intra-individual variation of serologic inflammatory biomarkers.(Cytokine, 2017-02) McKay, Heather S; Margolick, Joseph B; Martínez-Maza, Otoniel; Lopez, Joseph; Phair, John; Rappocciolo, Giovanna; Denny, Thomas N; Magpantay, Larry I; Jacobson, Lisa P; Bream, Jay HBACKGROUND: Circulating cytokines, chemokines, and soluble cytokine receptors can serve as biomarkers of inflammation and immune dysregulation. Good reliability of multiplex platforms, which allow for simultaneous, comprehensive biomarker assessment, is critical for their utility in epidemiologic studies. We examined the reliability of the Meso-Scale Discovery (MSD) platform to simultaneously quantitate 15 cytokines and chemokines and the Luminex platform (R&D Systems) to quantitate 5 soluble receptors and 2 chemokines and cytokines and evaluated long-term within-person correlation of these biomarkers. METHODS: The detectability and reliability of these assay systems were assessed using the same external controls across plates and archived sera from 250 HIV(-) men in the Multicenter AIDS Cohort Study. Using up to four visits per person from 1984 to 2009, age-adjusted intraclass correlation coefficients (ICC) of biomarkers with >80% detectability (CCL11, CXCL8, CXCL10, CCL2, CCL4, CCL13, CCL17, CXCL13, IL-10, IL-12p70, IL-6, TNF-α, BAFF, sCD14, sCD27, sgp130, sIL-2Rα, and sTNF-R2) were obtained using linear mixed models. RESULTS: Most biomarkers were detectable in 80% of control samples; IFN-γ, GM-CSF, and IL-2 were undetectable in >20% of samples. Among the HIV-uninfected men, most biomarkers showed fair to strong within-person correlation (ICC>0.40) up to 15years. The ICC for CXCL8 was good in the short term but decreased with increasing time between visits, becoming lower (ICC<0.40) after 8years. CONCLUSIONS: These multiplexed assays showed acceptable reliability for use in epidemiologic research, despite some technical variability and limitations in cytokine quantitation. Most biomarkers displayed moderate-to-excellent intra-individual variability over the long term, suggesting their utility in prospective studies investigating etiologic associations with diverse chronic conditions.