Robust classification of bacterial and viral infections via integrated host gene expression diagnostics

Science Translational Medicine

Volumn 8, Issue 346, 2016, Pages

  Sweeney, Timothy E ^a   Wong, Hector R ^b,c   Khatri, Purvesh ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CINCINNATI CHILDREN S HOSPITAL RESEARCH FOUNDATION   (United States)

^c UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; BACTERIAL INFECTION; COHORT ANALYSIS; DISEASE CLASSIFICATION; GENE EXPRESSION; HUMAN; MAJOR CLINICAL STUDY; PATIENT IDENTIFICATION; PRIORITY JOURNAL; SCORING SYSTEM; SENSITIVITY AND SPECIFICITY; SEPSIS; SEPSIS METASCORE; VALIDATION PROCESS; VIRUS INFECTION; ANIMAL; CLASSIFICATION; METABOLISM; THEORETICAL MODEL;

ANTIINFECTIVE AGENT;

ANIMALS; ANTI-BACTERIAL AGENTS; BACTERIAL INFECTIONS; GENE EXPRESSION; HUMANS; MODELS, THEORETICAL; VIRUS DISEASES;

EID: 84978062345     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aaf7165     Document Type: Article

References (67)

1. R. Ferrer, I. Martin-Loeches, G. Phillips, T. M. Osborn, S. Townsend, R. P. Dellinger, A. Artigas, C. Schorr, M. M. Levy, Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: Results from a guideline-based performance improvement program. Crit. Care Med. 42, 1749-1755 (2014).
2. S. Fridkin, J. Baggs, R. Fagan, S. Magill, L. A. Pollack, P. Malpiedi, R. Slayton, K. Khader, M. A. Rubin, M. Jones, M. H. Samore, G. Dumyati, E. Dodds-Ashley, J. Meek, K. Yousey-Hindes, J. Jernigan, N. Shehab, R. Herrera, C. L. McDonald, A. Schneider, A. Srinivasan; Centers for Disease Control and Prevention (CDC), Vital signs: Improving antibiotic use among hospitalized patients. Morb. Mortal. Wkly. Rep. 63, 194-200 (2014).
3. C. G. Grijalva, J. P. Nuorti, M. R. Griffin, Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA 302, 758-766 (2009).
4. J. Andrews, in 9th International Conference on Typhoid and Invasive NTS Disease (Bali, Indonesia, 2015).
5. National Strategy and Action Plan for Combating Antibiotic Resistant Bacteria (Nova Publishers, New York, 2015).
6. O. Liesenfeld, L. Lehman, K.-P. Hunfeld, G. Kost, Molecular diagnosis of sepsis: New aspects and recent developments. Eur. J. Microbiol. Immunol. 4, 1-25 (2014).
7. T. E. Sweeney, A. Shidham, H. R. Wong, P. Khatri, A comprehensive time-course-based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set. Sci. Transl. Med. 7, 287ra271 (2015).
8. T. E. Sweeney, P. Khatri, Comprehensive validation of the FAIM3:PLAC8 ratio in time-matched public gene expression aata. Am. J. Respir. Crit. Care Med. 192, 1260-1261 (2015).
9. L. McHugh, T. A. Seldon, R. A. Brandon, J. T. Kirk, A. Rapisarda, A. J. Sutherland, J. J. Presneill, D. J. Venter, J. Lipman, M. R. Thomas, P. M. C. Klein Klouwenberg, L. van Vught, B. Scicluna, M. Bonten, O. L. Cremer, M. J. Schultz, T. van der Poll, T. D. Yager, R. B. Brandon, A molecular host response assay to discriminate between sepsis and infection-negative systemic inflammation in critically ill patients: Discovery and validation in independent cohorts. PLOS Med. 12, e1001916 (2015).
10. B. P. Scicluna, P. M. C. Klein Klouwenberg, L. A. van Vught, M. A. Wiewel, D. S. Y. Ong, A. H. Zwinderman, M. Franitza, M. R. Toliat, P. Nürnberg, A. J. Hoogendijk, J. Horn, O. L. Cremer, M. J. Schultz, M. J. Bonten, T. van der Poll, A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. Am. J. Respir. Crit. Care Med. 192, 826-835 (2015).
11. X. Hu, J. Yu, S. D. Crosby, G. A. Storch, Gene expression profiles in febrile children with defined viral and bacterial infection. Proc. Natl. Acad. Sci. U.S.A. 110, 12792-12797 (2013).
12. A. K. Zaas, T. Burke, M. Chen, M. McClain, B. Nicholson, T. Veldman, E. L. Tsalik, V. Fowler, E. P. Rivers, R. Otero, S. F. Kingsmore, D. Voora, J. Lucas, A. O. Hero, L. Carin, C. W. Woods, G. S. Ginsburg, A host-based RT-PCR gene expression signature to identify acute respiratory viral infection. Sci. Transl. Med. 5, 203ra126 (2013).
13. N. M. Suarez, E. Bunsow, A. R. Falsey, E. E. Walsh, A. Mejias, O. Ramilo, Superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults. J. Infect. Dis. 212, 213-222 (2015).
14. E. L. Tsalik, R. Henao, M. Nichols, T. Burke, E. R. Ko, M. T. McClain, L. L. Hudson, A. Mazur, D. H. Freeman, T. Veldman, R. J. Langley, E. B. Quackenbush, S. W. Glickman, C. B. Cairns, A. K. Jaehne, E. P. Rivers, R. M. Otero, A. K. Zaas, S. F. Kingsmore, J. Lucas, V. G. Fowler Jr., L. Carin, G. S. Ginsburg, C. W. Woods, Host gene expression classifiers diagnose acute respiratory illness etiology. Sci. Transl. Med. 8, 322ra311 (2016).
15. M. Andres-Terre, H. M. McGuire, Y. Pouliot, E. Bongen, T. E. Sweeney, C. M. Tato, P. Khatri, Integrated, multi-cohort analysis identifies conserved transcriptional signatures across multiple respiratory viruses. Immunity 43, 1199-1211 (2015).
16. P. Khatri, S. Roedder, N. Kimura, K. De Vusser, A. A. Morgan, Y. Gong, M. P. Fischbein, R. C. Robbins, M. Naesens, A. J. Butte, M. M. Sarwal, A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. J. Exp. Med. 210, 2205-2221 (2013).
17. T. E. Sweeney, L. Braviak, C. M. Tato, P. Khatri, Genome-wide expression for diagnosis of pulmonary tuberculosis: A multicohort analysis. Lancet Respir. Med. 4, 213-224 (2016).
18. T. P. Shanley, N. Cvijanovich, R. Lin, G. L. Allen, N. J. Thomas, A. Doctor, M. Kalyanaraman, N. M. Tofil, S. Penfil, M. Monaco, K. Odoms, M. Barnes, B. Sakthivel, B. J. Aronow, H. R. Wong, Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock. Mol. Med. 13, 495-508 (2007).
19. H. R. Wong, T. P. Shanley, B. Sakthivel, N. Cvijanovich, R. Lin, G. L. Allen, N. J. Thomas, A. Doctor, M. Kalyanaraman, N. M. Tofil, S. Penfil, M. Monaco, M. A. Tagavilla, K. Odoms, K. Dunsmore, M. Barnes, B. J. Aronow; Genomics of Pediatric SIRS.Septic Shock Investigators, Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiol. Genomics 30, 146-155 (2007).
20. N. Cvijanovich, T. P. Shanley, R. Lin, G. L. Allen, N. J. Thomas, P. Checchia, N. Anas, R. J. Freishtat, M. Monaco, K. Odoms, B. Sakthivel, H. R. Wong; Genomics Pediatric SIRS/Septic Shock Investigators, Validating the genomic signature of pediatric septic shock. Physiol. Genomics 34, 127-134 (2008).
21. H. R. Wong, N. Cvijanovich, G. L. Allen, R. Lin, N. Anas, K. Meyer, R. J. Freishtat, M. Monaco, K. Odoms, B. Sakthivel, T. P. Shanley Genomics of Pediatic SIRS/Septc Shock Investigators, Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit. Care Med. 37, 1558-1566 (2009).
22. H. R. Wong, N. Z. Cvijanovich, M. Hall, G. L. Allen, N. J. Thomas, R. J. Freishtat, N. Anas, K. Meyer, P. A. Checchia, R. Lin, M. T. Bigham, A. Sen, J. Nowak, M. Quasney, J. W. Henricksen, A. Chopra, S. Banschbach, E. Beckman, K. Harmon, P. Lahni, T. P. Shanley, Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit. Care 16, R213 (2012).
23. O. Ramilo, W. Allman, W. Chung, A. Mejias, M. Ardura, C. Glaser, K. M. Wittkowski, B. Piqueras, J. Banchereau, A. K. Palucka, D. Chaussabel, Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109, 2066-2077 (2007).
24. G. Parnell, A. McLean, D. Booth, S. Huang, M. Nalos, B. Tang, Aberrant cell cycle and apoptotic changes characterise severe influenza A infection - a meta-analysis of genomic signatures in circulating leukocytes. PLOS One 6, e17186 (2011).
25. G. P. Parnell, A. S. McLean, D. R. Booth, N. J. Armstrong, M. Nalos, S. J. Huang, J. Manak, W. Tang, O.-Y. Tam, S. Chan, B. M. Tang, A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia. Crit. Care 16, R157 (2012).
26. J. A. Herberg, M. Kaforou, S. Gormley, E. R. Sumner, S. Patel, K. D. J. Jones, S. Paulus, C. Fink, F. Martinon-Torres, G. Montana, V. J. Wright, M. Levin, Transcriptomic profiling in childhood H1N1/09 influenza reveals reduced expression of protein synthesis genes. J. Infect. Dis. 208, 1664-1668 (2013).
27. S. J. Popper, V. E. Watson, C. Shimizu, J. T. Kanegaye, J. C. Burns, D. A. Relman, Gene transcript abundance profiles distinguish Kawasaki disease from adenovirus infection. J. Infect. Dis. 200, 657-666 (2009).
28. C. L. Smith, P. Dickinson, T. Forster, M. Craigon, A. Ross, M. R. Khondoker, R. France, A. Ivens, D. J. Lynn, J. Orme, A. Jackson, P. Lacaze, K. L. Flanagan, B. J. Stenson, P. Ghazal, Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nat. Commun. 5, 4649(2014).
29. R. Almansa, L. Socias, M. Sanchez-Garcia, I. Martín-Loeches, M. del Olmo, D. Andaluz-Ojeda, F. Bobillo, L. Rico, A. Herrero, V. Roig, C. A. San-Jose, S. Rosich, J. Barbado, C. Disdier, R. O. de Lejarazu, M. C. Gallegos, V. Fernandez, J. F. Bermejo-Martin, Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes. BMC Res. Notes 5, 401 (2012).
30. M. N. Lee, C. Ye, A.-C. Villani, T. Raj, W. Li, T. M. Eisenhaure, S. H. Imboywa, P. I. Chipendo, F. A. Ran, K. Slowikowski, L. D. Ward, K. Raddassi, C. McCabe, M. H. Lee, I. Y. Frohlich, D. A. Hafler, M. Kellis, S. Raychaudhuri, F. Zhang, B. E. Stranger, C. O. Benoist, P. L. De Jager, A. Regev, N. Hacohen, Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014).
31. W. E. Johnson, C. Li, A. Rabinovic, Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118-127 (2007).
32. Y. Zhai, L. M. Franco, R. L. Atmar, J. M. Quarles, N. Arden, K. L. Bucasas, J. M. Wells, D. Niño, X. Wang, G. E. Zapata, C. A. Shaw, J. W. Belmont, R. B. Couch, Host transcriptional response to influenza and other acute respiratory viral infections - a prospective cohort study. PLOS Pathog. 11, e1004869 (2015).
33. + monocyte population that stimulates plasmablast differentiation. Cell Host Microbe 16, 115-127 (2014).
34. A. Mejias, B. Dimo, N. M. Suarez, C. Garcia, M. C. Suarez-Arrabal, T. Jartti, D. Blankenship, A. Jordan-Villegas, M. I. Ardura, Z. Xu, J. Banchereau, D. Chaussabel, O. Ramilo, Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLOS Med. 10, e1001549 (2013).
35. J.-E. Berdal, T. E. Mollnes, T. Wæhre, O. K. Olstad, B. Halvorsen, T. Ueland, J. H. Laake, M. T. Furuseth, A. Maagaard, H. Kjekshus, P. Aukrust, C. M. Jonassen, Excessive innate immune response and mutant D222G/N in severe A (H1N1) pandemic influenza. J. Infect. 63, 308-316 (2011).
36. J. F. Bermejo-Martin, I. Martin-Loeches, J. Rello, A. Antón, R. Almansa, L. Xu, G. Lopez-Campos, T. Pumarola, L. Ran, P. Ramirez, D. Banner, D. C. Ng, L. Socias, A. Loza, D. Andaluz, E. Maravi, M. J. Gómez-Sánchez, M. Gordón, M. C. Gallegos, V. Fernandez, S. Aldunate, C. León, P. Merino, J. Blanco, F. Martin-Sanchez, L. Rico, D. Varillas, V. Iglesias, M. Á. Marcos, F. Gandía, F. Bobillo, B. Nogueira, S. Rojo, S. Resino, C. Castro, R. Ortiz de Lejarazu, D. Kelvin, Host adaptive immunity deficiency in severe pandemic influenza. Crit. Care 14, R167 (2010).
37. A. K. Zaas, M. Chen, J. Varkey, T. Veldman, A. O. Hero III, J. Lucas, Y. Huang, R. Turner, A. Gilbert, R. Lambkin-Williams, N. C. Øien, B. Nicholson, S. Kingsmore, L. Carin, C. W. Woods, G. S. Ginsburg, Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6, 207-217 (2009).
38. C. A. M. van de Weg, H.-J. van den Ham, M. A. Bijl, F. Anfasa, F. Zaaraoui-Boutahar, B. E. Dewi, L. Nainggolan, W. F. J. van IJcken, A. D. M. E. Osterhaus, B. E. Martina, E. C. M. van Gorp, A. C. Andeweg, Time since onset of disease and individual clinical markers associate with transcriptional changes in uncomplicated dengue. PLOS Negl. Trop. Dis. 9, e0003522 (2015).
39. L. Conejero, K. Potempa, C. M. Graham, N. Spink, S. Blankley, F. J. Salguero, R. Pankla-Sranujit, P. Khaenam, J. F. Banchereau, V. Pascual, D. Chaussabel, G. Lertmemongkolchai, A. O'Garra, G. J. Bancroft, The blood transcriptome of experimental melioidosis reflects disease severity and shows considerable similarity with the human disease. J. Immunol. 195, 3248-3261 (2015).
40. M.-A. Cazalis, A. Lepape, F. Venet, F. Frager, B. Mougin, H. Vallin, M. Paye, A. Pachot, G. Monneret, Early and dynamic changes in gene expression in septic shock patients: A genome-wide approach. Intensive Care Med. Exp. 2, 20 (2014).
41. M. Lill, S. Kõks, U. Soomets, L. C. Schalkwyk, C. Fernandes, I. Lutsar, P. Taba, Peripheral blood RNA gene expression profiling in patients with bacterial meningitis. Front. Neurosci. 7, 33 (2013).
42. S. H. Ahn, E. L. Tsalik, D. D. Cyr, Y. Zhang, J. C. van Velkinburgh, R. J. Langley, S. W. Glickman, C. B. Cairns, A. K. Zaas, E. P. Rivers, R. M. Otero, T. Veldman, S. F. Kingsmore, J. Lucas, C. W. Woods, G. S. Ginsburg, V. G. Fowler Jr., Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans. PLOS One 8, e48979 (2013).
43. F. Thuny, J. Textoris, A. B. Amara, A. E. Filali, C. Capo, G. Habib, D. Raoult, J.-L. Mege, The gene expression analysis of blood reveals S100A11 and AQP9 as potential biomarkers of infective endocarditis. PLOS One 7, e31490 (2012).
44. A. Sutherland, M. Thomas, R. A. Brandon, R. B. Brandon, J. Lipman, B. Tang, A. McLean, R. Pascoe, G. Price, T. Nguyen, G. Stone, D. Venter, Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis. Crit. Care 15, R149 (2011).
45. M. P. R. Berry, C. M. Graham, F. W. McNab, Z. Xu, S. A. A. Bloch, T. Oni, K. A. Wilkinson, R. Banchereau, J. Skinner, R. J. Wilkinson, C. Quinn, D. Blankenship, R. Dhawan, J. J. Cush, A. Mejias, O. Ramilo, O. M. Kon, V. Pascual, J. Banchereau, D. Chaussabel, A. O'Garra, An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466, 973-977 (2010).
46. R. Pankla, S. Buddhisa, M. Berry, D. M. Blankenship, G. J. Bancroft, J. Banchereau, G. Lertmemongkolchai, D. Chaussabel, Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis. Genome Biol. 10, R127 (2009).
47. A. D. Irwin, F. Marriage, L. A. Mankhambo, G. Jeffers, R. Kolamunnage-Dona, M. Guiver, B. Denis, E. M. Molyneux, M. E. Molyneux, P. J. Day, E. D. Carrol, Novel biomarker combination improves the diagnosis of serious bacterial infections in Malawian children. BMC Med. Genomics 5, 13 (2012).
48. C. I. Bloom, C. M. Graham, M. P. R. Berry, F. Rozakeas, P. S. Redford, Y. Wang, Z. Xu, K. A. Wilkinson, R. J. Wilkinson, Y. Kendrick, G. Devouassoux, T. Ferry, M. Miyara, D. Bouvry, D. Valeyre, V. Dominique, G. Gorochov, D. Blankenship, M. Saadatian, P. Vanhems, H. Beynon, R. Vancheeswaran, M. Wickremasinghe, D. Chaussabel, J. Banchereau, V. Pascual, L.-p. Ho, M. Lipman, A. O'Garra, Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. PLOS One 8, e70630 (2013).
49. M. Emonts, "Polymorphisms in Immune Response Genes in Infectious Diseases and Autoimmune Diseases," thesis, Erasmus University Rotterdam, Rotterdam, Netherlands (2008).
50. M. I. Ardura, R. Banchereau, A. Mejias, T. Di Pucchio, C. Glaser, F. Allantaz, V. Pascual, J. Banchereau, D. Chaussabel, O. Ramilo, Enhanced monocyte response and decreased central memory T cells in children with invasive Staphylococcus aureus infections. PLOS One 4, e5446 (2009).
51. K. Liu, L. Chen, R. Kaur, M. Pichichero, Transcriptome signature in young children with acute otitis media due to Streptococcus pneumoniae. Microbes Infect. 14, 600-609 (2012).
52. I. Ioannidis, B. McNally, M. Willette, M. E. Peeples, D. Chaussabel, J. E. Durbin, O. Ramilo, A. Mejias, E. Flaño, Plasticity and virus specificity of the airway epithelial cell immune response during respiratory virus infection. J. Virol. 86, 5422-5436 (2012).
53. S. J. Popper, A. Gordon, M. Liu, A. Balmaseda, E. Harris, D. A. Relman, Temporal dynamics of the transcriptional response to dengue virus infection in Nicaraguan children. PLOS Negl. Trop. Dis. 6, e1966 (2012).
54. H. K. Brand, I. M. Ahout, D. de Ridder, A. van Diepen, Y. Li, M. Zaalberg, A. Andeweg, N. Roeleveld, R. de Groot, A. Warris, P. W. M. Hermans, G. Ferwerda, F. J. Staal, Olfactomedin 4 serves as a marker for disease severity in pediatric Respiratory Syncytial Virus (RSV) infection. PLOS One 10, e0131927 (2015).
55. C. Wacker, A. Prkno, F. M. Brunkhorst, P. Schlattmann, Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis. Lancet Infect. Dis. 13, 426-435 (2013).
56. M. M. Kulkarni, Digital multiplexed gene expression analysis using the NanoString nCounter system. Curr. Protoc. Mol. Biol. Chapter 25, Unit25B.10 (2011).
57. E. L. Tsalik, Y. Li, L. L. Hudson, V. H. Chu, T. Himmel, A. T. Limkakeng, J. N. Katz, S. W. Glickman, M. T. McClain, K. E. Welty-Wolf, V. G. Fowler, G. S. Ginsburg, C. W. Woods, S. D. Reed, Potential cost-effectiveness of early identification of hospital-acquired infection in critically Ill patients. Ann. Am. Thorac. Soc. 13, 401-413 (2016).
58. D. N. Gilbert, Procalcitonin as a biomarker in respiratory tract infection. Clin. Infect. Dis. 52 (suppl. 4), S346-S350 (2011).
59. K. Oved, A. Cohen, O. Boico, R. Navon, T. Friedman, L. Etshtein, O. Kriger, E. Bamberger, Y. Fonar, R. Yacobov, R. Wolchinsky, G. Denkberg, Y. Dotan, A. Hochberg, Y. Reiter, M. Grupper, I. Srugo, P. Feigin, M. Gorfine, I. Chistyakov, R. Dagan, A. Klein, I. Potasman, E. Eden, A novel host-proteome signature for distinguishing between acute bacterial and viral infections. PLOS One 10, e0120012 (2015).
60. C. Valim, R. Ahmad, M. Lanaspa, Y. Tan, S. Acácio, M. A. Gillette, K. D. Almendinger, D. A. Milner Jr., L. Madrid, K. Pellé, J. Harezlak, J. Silterra, P. L. Alonso, S. A. Carr, J. P. Mesirov, D. F. Wirth, R. C. Wiegand, Q. Bassat, Responses to bacteria, virus, and malaria distinguish the etiology of pediatric clinical pneumonia. Am. J. Respir. Crit. Care Med. 193, 448-459 (2016).
61. T. Tolfvenstam, A. Lindblom, M. J. Schreiber, L. Ling, A. Chow, E. E. Ooi, M. L. Hibberd, Characterization of early host responses in adults with dengue disease. BMC Infect. Dis. 11, 209 (2011).
62. T. Vanden Berghe, A. Linkermann, S. Jouan-Lanhouet, H. Walczak, P. Vandenabeele, Regulated necrosis: The expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Biol. 15, 135-147 (2014).
63. H. Ashida, M. Kim, M. Schmidt-Supprian, A. Ma, M. Ogawa, C. Sasakawa, A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-κB-mediated inflammatory response. Nat. Cell Biol. 12, 66-73 (2010).
64. M. Zhu, O. Granillo, R. Wen, K. Yang, X. Dai, D. Wang, W. Zhang, Negative regulation of lymphocyte activation by the adaptor protein LAX. J. Immunol. 174, 5612-5619 (2005).
65. E. A. Federzoni, P. J. M. Valk, B. E. Torbett, T. Haferlach, B. Löwenberg, M. F. Fey, M. P. Tschan, PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells. Blood 119, 4963-4970 (2012).
66. Y. Benjamini, Y. Hochberg, Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B 57, 289-300 (1995).
67. A. D. M. Kester, F. Buntinx, Meta-analysis of ROC curves. Med. Decis. Making 20, 430-439 (2000).